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Sample records for adenosine triphosphate-based chemotherapy

  1. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided versus empirical chemotherapy in unresectable non-small cell lung cancer.

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    Moon, Yong Wha; Sohn, Joo Hyuk; Kim, Yong Tai; Chang, Hyun; Jeong, Jae Heon; Lee, Young Joo; Chang, Joon; Kim, Se Kyu; Jung, Minkyu; Hong, Soojung; Choi, Sung Ho; Kim, Joo-Hang

    2009-10-01

    We retrospectively compared adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided and empirical chemotherapies for unresectable non-small cell lung cancer (NSCLC) in this case-control study. Unresectable NSCLC patients receiving ATP-CRA-guided platinum-based doublets as first-line therapy were enrolled as cases (n=27; 14 platinum-sensitive and 13 platinum-resistant patients). Performance status, stage, and chemotherapeutic regimen-matched patients receiving empirical chemotherapy were selected from the retrospective database as controls (n=93) in a case to control ratio of approximately 1:3. Response rate and survival (progression-free; overall) in both groups were not significantly different. However, the platinum-sensitive subgroup by ATP-CRA showed a higher response rate than the empirical group (71 versus 38%; p=0.023) with a trend toward longer progression-free survival (8.7 versus 4.8 months for platinum-sensitive versus empirical; p=0.223) and overall survival (not reached versus 12.6 months for platinum-sensitive versus empirical for p=0.134). ATP-CRA may be helpful in selecting platinum-responsive patients in unresectable NSCLC. We consider that nonplatinum doublets in platinum-resistant patients by ATP-CRA may be a more adapted approach than platinum-based doublets in future clinical trials.

  2. A feasibility study of adenosine triphosphate-based chemotherapy response assay (ATP-CRA) as a chemosensitivity test for lung cancer.

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    Kang, Shin Myung; Park, Moo Suk; Chang, Joon; Kim, Se Kyu; Kim, Haeryoung; Shin, Dong-Hwan; Chung, Kyung Young; Kim, Dae Joon; Sohn, Joo Hyuk; Choi, Sung Ho; Kim, Jeongmi; Yoon, Eun Jin; Kim, Joo-Hang

    2005-08-01

    A chemosensitivity test can reflect the differences in responses of individual cancer patients to chemotherapeutic agents. The adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is an accurate method, which does not require a large amount of tissue specimen. So far, no studies have evaluated the utility of the ATP-CRA in Korea. Therefore, we investigated the clinical usefulness of the ATP-CRA in 53 patients with lung cancer. Tumor tissues were obtained from bronchoscopic biopsies or surgical resections. The validity of ATP-CRA was assessed focusing on the success rate, experimental error level (intraassay mean coefficient of variation [CV]) and reproducibility. The overall success rate of ATP-CRA was 90.6% (48/53). Normal cells were effectively eliminated from the tumor tissues with the use of ficoll gradient centrifugation and immunomagnetic separation, which was confirmed using loss of heterozygosity analysis of the 3p deletion. The mean CV of ATP assays was 10.5+/-4.6%. The reproducibility of ATP assays was 94+/-3.8%. The results of the ATP assays were reported to physicians within 7 days of specimen collection. More than 6 anticancer drugs were tested on the tumor specimens obtained from bronchoscopic biopsies. The ATP-CRA is a stable, accurate and potentially practical chemosensitivity test in patients with lung cancer.

  3. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided platinum-based 2-drug chemotherapy for unresectable nonsmall-cell lung cancer.

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    Moon, Yong Wha; Choi, Sung Ho; Kim, Yong Tai; Sohn, Joo Hyuk; Chang, Joon; Kim, Se Kyu; Park, Moo Suk; Chung, Kyung Young; Lee, Hyoun Ju; Kim, Joo-Hang

    2007-05-01

    The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC). The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC. Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P=.036), longer progression-free survival (P=.060), and longer overall survival (P=.025). Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups. Copyright (c) 2007 American Cancer Society

  4. Visual and Plasmon Resonance Absorption Sensor for Adenosine Triphosphate Based on the High Affinity between Phosphate and Zr(IV).

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    Qi, Wenjing; Liu, Zhongyuan; Zhang, Wei; Halawa, Mohamed Ibrahim; Xu, Guobao

    2016-10-12

    Zr(IV) can form phosphate and Zr(IV) (-PO₃ 2- -Zr 4+ -) complex owing to the high affinity between Zr(IV) with phosphate. Zr(IV) can induce the aggregation of gold nanoparticles (AuNPs), while adenosine triphosphate(ATP) can prevent Zr(IV)-induced aggregation of AuNPs. Herein, a visual and plasmon resonance absorption (PRA)sensor for ATP have been developed using AuNPs based on the high affinity between Zr(IV)with ATP. AuNPs get aggregated in the presence of certain concentrations of Zr(IV). After the addition of ATP, ATP reacts with Zr(IV) and prevents AuNPs from aggregation, enabling the detection of ATP. Because of the fast interaction of ATP with Zr(IV), ATP can be detected with a detection limit of 0.5 μM within 2 min by the naked eye. Moreover, ATP can be detected by the PRA technique with higher sensitivity. The A 520nm / A 650nm values in PRA spectra increase linearly with the concentrations of ATP from 0.1 μM to 15 μM (r = 0.9945) with a detection limit of 28 nM. The proposed visual and PRA sensor exhibit good selectivity against adenosine, adenosine monophosphate, guanosine triphosphate, cytidine triphosphate and uridine triphosphate. The recoveries for the analysis of ATP in synthetic samples range from 95.3% to 102.0%. Therefore, the proposed novel sensor for ATP is promising for real-time or on-site detection of ATP.

  5. Visual and Plasmon Resonance Absorption Sensor for Adenosine Triphosphate Based on the High Affinity between Phosphate and Zr(IV

    Directory of Open Access Journals (Sweden)

    Wenjing Qi

    2016-10-01

    Full Text Available Zr(IV can form phosphate and Zr(IV (–PO32−–Zr4+– complex owing to the high affinity between Zr(IV with phosphate. Zr(IV can induce the aggregation of gold nanoparticles (AuNPs, while adenosine triphosphate(ATP can prevent Zr(IV-induced aggregation of AuNPs. Herein, a visual and plasmon resonance absorption (PRAsensor for ATP have been developed using AuNPs based on the high affinity between Zr(IVwith ATP. AuNPs get aggregated in the presence of certain concentrations of Zr(IV. After the addition of ATP, ATP reacts with Zr(IV and prevents AuNPs from aggregation, enabling the detection of ATP. Because of the fast interaction of ATP with Zr(IV, ATP can be detected with a detection limit of 0.5 μM within 2 min by the naked eye. Moreover, ATP can be detected by the PRA technique with higher sensitivity. The A520nm/A650nm values in PRA spectra increase linearly with the concentrations of ATP from 0.1 μM to 15 μM (r = 0.9945 with a detection limit of 28 nM. The proposed visual and PRA sensor exhibit good selectivity against adenosine, adenosine monophosphate, guanosine triphosphate, cytidine triphosphate and uridine triphosphate. The recoveries for the analysis of ATP in synthetic samples range from 95.3% to 102.0%. Therefore, the proposed novel sensor for ATP is promising for real-time or on-site detection of ATP.

  6. Visual and Plasmon Resonance Absorption Sensor for Adenosine Triphosphate Based on the High Affinity between Phosphate and Zr(IV)

    OpenAIRE

    Qi, Wenjing; Liu, Zhongyuan; Zhang, Wei; Halawa, Mohamed Ibrahim; Xu, Guobao

    2016-01-01

    Zr(IV) can form phosphate and Zr(IV) (?PO3 2??Zr4+?) complex owing to the high affinity between Zr(IV) with phosphate. Zr(IV) can induce the aggregation of gold nanoparticles (AuNPs), while adenosine triphosphate(ATP) can prevent Zr(IV)-induced aggregation of AuNPs. Herein, a visual and plasmon resonance absorption (PRA)sensor for ATP have been developed using AuNPs based on the high affinity between Zr(IV)with ATP. AuNPs get aggregated in the presence of certain concentrations of Zr(IV). Aft...

  7. Adenosine metabolism in Toxoplasma gondii: potential targets for chemotherapy.

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    el Kouni, Mahmoud H

    2007-01-01

    Toxoplasma gondii is an intracellular parasitic protozoan that infects approximately a billion people worldwide. Infection with T. gondii represents a major health problem for immunocompromised individuals, such as AIDS patients, organ transplant recipients, and the unborn children of infected mothers. Currently available drugs usually do not eradicate infection and as many as 50% of the patients do not respond to this therapy. Furthermore, they are ineffective against T. gondii tissue cysts. In addition, prolonged exposure to these drugs induces serious host toxicity forcing the discontinuation of the therapy. Finally, there is no effective vaccine currently available for the treatment of toxoplasmosis. Therefore, it is necessary to develop new and effective drugs for the treatment and management of toxoplasmosis. The rational design of a drug depends on the exploitation of fundamental biochemical or physiological differences between pathogens and their host. Some of the most striking differences between T. gondii and their mammalian host are found in purine metabolism. T. gondii, like most parasites studied, lack the ability to synthesize purines do novo and depend on the salvage of purines from their host to satisfy their requirements of purines. In this respect, the salvage of adenosine is the major source of purines in T. gondii. Therefore, interference with adenosine uptake and metabolism in T. gondii can be selectively detrimental to the parasite. The host cells, on the other hand, can still obtain their purine requirements by their de novo pathways. This review will focus on the broad aspects of the adenosine transport and the enzyme adenosine kinase (EC 2.7.1.20) which are the two primary routes for adenosine utilization in T. gondii, in an attempt to illustrate their potentials as targets for chemotherapy against this parasite.

  8. [A prospective study of adenosine triphosphate-tumor chemosensitivity assay directed chemotherapy in patients with recurrent ovarian cancer].

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    Gao, Yu-tao; Wu, Ling-ying; Zhang, Wei; Zhao, Dan; Li, Ning; Tian, Hai-mei; Wang, Xiao-bing; Li, Mo; Sun, Yang-chun; Li, Nan; Li, Xiao-guang

    2013-05-01

    To investigate the efficacy of adenosine triphosphate (ATP)-tumor chemosensitivity assay (TCA) directed chemotherapy in patients with recurrent epithelial ovarian cancer. From August 2010 to June 2012, recurrent epithelial ovarian cancer patients were prospectively enrollmented in Cancer Hospital, Peking Union Medical College,Chinese Academy of Medical Sciences.The entry criteria are as follows: (1) Histologically proven to be epithelial ovarian cancer. (2) Patients of recurrent ovarian cancer with bidimensionally measurable tumor, or ascitic or pleural fluid for testing. (3) Karnofsky performance status > 60. (4) A life expectancy of at least more than 6 months.According to patients desires, they were assigned into two groups: assay-directed therapy group and physician's-choice therapy group, patients' clinical and pathological characteristics, response rate to chemotherapy and progression-free survival (PFS) were compared between two groups. A total of 113 patients with recurrent epithelial ovarian cancer were prospectively enrollmented to assay-directed chemotherapy (n = 56) or physician's-choice chemotherapy (n = 57).There was no difference in median age,types of recurrence, surgical-pathological stage, pathological type, tumor grade, times of recurrence, residual disease at secondary cytoreductive surgery between assay-directed group and physician's-choice group. The overall response rate (ORR) and median PFS in the ATP-TCA group was 66% (37/56) and 7 months, while the ORR in the control group was 46% (26/57, P = 0.037), the median PFS was 4 months (P = 0.040). For platinum-resistant patients, the ORR between ATP-TCA directed chemotherapy 59% (16/27) and control group 25% (7/28) were significantly different (P = 0.010), and the median PFS between two groups were also significantly different (5 months and 2 months, respectively, P = 0.003). ATP-TCA directed chemotherapy could improve ORR and PFS in patients with recurrent epithelial ovarian cancer, especially

  9. Chemotherapy

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    ... nurse can help you balance the risks of chemotherapy against the potential benefits. It is important to note that the information provided here is basic and does not take the place of professional advice. If you have any questions ... Publication Quimioterapia (Chemotherapy) Una publicación de ...

  10. Target recycling amplification for label-free and sensitive colorimetric detection of adenosine triphosphate based on un-modified aptamers and DNAzymes.

    Science.gov (United States)

    Gong, Xue; Li, Jinfu; Zhou, Wenjiao; Xiang, Yun; Yuan, Ruo; Chai, Yaqin

    2014-05-30

    Based on target recycling amplification, the development of a new label-free, simple and sensitive colorimetric detection method for ATP by using un-modified aptamers and DNAzymes is described. The association of the model target molecules (ATP) with the corresponding aptamers of the dsDNA probes leads to the release of the G-quadruplex sequences. The ATP-bound aptamers can be further degraded by Exonuclease III to release ATP, which can again bind the aptamers of the dsDNA probes to initiate the target recycling amplification process. Due to this target recycling amplification, the amount of the released G-quadruplex sequences is significantly enhanced. Subsequently, these G-quadruplex sequences bind hemin to form numerous peroxidase mimicking DNAzymes, which cause substantially intensified color change of the probe solution for highly sensitive colorimetric detection of ATP down to the sub-nanomolar (0.33nM) level. Our method is highly selective toward ATP against other control molecules and can be performed in one single homogeneous solution, which makes our sensing approach hold great potential for sensitive colorimetric detection of other small molecules and proteins. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Adenosine and preeclampsia.

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    Salsoso, Rocío; Farías, Marcelo; Gutiérrez, Jaime; Pardo, Fabián; Chiarello, Delia I; Toledo, Fernando; Leiva, Andrea; Mate, Alfonso; Vázquez, Carmen M; Sobrevia, Luis

    2017-06-01

    Adenosine is an endogenous nucleoside with pleiotropic effects in different physiological processes including circulation, renal blood flow, immune function, or glucose homeostasis. Changes in adenosine membrane transporters, adenosine receptors, and corresponding intracellular signalling network associate with development of pathologies of pregnancy, including preeclampsia. Preeclampsia is a cause of maternal and perinatal morbidity and mortality affecting 3-5% of pregnancies. Since the proposed mechanisms of preeclampsia development include adenosine-dependent biological effects, adenosine membrane transporters and receptors, and the associated signalling mechanisms might play a role in the pathophysiology of preeclampsia. Preeclampsia associates with increased adenosine concentration in the maternal blood and placental tissue, likely due to local hypoxia and ischemia (although not directly demonstrated), microthrombosis, increased catecholamine release, and platelet activation. In addition, abnormal expression and function of equilibrative nucleoside transporters is described in foetoplacental tissues from preeclampsia; however, the role of adenosine receptors in the aetiology of this disease is not well understood. Adenosine receptors activation may be related to abnormal trophoblast invasion, angiogenesis, and ischemia/reperfusion mechanisms in the placenta from preeclampsia. These mechanisms may explain only a low fraction of the associated abnormal transformation of spiral arteries in preeclampsia, triggering cellular stress and inflammatory mediators release from the placenta to the maternal circulation. Although increased adenosine concentration in preeclampsia may be a compensatory or adaptive mechanism favouring placental angiogenesis, a poor angiogenic state is found in preeclampsia. Thus, preeclampsia-associated complications might affect the cell response to adenosine due to altered expression and activity of adenosine receptors, membrane transporters

  12. Association between Chemotherapy-Response Assays and Subsets of Tumor-Infiltrating Lymphocytes in Gastric Cancer: A Pilot Study.

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    Lee, Jee Youn; Son, Taeil; Cheong, Jae-Ho; Hyung, Woo Jin; Noh, Sung Hoon; Kim, Choong-Bai; Park, Chung-Gyu; Kim, Hyoung-Il

    2015-12-01

    The purpose of this pilot study was to evaluate the association between adenosine triphosphate-based chemotherapy response assays (ATP-CRAs) and subsets of tumor infiltrating lymphocytes (TILs) in gastric cancer. In total, 15 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2011. Chemotherapy response assays were performed on tumor cells from these samples using 11 chemotherapeutic agents, including etoposide, doxorubicin, epirubicin, mitomycin, 5-fluorouracil (5-FU), oxaliplatin, irinotecan, docetaxel, paclitaxel, methotrexate, and cisplatin. TILs in the tissue samples were evaluated using antibodies specific for CD3, CD4, CD8, Foxp3, and Granzyme B. The highest cancer cell death rates were induced by etoposide (44.8%), 5-FU (43.1%), and mitomycin (39.9%). Samples from 10 patients who were treated with 5-FU were divided into 5-FU-sensitive and -insensitive groups according to median cell death rate. No difference was observed in survival between the two groups (P=0.216). Only two patients were treated with a chemotherapeutic agent determined by an ATP-CRA and there was no significant difference in overall survival compared with that of patients treated with their physician's choice of chemotherapeutic agent (P=0.105). However, a high number of CD3 TILs was a favorable prognostic factor (P=0.008). Pearson's correlation analyses showed no association between cancer cell death rates in response to chemotherapeutic agents and subsets of TILs. Cancer cell death rates in response to specific chemotherapeutic agents were not significantly associated with the distribution of TIL subsets.

  13. Adenosine and sleep

    International Nuclear Information System (INIS)

    Yanik, G.M. Jr.

    1987-01-01

    Behavioral and biochemical approaches have been used to determine the relative contribution of endogenous adenosine and adenosine receptors to the sleep-wake cycle in the rat. Adenosine concentrations in specific areas of the rat brain were not affected by 24 hours of total sleep deprivation, or by 24 or 48 hours of REM sleep deprivation. In order to assess the effect of REM sleep deprivation on adenosine A 1 receptors, 3 H-L-PIA binding was measured. The Bmax values for 3 H-L-PIA binding to membrane preparations of the cortices and corpus striata from 48 hour REM sleep-deprived animals were increased 14.8% and 23%, respectively. These increases were not maintained following the cessation of sleep deprivation and recovered within 2 hours. The results of a 96 hour REM deprivation experiment were similar to those of the 48 hour REM sleep deprivation experiment. However, these increases were not evident in similar structures taken from stress control animals, and conclusively demonstrated that the changes in 3 H-L-PIA binding resulted from REM sleep deprivation and not from stress

  14. Adenosine Receptors and Wound Healing

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    Bruce N. Cronstein

    2004-01-01

    Full Text Available Recent studies have demonstrated that application of topical adenosine A2A receptor agonists promotes more rapid wound closure and clinical studies are currently underway to determine the utility of topical A2A adenosine receptor agonists in the therapy of diabetic foot ulcers. The effects of adenosine A2A receptors on the cells and tissues of healing wounds have only recently been explored. We review here the known effects of adenosine A2A receptor occupancy on the cells involved in wound healing.

  15. Adenosine receptor desensitization and trafficking.

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    Mundell, Stuart; Kelly, Eamonn

    2011-05-01

    As with the majority of G-protein-coupled receptors, all four of the adenosine receptor subtypes are known to undergo agonist-induced regulation in the form of desensitization and trafficking. These processes can limit the ability of adenosine receptors to couple to intracellular signalling pathways and thus reduce the ability of adenosine receptor agonists as well as endogenous adenosine to produce cellular responses. In addition, since adenosine receptors couple to multiple signalling pathways, these pathways may desensitize differentially, while the desensitization of one pathway could even trigger signalling via another. Thus, the overall picture of adenosine receptor regulation can be complex. For all adenosine receptor subtypes, there is evidence to implicate arrestins in agonist-induced desensitization and trafficking, but there is also evidence for other possible forms of regulation, including second messenger-dependent kinase regulation, heterologous effects involving G proteins, and the involvement of non-clathrin trafficking pathways such as caveolae. In this review, the evidence implicating these mechanisms is summarized for each adenosine receptor subtype, and we also discuss those issues of adenosine receptor regulation that remain to be resolved as well as likely directions for future research in this field. Copyright © 2010 Elsevier B.V. All rights reserved.

  16. Involvement of A1 adenosine receptors and neural pathways in adenosine-induced bronchoconstriction in mice.

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    Hua, Xiaoyang; Erikson, Christopher J; Chason, Kelly D; Rosebrock, Craig N; Deshpande, Deepak A; Penn, Raymond B; Tilley, Stephen L

    2007-07-01

    High levels of adenosine can be measured from the lungs of asthmatics, and it is well recognized that aerosolized 5'AMP, the precursor of adenosine, elicits robust bronchoconstriction in patients with this disease. Characterization of mice with elevated adenosine levels secondary to the loss of adenosine deaminase (ADA) expression, the primary metabolic enzyme for adenosine, further support a role for this ubiquitous mediator in the pathogenesis of asthma. To begin to identify pathways by which adenosine can alter airway tone, we examined adenosine-induced bronchoconstriction in four mouse lines, each lacking one of the receptors for this nucleoside. We show, using direct measures of airway mechanics, that adenosine can increase airway resistance and that this increase in resistance is mediated by binding the A(1) receptor. Further examination of this response using pharmacologically, surgically, and genetically manipulated mice supports a model in which adenosine-induced bronchoconstriction occurs indirectly through the activation of sensory neurons.

  17. Metronomic chemotherapy.

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    Mutsaers, Anthony J

    2009-08-01

    Chemotherapy drugs are usually administered at doses that are high enough to result in an obligatory break period to allow for the observation of potential side effects and institution of supportive care, if required. In recent years, efforts to administer chemotherapy on a more continuous basis, with a much shorter break period, or none at all, have received increased interest, and the practice has come to be known as metronomic chemotherapy. The basis for success with this currently investigational approach may be rooted in continuous drug exposure to susceptible cancer cells, inhibition of tumor blood vessel growth-a process known as tumor angiogenesis, and/or alterations in tumor immunology. Increased benefit also appears to occur when metronomic chemotherapy is used in combination with newer, targeted antiangiogenic agents, and therefore represents a promising approach to combination therapy, particularly as targeted oncology drugs make their way into veterinary oncology applications. There is still much to be learned in this field, especially with regard to optimization of the proper drugs, dose, schedule, and tumor applications. However, the low cost, ease of administration, and acceptable toxicity profiles potentially associated with this therapeutic strategy make metronomic chemotherapy protocols attractive and suitable to veterinary applications. Preliminary clinical trial results have now been reported in both human and veterinary medicine, including adjuvant treatment of canine splenic hemangiosarcoma and incompletely resected soft tissue sarcoma, and, further, more powerful studies are currently ongoing.

  18. Partial separation of platelet and placental adenosine receptors from adenosine A2-like binding protein

    International Nuclear Information System (INIS)

    Zolnierowicz, S.; Work, C.; Hutchison, K.; Fox, I.H.

    1990-01-01

    The ubiquitous adenosine A2-like binding protein obscures the binding properties of adenosine receptors assayed with 5'-N-[ 3 H]ethylcarboxamidoadenosine [( 3 H]NECA). To solve this problem, we developed a rapid and simple method to separate adenosine receptors from the adenosine A2-like binding protein. Human platelet and placental membranes were solubilized with 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. The soluble platelet extract was precipitated with polyethylene glycol and the fraction enriched in adenosine receptors was isolated from the precipitate by differential centrifugation. The adenosine A2-like binding protein was removed from the soluble placental extract with hydroxylapatite and adenosine receptors were precipitated with polyethylene glycol. The specificity of the [ 3 H]NECA binding is typical of an adenosine A2 receptor for platelets and an adenosine A1 receptor for placenta. This method leads to enrichment of adenosine A2 receptors for platelets and adenosine A1 receptors for placenta. This provides a useful preparation technique for pharmacologic studies of adenosine receptors

  19. The A2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism.

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    Mølck, Christina; Ryall, James; Failla, Laura M; Coates, Janine L; Pascussi, Jean-Marc; Heath, Joan K; Stewart, Gregory; Hollande, Frédéric

    2016-12-01

    Adenosine is a multifaceted regulator of tumor progression. It modulates immune cell activity as well as acting directly on tumor cells. The A 2b adenosine receptor (A 2b -AR) is thought to be an important mediator of these effects. In this study we sought to analyze the contribution of the A 2b -AR to the behavior of colorectal cancer cells. The A 2b -AR antagonist PSB-603 changed cellular redox state without affecting cellular viability. Quantification of cellular bioenergetics demonstrated that PSB-603 increased basal oxygen consumption rates, indicative of enhanced mitochondrial oxidative phosphorylation. Unexpectedly, pharmacological and genetic approaches to antagonize AR-related signalling of PSB-603 did not abolish the response, suggesting that it was AR-independent. PSB-603 also induced acute increases in reactive oxygen species, and PSB-603 synergized with chemotherapy treatment to increase colorectal cancer cell death, consistent with the known link between cellular metabolism and chemotherapy response. PSB-603 alters cellular metabolism in colorectal cancer cells and increases their sensitivity to chemotherapy. Although requiring more mechanistic insight into its A 2b -AR-independent activity, our results show that PSB-603 may have clinical value as an anti-colorectal cancer therapeutic. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Types of chemotherapy

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    ... this page: //medlineplus.gov/ency/patientinstructions/000910.htm Types of chemotherapy To use the sharing features on this page, ... cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html . Updated February 15, ...

  1. chemotherapy patients

    Directory of Open Access Journals (Sweden)

    Katarzyna Augustyniuk

    2016-02-01

    Full Text Available Background . Complementary and alternative medicine (CAM practices for cancer have become popular among oncology patients. An increasing interest in alternative medicine can be explained by the inefficiency of conventional treatment, dissatisfaction with treating patients like objects, and the will to use all available treatment methods. Objectives . The authors assessed how often patients use CAM methods, and which of them are most popular. Material and methods . The study was conducted in Military Hospital no. 109 and the Independent Public Clinical Hospital no. 1 in Szczecin among 100 chemotherapy patients. This survey-based study was performed using an original questionnaire. Results. Most respondents (68% did not use alternative methods to fight the disease. The most popular treatment methods were: herbal medicine (50%, alternative medicine preparations (38% and diet (25%, and the least common: hypnosis (3% and aromatherapy (3%. Analyzed sociodemographic factors had no effects on a choice of a CAM method. Patients obtained information about CAM methods mainly from the Internet (40%, medical staff (37% and literature (31%. Conclusions . 1. Using CAM by patients receiving chemotherapy for neoplasms is quite a common phenomenon. 2. CAM were more often chosen by women. Neither the duration of the disease nor sociodemographic data had effects on making the decision to use CAM methods. 3. The most popular CAM were: herbal medicine, alternative medicine preparations, and diet. 4. Cancer patients should receive special support from nurses and doctors as well as other members of the therapeutic team. Oncology patients should never be left on their own so that they were forced to seek help and support in therapies unconfirmed by scientific investigation.

  2. Role of adenosine receptors in caffeine tolerance

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    Holtzman, S.G.; Mante, S.; Minneman, K.P. (Emory Univ. School of Medicine, Atlanta, GA (USA))

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.

  3. Role of adenosine receptors in caffeine tolerance

    International Nuclear Information System (INIS)

    Holtzman, S.G.; Mante, S.; Minneman, K.P.

    1991-01-01

    Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity

  4. Malaria chemotherapy.

    Science.gov (United States)

    Winstanley, Peter; Ward, Stephen

    2006-01-01

    Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.

  5. Adenosine induced ventricular arrhythmias in the emergency room

    NARCIS (Netherlands)

    Tan, H. L.; Spekhorst, H. H.; Peters, R. J.; Wilde, A. A.

    2001-01-01

    While adenosine effectively terminates most supraventricular tachycardias (SVT), rare case reports have demonstrated its proarrhythmic potential, including induction of ventricular tachycardia (VT). The aim of this study was to define the proarrhythmic effects of adenosine in a large, unselected

  6. Chemotherapy to Treat Cancer

    Science.gov (United States)

    Chemotherapy is a type of cancer treatment that uses drugs to kill cancer cells. Learn how chemotherapy works against cancer, why it causes side effects, and how it is used with other cancer treatments.

  7. A2A adenosine receptor ligand binding and signalling is allosterically modulated by adenosine deaminase.

    Science.gov (United States)

    Gracia, Eduard; Pérez-Capote, Kamil; Moreno, Estefanía; Barkešová, Jana; Mallol, Josefa; Lluís, Carme; Franco, Rafael; Cortés, Antoni; Casadó, Vicent; Canela, Enric I

    2011-05-01

    A2ARs (adenosine A2A receptors) are highly enriched in the striatum, which is the main motor control CNS (central nervous system) area. BRET (bioluminescence resonance energy transfer) assays showed that A2AR homomers may act as cell-surface ADA (adenosine deaminase; EC 3.5.4.4)-binding proteins. ADA binding affected the quaternary structure of A2ARs present on the cell surface. ADA binding to adenosine A2ARs increased both agonist and antagonist affinity on ligand binding to striatal membranes where these proteins are co-expressed. ADA also increased receptor-mediated ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Collectively, the results of the present study show that ADA, apart from regulating the concentration of extracellular adenosine, may behave as an allosteric modulator that markedly enhances ligand affinity and receptor function. This powerful regulation may have implications for the physiology and pharmacology of neuronal A2ARs.

  8. Structural Mapping of Adenosine Receptor Mutations

    DEFF Research Database (Denmark)

    Jespers, Willem; Schiedel, Anke C; Heitman, Laura H

    2018-01-01

    The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemente...

  9. AMP and adenosine are both ligands for adenosine 2B receptor signaling.

    Science.gov (United States)

    Holien, Jessica K; Seibt, Benjamin; Roberts, Veena; Salvaris, Evelyn; Parker, Michael W; Cowan, Peter J; Dwyer, Karen M

    2018-01-15

    Adenosine is considered the canonical ligand for the adenosine 2B receptor (A 2B R). A 2B R is upregulated following kidney ischemia augmenting post ischemic blood flow and limiting tubular injury. In this context the beneficial effect of A 2B R signaling has been attributed to an increase in the pericellular concentration of adenosine. However, following renal ischemia both kidney adenosine monophosphate (AMP) and adenosine levels are substantially increased. Using computational modeling and calcium mobilization assays, we investigated whether AMP could also be a ligand for A 2B R. The computational modeling suggested that AMP interacts with more favorable energy to A 2B R compared with adenosine. Furthermore, AMPαS, a non-hydrolyzable form of AMP, increased calcium uptake by Chinese hamster ovary (CHO) cells expressing the human A 2B R, indicating preferential signaling via the G q pathway. Therefore, a putative AMP-A 2B R interaction is supported by the computational modeling data and the biological results suggest this interaction involves preferential G q activation. These data provide further insights into the role of purinergic signaling in the pathophysiology of renal IRI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  11. Effects of adenosine infusion into renal interstitium on renal hemodynamics

    International Nuclear Information System (INIS)

    Pawlowska, D.; Granger, J.P.; Knox, F.G.

    1987-01-01

    This study was designed to investigate the hemodynamic effects of exogenous adenosine in the interstitium of the rat kidney. Adenosine or its analogues were infused into the renal interstitium by means of chronically implanted capsules. In fusion of adenosine decreased glomerular filtration rate (GFR) from 0.81 +/- 0.06 to 0.37 +/- 0.06 ml/min while having no effect on renal blood flow (RBF). The metabolically stable analogue, 2-chloradenosine (2-ClAdo), decreased GFR from 0.73 +/- 0.07 to 021 +/- 0.06 ml/min. Interstitial infusion of theophylline, an adenosine receptor antagonist, completely abolished the effects of adenosine and 2-ClAdo on GFR. The distribution of adenosine, when infused into the renal interstitium, was determined using radiolabeled 5'-(N-ethyl)-carboxamidoadenosine (NECA), a metabolically stable adenosine agonist. After continuous infusion, [ 3 H]NECA was distributed throughout the kidney. The effects of NECA to reduce GFR were similar to those of adenosine and 2-ClAdo. They conclude that increased levels of adenosine in the renal interstitium markedly decrease GFR without affecting RBF in steady-state conditions. The marked effects of adenosine agonists during their infusion into the renal interstitium and the complete blockade of these effects by theophylline suggest an extracellular action of adenosine

  12. Amyotrophic Lateral Sclerosis (ALS and Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Ana M. Sebastião

    2018-04-01

    Full Text Available In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS. Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A2A receptors (A2AR, most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A2AR antagonists. It may happen that there are time windows where A2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression.

  13. Adenosine deaminase activity of erythrocytes in hyperuricemia

    International Nuclear Information System (INIS)

    Krueger, W.; Richter, V.; Beenken, O.; Weinhold, D.; Hirschberg, K.; Rotzsch, W.; Akademie der Wissenschaften der DDR, Leipzig. Zentralinstitut fuer Isotopen- und Strahlenforschung)

    1982-01-01

    Erythrocytic adenosine deaminase (ADA) activity was determined in 55 patients with primary hyperuricemia and in 37 healthy control persons. Unlike the controls, the ADA activity in the patient group showed a two-peak response. Hyperuricemia patients with high ADA activity also exhibited increased uric acid excretion and elevated 15 N incorporation into uric acid. High activity values of erythrocytic ADA can be interpreted as an uric acid overproduction, giving hints for a therapeutic plan. (author)

  14. Chemotherapy disruption of efficient radiotherapy

    International Nuclear Information System (INIS)

    Nervi, C.; Friedman, M.

    1974-01-01

    Studies on the use of chemotherapy in combination with radiotherapy are reviewed. Some topics discussed are: indications for the use of combined chemotherapy and radiotherapy; improvement of the therapeutic ratio following the use of methotrexate; advantages of preirradiation and postirradiation chemotherapy; side effects following simultaneous chemotherapy and radiotherapy; and effects of chemotherapy on cure rate of radiosensitive and radioresistant tumors. (U.S.)

  15. N6-(2-Hydroxyethyl)-Adenosine Exhibits Insecticidal Activity against Plutella xylostella via Adenosine Receptors.

    Science.gov (United States)

    Fang, Ming; Chai, Yiqiu; Chen, Guanjv; Wang, Huidong; Huang, Bo

    The diamondback moth, Plutella xylostella, is one of the most important pests of cruciferous crops. We have earlier shown that N6-(2-hydroxyethyl)-adenosine (HEA) exhibits insecticidal activity against P. xylostella. In the present study we investigated the possible mechanism of insecticidal action of HEA on P. xylostella. HEA is a derivative of adenosine, therefore, we speculated whether it acts via P. xylostella adenosine receptor (PxAdoR). We used RNAi approach to silence PxAdoR gene and used antagonist of denosine receptor (AdoR) to study the insecticidal effect of HEA. We cloned the whole sequence of PxAdoR gene. A BLAST search using NCBI protein database showed a 61% identity with the Drosophila adenosine receptor (DmAdoR) and a 32-35% identity with human AdoR. Though the amino acids sequence of PxAdoR was different compared to other adenosine receptors, most of the amino acids that are known to be important for adenosine receptor ligand binding and signaling were present. However, only 30% binding sites key residues was similar between PxAdoR and A1R. HEA, at a dose of 1 mg/mL, was found to be lethal to the second-instar larvae of P. xylostella, and a significant reduction of mortality and growth inhibition ratio were obtained when HEA was administered to the larvae along with PxAdoR-dsRNA or antagonist of AdoR (SCH58261) for 36, 48, or 60 h. Especially at 48 h, the rate of growth inhibition of the PxAdoR knockdown group was 3.5-fold less than that of the HEA group, and the corrected mortality of SCH58261 group was reduced almost 2-fold compared with the HEA group. Our findings show that HEA may exert its insecticidal activity against P. xylostella larvae via acting on PxAdoR.

  16. N6-(2-Hydroxyethyl)-Adenosine Exhibits Insecticidal Activity against Plutella xylostella via Adenosine Receptors

    Science.gov (United States)

    Fang, Ming; Chai, Yiqiu; Chen, Guanjv; Wang, Huidong; Huang, Bo

    2016-01-01

    The diamondback moth, Plutella xylostella, is one of the most important pests of cruciferous crops. We have earlier shown that N6-(2-hydroxyethyl)-adenosine (HEA) exhibits insecticidal activity against P. xylostella. In the present study we investigated the possible mechanism of insecticidal action of HEA on P. xylostella. HEA is a derivative of adenosine, therefore, we speculated whether it acts via P. xylostella adenosine receptor (PxAdoR). We used RNAi approach to silence PxAdoR gene and used antagonist of denosine receptor (AdoR) to study the insecticidal effect of HEA. We cloned the whole sequence of PxAdoR gene. A BLAST search using NCBI protein database showed a 61% identity with the Drosophila adenosine receptor (DmAdoR) and a 32–35% identity with human AdoR. Though the amino acids sequence of PxAdoR was different compared to other adenosine receptors, most of the amino acids that are known to be important for adenosine receptor ligand binding and signaling were present. However, only 30% binding sites key residues was similar between PxAdoR and A1R. HEA, at a dose of 1 mg/mL, was found to be lethal to the second-instar larvae of P. xylostella, and a significant reduction of mortality and growth inhibition ratio were obtained when HEA was administered to the larvae along with PxAdoR-dsRNA or antagonist of AdoR (SCH58261) for 36, 48, or 60 h. Especially at 48 h, the rate of growth inhibition of the PxAdoR knockdown group was 3.5-fold less than that of the HEA group, and the corrected mortality of SCH58261 group was reduced almost 2-fold compared with the HEA group. Our findings show that HEA may exert its insecticidal activity against P. xylostella larvae via acting on PxAdoR. PMID:27668428

  17. Measurement of plasma adenosine concentration: methodological and physiological considerations

    International Nuclear Information System (INIS)

    Gewirtz, H.; Brown, P.; Most, A.S.

    1987-01-01

    This study tested the hypothesis that measurements of plasma adenosine concentration made on samples of blood obtained in dipyridamole and EHNA (i.e., stopping solution) may be falsely elevated as a result of ongoing in vitro production and accumulation of adenosine during sample processing. Studies were performed with samples of anticoagulated blood obtained from anesthesized domestic swine. Adenosine concentration of ultra filtrated plasma was determined by HPLC. The following parameters were evaluated: (i) rate of clearance of [ 3 H]adenosine added to plasma, (ii) endogenous adenosine concentration of matched blood samples obtained in stopping solution alone, stopping solution plus EDTA, and perchloric acid (PCA), (iii) plasma and erythrocyte endogenous adenosine concentration in nonhemolyzed samples, and (iv) plasma adenosine concentration of samples hemolyzed in the presence of stopping solution alone or stopping solution plus EDTA. We observed that (i) greater than or equal to 95% of [ 3 H]adenosine added to plasma is removed from it by formed elements of the blood in less than 20 s, (ii) plasma adenosine concentration of samples obtained in stopping solution alone is generally 10-fold greater than that of matched samples obtained in stopping solution plus EDTA, (iii) deliberate mechanical hemolysis of blood samples obtained in stopping solution alone resulted in substantial augmentation of plasma adenosine levels in comparison with matched nonhemolyzed specimens--addition of EDTA to stopping solution prevented this, and (iv) adenosine content of blood samples obtained in PCA agreed closely with the sum of plasma and erythrocyte adenosine content of samples obtained in stopping solution plus EDTA

  18. Turnover of adenosine in plasma of human and dog blood

    International Nuclear Information System (INIS)

    Moeser, G.H.S.; Schrader, J.; Deussen, A.

    1989-01-01

    To determine half-life and turnover of plasma adenosine, heparinized blood from healthy volunteers was incubated with radiolabeled adenosine in the physiological concentration range of 0.1-1 microM. Plasma levels of adenosine in vitro were 82 +/- 14 nM and were similar to those determined immediately after blood collection with a ''stopping solution.'' Dipyridamole (83 microM) and erythro-9(2-hydroxynon-3yl)-adenine (EHNA) (8 microM) did not measurably alter basal adenosine levels but completely blocked the uptake of added adenosine. Inhibition of ecto-5'-nucleotidase with 100 microM alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP) reduced plasma adenosine to 22 +/- 6 nM. For the determination of adenosine turnover, the decrease in specific radioactivity of added [ 3 H]adenosine was measured using a dipyridamole-containing stopping solution. Without altering basal adenosine levels, the half-life was estimated to be 0.6 s. Similar experiments were carried out with washed erythrocytes or in the presence of AOPCP, yielding half-lives of 0.7 and 0.9 s, respectively. When the initial adenosine concentration was 1 microM, its specific activity decreased by only 11% within 5 s, whereas total plasma adenosine exponentially decreased with a half-life of 1.5 s. Venous plasma concentrations were measured after relief of a 3-min forearm ischemia. Changes in plasma adenosine did not correlate well with changes in blood flow but were augmented in the presence of dipyridamole

  19. Postoperative Chemotherapy for Medulloblastoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-03-01

    Full Text Available The survival rate and cognitive function of 43 children, age <3 years, with medulloblastoma treated with intensive postoperative chemotherapy alone, without radiotherapy, were determined at the University of Wurzburg and other centers in Germany Chemotherapy consisted of three two-month cycles of cyclophosphamide, methotrexate, vincristine, carboplatin, and etoposide.

  20. Adenosine contribution to normal renal physiology and chronic kidney disease.

    Science.gov (United States)

    Oyarzún, Carlos; Garrido, Wallys; Alarcón, Sebastián; Yáñez, Alejandro; Sobrevia, Luis; Quezada, Claudia; San Martín, Rody

    2017-06-01

    Adenosine is a nucleoside that is particularly interesting to many scientific and clinical communities as it has important physiological and pathophysiological roles in the kidney. The distribution of adenosine receptors has only recently been elucidated; therefore it is likely that more biological roles of this nucleoside will be unveiled in the near future. Since the discovery of the involvement of adenosine in renal vasoconstriction and regulation of local renin production, further evidence has shown that adenosine signaling is also involved in the tubuloglomerular feedback mechanism, sodium reabsorption and the adaptive response to acute insults, such as ischemia. However, the most interesting finding was the increased adenosine levels in chronic kidney diseases such as diabetic nephropathy and also in non-diabetic animal models of renal fibrosis. When adenosine is chronically increased its signaling via the adenosine receptors may change, switching to a state that induces renal damage and produces phenotypic changes in resident cells. This review discusses the physiological and pathophysiological roles of adenosine and pays special attention to the mechanisms associated with switching homeostatic nucleoside levels to increased adenosine production in kidneys affected by CKD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Primary adenosine monophosphate (AMP) deaminase deficiency in a hypotonic infant.

    Science.gov (United States)

    Castro-Gago, Manuel; Gómez-Lado, Carmen; Pérez-Gay, Laura; Eirís-Puñal, Jesús; Martínez, Elena Pintos; García-Consuegra, Inés; Martín, Miguel Angel

    2011-06-01

    The spectrum of the adenosine monophosphate (AMP) deaminase deficiency ranges from asymptomatic carriers to patients who manifest exercise-induced muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. However, previous to the introduction of molecular techniques, rare cases with congenital weakness and hypotonia have also been reported. We report a 6-month-old girl with the association of congenital muscle weakness and hypotonia, muscle deficiency of adenosine monophosphate deaminase, and the homozygous C to T mutation at nucleotide 34 of the adenosine monophosphate deaminase-1 gene. This observation indicates the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by congenital muscle weakness and hypotonia.

  2. Circadian variations of adenosine and of its metabolism. Could adenosine be a molecular oscillator for circadian rhythms?

    Science.gov (United States)

    Chagoya de Sánchez, V

    1995-03-01

    The present review describes the biological implications of the periodic changes of adenosine concentrations in different tissues of the rat. Adenosine is a purine molecule that could have been formed in the prebiotic chemical evolution and has been preserved. The rhythmicity of this molecule, as well as its metabolism and even the presence of specific receptors, suggests a regulatory role in eukaryotic cells and in multicellular organisms. Adenosine may be considered a chemical messenger and its action could take place at the level of the same cell (autocrine), the same tissue (paracrine), or on separate organs (endocrine). Exploration of the circadian variations of adenosine was planned considering the liver as an important tissue for purine formation, the blood as a vehicle among tissues, and the brain as the possible acceptor for hepatic adenosine or its metabolites. The rats used in these studies were adapted to a dark-light cycle of 12 h with an unrestrained feeding and drinking schedule. The metabolic control of adenosine concentration in the different tissues studied through the 24-h cycle is related to the activity of adenosine-metabolizing enzyme: 5'-nucleotidase adenosine deaminase, adenosine kinase, and S-adenosylhomocysteine hydrolase. Some possibilities of the factors modulating the activity of these enzymes are commented upon. The multiphysiological action of adenosine could be mediated by several actions: (i) by interaction with extracellular and intracellular receptors and (ii) through its metabolism modulating the methylation pathway, possibly inducing physiological lipoperoxidation, or participating in the energetic homeostasis of the cell. The physiological meaning of the circadian variations of adenosine and its metabolism was focused on: maintenance of the energetic homeostasis of the tissues, modulation of membrane structure and function, regulation of fasting and feeding metabolic pattern, and its participation in the sleep-wake cycle. From

  3. Effects of high doses of intracoronary adenosine on the assessment of fractional flow reserve

    Directory of Open Access Journals (Sweden)

    Ahmed Khashaba

    2014-03-01

    Conclusions: Intracoronary adenosine, at doses higher than currently suggested, lows obtaining FFR values similar to IV adenosine. Intravenous adenosine, which remains the gold standard, might thus be reserved for those lesions with equivocal FFR values.

  4. Adenosine deaminase-related growth factors stimulate cell proliferation in Drosophila by depleting extracellular adenosine

    Czech Academy of Sciences Publication Activity Database

    Žurovec, Michal; Doležal, Tomáš; Gaži, Michal; Pavlová, Eva; Bryant, P. J.

    2002-01-01

    Roč. 99, č. 7 (2002), s. 4403-4408 ISSN 0027-8424 R&D Projects: GA ČR GA204/01/1022; GA AV ČR IAA5007107 Institutional research plan: CEZ:AV0Z5007907 Keywords : adenosine daminase * minimal medium Subject RIV: CE - Biochemistry Impact factor: 10.701, year: 2002

  5. AMP Is an Adenosine A1 Receptor Agonist*

    Science.gov (United States)

    Rittiner, Joseph E.; Korboukh, Ilia; Hull-Ryde, Emily A.; Jin, Jian; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.

    2012-01-01

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5′-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5′-monophosphonate, ACP) directly activated the adenosine A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A1R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A1R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A1R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A1R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine. PMID:22215671

  6. Application of the newly developed Japanese adenosine normal database for adenosine stress myocardial scintigraphy.

    Science.gov (United States)

    Harata, Shingo; Isobe, Satoshi; Morishima, Itsuro; Suzuki, Susumu; Tsuboi, Hideyuki; Sone, Takahito; Ishii, Hideki; Murohara, Toyoaki

    2015-10-01

    The currently available Japanese normal database (NDB) in stress myocardial perfusion scintigraphy recommended by the Japanese Society of Nuclear Medicine (JSNM-NDB) is created based on the data from exercise tests. The newly developed adenosine normal database (ADS-NDB) remains to be validated for patients undergoing adenosine stress test. We tested whether the diagnostic accuracy of adenosine stress test is improved by the use of ADS-NDB (Kanazawa University). Of 233 consecutive patients undergoing (99m)Tc-MIBI adenosine stress test, 112 patients were tested. The stress/rest myocardial (99m)Tc-MIBI single-photon emission computed tomography (SPECT) images were analyzed by AutoQUANT 7.2 with both ADS-NDB and JSNM-NDB. The summed stress score (SSS) and summed difference score (SDS) were calculated. The agreements of the post-stress defect severity between ADS-NDB and JSNM-NDB were assessed using a weighted kappa statistic. In all patients, mean SSSs of all, right coronary artery (RCA), left anterior descending (LAD), and left circumflex (LCx) territories were significantly lower with ADS-NDB than those with JSNM-NDB. Mean SDSs in all, RCA, and LAD territories were significantly lower with ADS-NDB than those with JSNM-NDB. In 28 patients with significant coronary stenosis, the mean SSS in the RCA territory was significantly lower with ADS-NDB than that with JSNM-NDB. In 84 patients without ischemia, both mean SSSs and SDSs in all, RCA, LAD, and LCx territories were significantly lower with ADS-NDB than those with JSNM-NDB. Weighted kappa values of all patients, patients with significant stenosis, and patients without ischemia were 0.89, 0.83, and 0.92, respectively. Differences were observed between results from ADS-NDB and JSNM-NDB. The diagnostic accuracy of adenosine stress myocardial perfusion scintigraphy may be improved by reducing false-positive results.

  7. Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.

    Science.gov (United States)

    Iriyama, Takayuki; Sun, Kaiqi; Parchim, Nicholas F; Li, Jessica; Zhao, Cheng; Song, Anren; Hart, Laura A; Blackwell, Sean C; Sibai, Baha M; Chan, Lee-Nien L; Chan, Teh-Sheng; Hicks, M John; Blackburn, Michael R; Kellems, Rodney E; Xia, Yang

    2015-02-24

    Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental adenosine coupled with excessive A₂B adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental adenosine, thereby contributing to preeclampsia. We determined that elevated placental adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental adenosine and the detrimental role of excess placental adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets. © 2014 American Heart Association, Inc.

  8. Involvement of adenosine in the antiinflammatory action of ketamine.

    Science.gov (United States)

    Mazar, Julia; Rogachev, Boris; Shaked, Gad; Ziv, Nadav Y; Czeiger, David; Chaimovitz, Cidio; Zlotnik, Moshe; Mukmenev, Igor; Byk, Gerardo; Douvdevani, Amos

    2005-06-01

    Ketamine is an anesthetic drug. Subanesthetic doses of ketamine have been shown to reduce interleukin-6 concentrations after surgery and to reduce mortality and the production of tumor necrosis factor alpha and interleukin 6 in septic animals. Similarly, adenosine was shown to reduce tumor necrosis factor alpha and mortality of septic animals. The aim of this study was to determine whether adenosine mediates the antiinflammatory effects of ketamine. Sepsis was induced in mice by lipopolysaccharide or Escherichia coli inoculation. Leukocyte recruitment and cytokine concentrations were used as inflammation markers. Adenosine concentrations were assayed by high-performance liquid chromatography, and the involvement of adenosine in the effects of ketamine was demonstrated by adenosine receptor agonists and antagonists. Ketamine markedly reduced mortality from sepsis, leukocyte recruitment, and tumor necrosis factor-alpha and interleukin-6 concentrations. Ketamine administration in mice and rats was associated with a surge at 20-35 min of adenosine in serum (up to 5 microm) and peritoneal fluid. The adenosine A2A receptor agonist CGS-21680 mimicked the effect of ketamine in peritonitis, whereas the A2A receptor antagonists DMPX and ZM 241385 blocked its antiinflammatory effects. In contrast, A1 and A3 receptor antagonists had no effect. ZM 241385 reversed the beneficial effect of ketamine on survival from bacterial sepsis. The current data suggest that the sepsis-protective antiinflammatory effects of ketamine are mediated by the release of adenosine acting through the A2A receptor.

  9. Chemotherapy in eye cancer

    African Journals Online (AJOL)

    is a drug used in a wide range of cancers, which produces ... lesions. In a 10-year retrospective review of .... disease and focal chemotherapy for selected high-risk ... of focal drug delivery methods to reduce recurrence .... the protein tubulin.

  10. Prevent Infections During Chemotherapy

    Centers for Disease Control (CDC) Podcasts

    This podcast discusses the importance of preventing infections in cancer patients who are undergoing chemotherapy. Dr. Lisa Richardson, CDC oncologist, talks about a new Web site for cancer patients and their caregivers.

  11. Reentry Tachycardia in Children: Adenosine Can Make It Worse.

    Science.gov (United States)

    Hien, Maximilian D; Benito Castro, Fernando; Fournier, Philippe; Filleron, Anne; Tran, Tu-Anh

    2016-10-08

    We report on a rare but severe complication of adenosine use in a child with reentry tachycardia. Treatment with adenosine, which is the standard medical therapy of atrioventricular reentry tachycardia, led to the development of an irregular wide complex tachycardia, caused by rapid ventricular response to atrial fibrillation. The girl was finally stabilized with electrical cardioversion. We analyze the pathomechanism and discuss possible treatment options. Atrial fibrillation, as well as its conduction to the ventricles, can be caused by adenosine. Rapid ventricular response in children with Wolff-Parkinson-White syndrome is more frequent than previously believed. A patient history of atrial fibrillation is a contraindication for cardioversion with adenosine and needs to be assessed in children with reentry tachycardia. High-risk patients may potentially profit from prophylactic comedication with antiarrhythmic agents, such as flecainide, ibutilide, or vernakalant, before adenosine administration.

  12. A High Affinity Adenosine Kinase from Anopheles gambiae

    Science.gov (United States)

    Cassera, María B.; Ho, Meng-Chiao; Merino, Emilio F.; Burgos, Emmanuel S.; Rinaldo-Matthis, Agnes; Almo, Steven C.; Schramm, Vern L.

    2011-01-01

    Genome analysis revealed a mosquito orthologue of adenosine kinase in Anopheles gambiae (AgAK; the most important vector for the transmission of Plasmodium falciparum in Africa). P. falciparum are purine auxotrophs and do not express an adenosine kinase but rely on their hosts for purines. AgAK was kinetically characterized and found to have the highest affinity for adenosine (Km 8.1 nM) of any known adenosine kinase. AgAK is specific for adenosine at the nucleoside site but several nucleotide triphosphate phosphoryl donors are tolerated. The AgAK crystal structure with a bound bisubstrate analogue Ap4A (2.0 Å resolution) reveals interactions for adenosine, ATP and the geometry for phosphoryl transfer. The polyphosphate charge is partly neutralized by a bound Mg2+ ion and an ion pair to a catalytic site Arg. The AgAK structure consists of a large catalytic core in a three-layered α/β/α sandwich, and a small cap domain in contact with adenosine. The specificity and tight-binding for adenosine arises from hydrogen bond interactions of Asn14, Leu16, Leu40, Leu133, Leu168, Phe168 and Thr171 and the backbone of Ile39 and Phe168 with the adenine ring as well as through hydrogen bond interactions between Asp18, Gly64 and Asn68 and the ribosyl 2′- and 3′-hydroxyl groups. The structure is more similar to human adenosine kinase (48% identity) than to AK from Toxoplasma gondii (31% identity). With this extraordinary affinity for AgAK, adenosine is efficiently captured and converted to AMP at near the diffusion limit, suggesting an important role of this enzyme to maintain the adenine nucleotide pool. mRNA analysis verifies that AgAK transcripts are produced in the adult insects. PMID:21247194

  13. Characterization of cardiac adenosine receptors using N6-phenyladenosines and a new radioligand, [125I]-(m-aminophenyl)adenosine

    International Nuclear Information System (INIS)

    Kwatra, M.M.; Hosey, M.M.; Green, R.

    1986-01-01

    The chick heart contains adenosine receptors with characteristics similar to the R adenosine receptors found in the CNS. They have synthesized several N 6 -phenyladenosines and tested their potencies for inhibiting the binding of [ 125 I](p-aminobenzyl)adenosine {[ 125 I]ABA) to chick heart membranes. Of the 12 compounds tested, N 6 -(p-aminobenzyl) adenosine (ABA) was the least potent (IC 50 ∼ 40 nM) while N 6 -(m-nitrophenyl)adenosine(MNPA) was the most potent (IC 50 ∼ 1 nM). The IC 50 of N 6 -(m-aminophenyl)adenosine(MAPA) was greater than that of N 6 -phenyladenosine(PA) while that of MNPA was less than that of PA. The effects of these electron-releasing (-NH 2 ) and electron-withdrawing (-NO 2 ) groups along with data obtained with other phenyl-substituted N 6 -phenyladenosines suggest that the electron density of the N 6 -nitrogen may affect the affinities of these compounds for the cardiac adenosine receptor. MAPA can be iodinated to produce a new ligand, [ 125 I]MAPA. This iodination, like that of ABA, increases the affinity of the compound and produces a ligand with good affinity and low nonspecific binding suitable for studies on tissues with low concentrations of adenosine receptors

  14. Molecular Evidence of Adenosine Deaminase Linking Adenosine A2A Receptor and CD26 Proteins.

    Science.gov (United States)

    Moreno, Estefanía; Canet, Júlia; Gracia, Eduard; Lluís, Carme; Mallol, Josefa; Canela, Enric I; Cortés, Antoni; Casadó, Vicent

    2018-01-01

    Adenosine is an endogenous purine nucleoside that acts in all living systems as a homeostatic network regulator through many pathways, which are adenosine receptor (AR)-dependent and -independent. From a metabolic point of view, adenosine deaminase (ADA) is an essential protein in the regulation of the total intracellular and extracellular adenosine in a tissue. In addition to its cytosolic localization, ADA is also expressed as an ecto-enzyme on the surface of different cells. Dipeptidyl peptidase IV (CD26) and some ARs act as binding proteins for extracellular ADA in humans. Since CD26 and ARs interact with ADA at opposite sites, we have investigated if ADA can function as a cell-to-cell communication molecule by bridging the anchoring molecules CD26 and A 2A R present on the surfaces of the interacting cells. By combining site-directed mutagenesis of ADA amino acids involved in binding to A 2A R and a modification of the bioluminescence resonance energy transfer (BRET) technique that allows detection of interactions between two proteins expressed in different cell populations with low steric hindrance (NanoBRET), we show direct evidence of the specific formation of trimeric complexes CD26-ADA-A 2A R involving two cells. By dynamic mass redistribution assays and ligand binding experiments, we also demonstrate that A 2A R-NanoLuc fusion proteins are functional. The existence of this ternary complex is in good agreement with the hypothesis that ADA could bridge T-cells (expressing CD26) and dendritic cells (expressing A 2A R). This is a new metabolic function for ecto-ADA that, being a single chain protein, it has been considered as an example of moonlighting protein, because it performs more than one functional role (as a catalyst, a costimulator, an allosteric modulator and a cell-to-cell connector) without partitioning these functions in different subunits.

  15. Molecular Evidence of Adenosine Deaminase Linking Adenosine A2A Receptor and CD26 Proteins

    Directory of Open Access Journals (Sweden)

    Estefanía Moreno

    2018-02-01

    Full Text Available Adenosine is an endogenous purine nucleoside that acts in all living systems as a homeostatic network regulator through many pathways, which are adenosine receptor (AR-dependent and -independent. From a metabolic point of view, adenosine deaminase (ADA is an essential protein in the regulation of the total intracellular and extracellular adenosine in a tissue. In addition to its cytosolic localization, ADA is also expressed as an ecto-enzyme on the surface of different cells. Dipeptidyl peptidase IV (CD26 and some ARs act as binding proteins for extracellular ADA in humans. Since CD26 and ARs interact with ADA at opposite sites, we have investigated if ADA can function as a cell-to-cell communication molecule by bridging the anchoring molecules CD26 and A2AR present on the surfaces of the interacting cells. By combining site-directed mutagenesis of ADA amino acids involved in binding to A2AR and a modification of the bioluminescence resonance energy transfer (BRET technique that allows detection of interactions between two proteins expressed in different cell populations with low steric hindrance (NanoBRET, we show direct evidence of the specific formation of trimeric complexes CD26-ADA-A2AR involving two cells. By dynamic mass redistribution assays and ligand binding experiments, we also demonstrate that A2AR-NanoLuc fusion proteins are functional. The existence of this ternary complex is in good agreement with the hypothesis that ADA could bridge T-cells (expressing CD26 and dendritic cells (expressing A2AR. This is a new metabolic function for ecto-ADA that, being a single chain protein, it has been considered as an example of moonlighting protein, because it performs more than one functional role (as a catalyst, a costimulator, an allosteric modulator and a cell-to-cell connector without partitioning these functions in different subunits.

  16. Adenosine: a putative mediator of bronchoconstriction in asthma

    Energy Technology Data Exchange (ETDEWEB)

    Mann, J.S.

    1987-01-01

    The protective effect of a muscarinic cholinergic antagonists, ipratropium bromide (IB) from inhaled adenosine- and methacholine-induced bronchoconstriction in asthma was studied. Inhaled IB protected from methacholine- but not adenosine-induced bronchoconstriction. Parasympathetically mediated bronchoconstriction is therefore unlikely to account for adenosine's airway effect in asthma. The capacity of theophylline, a bronchodilator and a competitive antagonist of adenosine at its cell surface receptors, to protect asthmatic subjects from adenosine- and histamine-induced bronchoconstriction was determined. Asthmatic airways are infiltrated with inflammatory cells. Human leucocytes prelabeled with (/sup 3/H)-adenine when activated with the calcium ionophore A23187 released labelled hypoxanthine, inosine and adenosine which was associated with a dose-related release of histamine. The chemotactic peptide f-MLP while inducing histamine release had an inconstant effect on release of label. In four of five experiments f-MLP produced a transient early increase in label release but in the remaining experiment no significant release was observed. Anti-human IgE failed to induce significant label release despite releasing histamine. Activated leucocytes are therefore a potential source of adenosine in asthma.

  17. Adenosine receptors and caffeine in retinopathy of prematurity.

    Science.gov (United States)

    Chen, Jiang-Fan; Zhang, Shuya; Zhou, Rong; Lin, Zhenlang; Cai, Xiaohong; Lin, Jing; Huo, Yuqing; Liu, Xiaoling

    2017-06-01

    Retinopathy of prematurity (ROP) is a major cause of childhood blindness in the world and is caused by oxygen-induced damage to the developing retinal vasculature, resulting in hyperoxia-induced vaso-obliteration and subsequent delayed retinal vascularization and hypoxia-induced pathological neovascularization driven by vascular endothelial growth factor (VEGF) signaling pathway in retina. Current anti-VEGF therapy has shown some effective in a clinical trial, but is associated with the unintended effects on delayed eye growth and retinal vasculature development of preterm infants. Notably, cellular responses to hypoxia are characterized by robust increases in extracellular adenosine production and the markedly induced adenosine receptors, which provide a novel target for preferential control of pathological angiogenesis without affecting normal vascular development. Here, we review the experimental evidence in support of adenosine receptor-based therapeutic strategy for ROP, including the aberrant adenosine signaling in oxygen-induced retinopathy and the role of three adenosine receptor subtypes (A 1 R, A 2A R, A 2B R) in development and treatment of ROP using oxygen-induced retinopathy models. The clinical and initial animal evidence that implicate the therapeutic effect of caffeine (a non-selective adenosine receptor antagonist) in treatment of ROP are highlighted. Lastly, we discussed the translational potential as well therapeutic advantage of adenosine receptor- and caffeine-based therapy for ROR and possibly other proliferative retinopathy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Characteristic molecular vibrations of adenosine receptor ligands.

    Science.gov (United States)

    Chee, Hyun Keun; Yang, Jin-San; Joung, Je-Gun; Zhang, Byoung-Tak; Oh, S June

    2015-02-13

    Although the regulation of membrane receptor activation is known to be crucial for molecular signal transduction, the molecular mechanism underlying receptor activation is not fully elucidated. Here we study the physicochemical nature of membrane receptor behavior by investigating the characteristic molecular vibrations of receptor ligands using computational chemistry and informatics methods. By using information gain, t-tests, and support vector machines, we have identified highly informative features of adenosine receptor (AdoR) ligand and corresponding functional amino acid residues such as Asn (6.55) of AdoR that has informative significance and is indispensable for ligand recognition of AdoRs. These findings may provide new perspectives and insights into the fundamental mechanism of class A G protein-coupled receptor activation. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  19. Mechanism-specific effects of adenosine on ventricular tachycardia.

    Science.gov (United States)

    Lerman, Bruce B; Ip, James E; Shah, Bindi K; Thomas, George; Liu, Christopher F; Ciaccio, Edward J; Wit, Andrew L; Cheung, Jim W; Markowitz, Steven M

    2014-12-01

    There is no universally accepted method by which to diagnose clinical ventricular tachycardia (VT) due to cAMP-mediated triggered activity. Based on cellular and clinical data, adenosine termination of VT is thought to be consistent with a diagnosis of triggered activity. However, a major gap in evidence mitigates the validity of this proposal, namely, defining the specificity of adenosine response in well-delineated reentrant VT circuits. To this end, we systematically studied the effects of adenosine in a model of canine reentrant VT and in human reentrant VT, confirmed by 3-dimensional, pace- and substrate mapping. Adenosine (12 mg [IQR 12-24]) failed to terminate VT in 31 of 31 patients with reentrant VT due to structural heart disease, and had no effect on VT cycle length (age, 67 years [IQR 53-74]); ejection fraction, 35% [IQR 20-55]). In contrast, adenosine terminated VT in 45 of 50 (90%) patients with sustained focal right or left outflow tract tachycardia. The sensitivity of adenosine for identifying VT due to triggered activity was 90% (95% CI, 0.78-0.97) and its specificity was 100% (95% CI, 0.89-1.0). Additionally, reentrant circuits were mapped in the epicardial border zone of 4-day-old infarcts in mongrel dogs. Adenosine (300-400 μg/kg) did not terminate sustained VT or have any effect on VT cycle length. These data support the concept that adenosine's effects on ventricular myocardium are mechanism specific, such that termination of VT in response to adenosine is diagnostic of cAMP-mediated triggered activity. © 2014 Wiley Periodicals, Inc.

  20. Synthesis of carbon-11 labelled cyclopentyltheophylline: A radioligand for PET studies of adenosine receptors

    International Nuclear Information System (INIS)

    Yorke, J.C.; Prenant, C.; Crouzel, C.

    1990-01-01

    Adenosine is presently considered as a neuromodulator, and an adenosine system has been described including secretory neurons, with a diffused distribution, specific receptors and a re-uptake system distributed heterogeneously in different anatomic areas. In order to localize the adenosine receptors in vivo by PET, the authors have synthesized the carbon-11 labelled 8-cyclopentyltheophylline, a known adenosine antagonist of A 1 receptors

  1. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors

    DEFF Research Database (Denmark)

    Gnad, Thorsten; Scheibler, Saskia; von Kügelgen, Ivar

    2014-01-01

    hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A...

  2. Hyperthermia and chemotherapy agent

    International Nuclear Information System (INIS)

    Roizin-Towle, L.; Hall, E.J.

    1981-01-01

    The use of chemotherapeutic agents for the treatment of cancer dates back to the late 19th century, but the modern era of chemotherapy drugs was ushered in during the 1940's with the development of the polyfunctional alkylating agent. Since then, numerous classes of drugs have evolved and the combined use of antineoplastic agents with other treatment modalities such as radiation or heat, remains a large relatively unexplored area. This approach, combining local hyperthermia with chemotherapy agents affords a measure of targeting and selective toxicity not previously available for drugs. In this paper, the effects of adriamycin, bleomycin and cis-platinum are examined. The adjuvant use of heat may also reverse the resistance of hypoxic cells noted for some chemotherapy agents

  3. Combination Chemotherapy for Influenza

    Directory of Open Access Journals (Sweden)

    Robert G. Webster

    2010-07-01

    Full Text Available The emergence of pandemic H1N1 influenza viruses in April 2009 and the continuous evolution of highly pathogenic H5N1 influenza viruses underscore the urgency of novel approaches to chemotherapy for human influenza infection. Anti-influenza drugs are currently limited to the neuraminidase inhibitors (oseltamivir and zanamivir and to M2 ion channel blockers (amantadine and rimantadine, although resistance to the latter class develops rapidly. Potential targets for the development of new anti-influenza agents include the viral polymerase (and endonuclease, the hemagglutinin, and the non-structural protein NS1. The limitations of monotherapy and the emergence of drug-resistant variants make combination chemotherapy the logical therapeutic option. Here we review the experimental data on combination chemotherapy with currently available agents and the development of new agents and therapy targets.

  4. Insulin and adenosine regulate the phosphatidylcholine concentration in isolated rat adipocyte plasma membranes.

    Science.gov (United States)

    Kiechle, F L; Sykes, E; Artiss, J D

    1995-01-01

    Blockade of adenosine receptors by 3-isobutyl-1-methylxanthine or degradation of endogenous adenosine with adenosine deaminase increased the phosphatidylcholine concentration in isolated rat adipocyte plasma membranes, an effect which was suppressed by the phosphatidylethanolamine methyltransferase inhibitor, S-adenosyl-L-homocysteine, and reversed by the adenosine analogue, N6-(L-phenylisopropyl)-adenosine. For example, the addition of N6-(L-phenylisopropyl)-adenosine to adenosine deaminase pretreated plasma membranes rapidly lowered the concentration of phosphatidylcholine by 171 nmol/mg at 30 seconds compared to control. Insulin-induced stimulation of phospholipid methylation in membranes treated with 3-isobutyl-1-methylxanthine or adenosine deaminase was achieved only after the addition of N6-(L-phenylisopropyl)-adenosine. These results suggest that adenosine receptor occupancy inhibits phospholipid methylation, is required for insulin stimulation of phospholipid methylation, and may perhaps activate a phosphatidylcholine-specific phospholipase C or phospholipase D.

  5. Chemotherapy in thyroid carcinoma

    International Nuclear Information System (INIS)

    Samuel, A.M.; Shah, D.H.

    1999-01-01

    Chemotherapy alone, either as a single drug or a combination of drugs with or without external radiation (ER) is useful for treatment of locally advanced disease and non iodine concentrating metastasis in differentiated thyroid cancers (DTC). The reported response is not encouraging, but the absence of better alternatives leave no choice for the treatment of such cases. However, for treatment of anaplastic thyroid cancers (ANC), chemotherapy (CT) in combination with ER results in local control. In medullary thyroid cancers (MTC), the results obtained with multimodal treatment are encouraging

  6. Extravasation of chemotherapy

    DEFF Research Database (Denmark)

    Langer, Seppo W

    2010-01-01

    Extravasation of chemotherapy is a feared complication of anticancer therapy. The accidental leakage of cytostatic agents into the perivascular tissues may have devastating short-term and long-term consequences for patients. In recent years, the increased focus on chemotherapy extravasation has led...... to the development of international guidelines that have proven useful tools in daily clinical practice. Moreover, the tissue destruction in one of the most dreaded types of extravasation (ie, anthracycline extravasation) now can effectively be prevented with a specific antidote, dexrazoxane....

  7. Chemotherapy-induced polyneuropathy

    DEFF Research Database (Denmark)

    Zedan, Ahmed; Vilholm, Ole Jakob

    2014-01-01

    Chemotherapy-induced polyneuropathy (CIPN) is a common, but underestimated, clinical challenge. Incidence varies depending on many factors that are equally as important as the type of chemotherapeutic agent itself. Moreover, the assessment of CIPN is still uncertain, as several of the most...... frequently used scales do not rely on a formal neurological evaluation and depend on patients' reports and examiners' interpretations. Therefore, the aim of this MiniReview was to introduce the most common chemotherapies that cause neuropathy, and in addition to this, highlight the most significant...

  8. Photoreaction of 4,5',8-trimethylpsoralen with adenosine

    International Nuclear Information System (INIS)

    Sangchul Shim; Seungju Choi

    1990-01-01

    The near-UV induced photoreaction of 4,5',8-trimethylpsoralen (TMP) with adenosine was investigated in a dry film state. Four major photoadducts were isolated and purified by reverse-phase liquid chromatography. The structures of the photoproducts were elucidated on the basis of spectroscopic methods, including UV, FT-IR, mass spectrometry (FAB and EI methods) and 1 H-NMR analysis. These photoproducts were characterized to be TMP-adenosine 1:1 adducts, which resulted from the covalent bond formation between the carbon C(4) of TMP and ribose 1' or 5' carbon of adenosine. Of the photoadducts, one photoadduct (V) was the major product, reflecting some selectivity in the photoreaction of TMP with adenosine in the solid state. (author)

  9. Mechanism of protection of adenosine from sulphate radical anion ...

    Indian Academy of Sciences (India)

    Unknown

    Keywords. Repair by caffeic acid; repair of adenosine radicals; oxidation by sulphate radical anions. ... known that hydroxycinnamic acids are natural anti- oxidants ... acid. 2. Experimental ..... ously and independently under kinetic conditions at.

  10. Adenosine-deaminase (ADA activity in Psoriasis (A Preliminary Study

    Directory of Open Access Journals (Sweden)

    S D Chaudhry

    1988-01-01

    Full Text Available Study of adenosine-deaminase activity ′in 23 patients hav-mg psoriasis compared with an equal number of healthy controls revealed significantly high ADA-activity in the psotiatic patients.

  11. Adenosine deaminase organic effect in normal and abnormal cerebrospinal fluid

    International Nuclear Information System (INIS)

    Hamad, A.M.; Samarai, M.A.

    2007-01-01

    To study the effect of the organic substances on adenosine deaminase (ADA) activity in normal and abnormal cerebrospinal fluid (CSF). Various concentrations of 2-mercaptopurine, Ame-tycine, Adenosine analogues (Guanine, Thymine) and ATP were tested to see their effect on ADA activity in normal and abnormal CSF. ADA activity in normal and abnormal CSF was remarkably decreased with the increasing of concentrations of substances tested. These effects may have important therapeutic implications. (author)

  12. Chemotherapy-induced hypocalcemia.

    Science.gov (United States)

    Ajero, Pia Marie E; Belsky, Joseph L; Prawius, Herbert D; Rella, Vincent

    2010-01-01

    To present a unique case of transient, asymptomatic chemotherapy-induced hypocalcemia not attributable to hypomagnesemia or tumor lysis syndrome and review causes of hypocalcemia related to cancer with and without use of chemotherapy. We present a case detailing the clinical and laboratory findings of a patient who had severe hypocalcemia during chemotherapy and discuss causes of hypocalcemia with an extensive literature review of chemotherapeutic agents associated with this biochemical abnormality. In a 90-year-old man, hypocalcemia developed during 2 courses of chemotherapy for Hodgkin lymphoma, with partial recovery between courses and normal serum calcium 10 months after completion of treatment. Magnesium, vitamin D, and parathyroid hormone levels were low normal. There was no evidence of tumor lysis syndrome. Of the various agents administered, vinca alkaloids seemed the most likely cause. Serial testing suggested that the underlying mechanism may have been acquired, reversible hypoparathyroidism. No other similar case was found in the published literature. The severe hypocalcemia in our patient could not be attributed to hypomagnesemia or tumor lysis syndrome, and it was clearly associated with the timing of his chemotherapeutic regimen. Possibilities include direct parathyroid hormone suppression or alteration of calcium sensing by the chemotherapeutic drugs. Serum calcium surveillance before and during chemotherapeutic management of cancer patients may reveal more instances and provide insight into the exact mechanism of this lesser known yet striking complication.

  13. After chemotherapy - discharge

    Science.gov (United States)

    You had chemotherapy treatment for your cancer. Your risk of infection, bleeding, and skin problems may be high. You may have mouth sores, an upset stomach, and diarrhea. You will probably get tired easily. Your appetite may be poor, but you should be able ...

  14. Enzymatic properties of Staphylococcus aureus adenosine synthase (AdsA)

    Science.gov (United States)

    2011-01-01

    Background Staphylococcus aureus is a human pathogen that produces extracellular adenosine to evade clearance by the host immune system, an activity attributed to the 5'-nucleotidase activity of adenosine synthase (AdsA). In mammals, conversion of adenosine triphosphate to adenosine is catalyzed in a two-step process: ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTDPases) hydrolyze ATP and ADP to AMP, whereas 5'-nucleotidases hydrolyze AMP to adenosine. NTPDases harbor apyrase conserved regions (ACRs) that are critical for activity. Results NTPDase ACR motifs are absent in AdsA, yet we report here that recombinant AdsA hydrolyzes ADP and ATP in addition to AMP. Competition assays suggest that hydrolysis occurs following binding of all three substrates at a unique site. Alanine substitution of two amino acids, aspartic acid 127 and histidine 196 within the 5'-nucleotidase signature sequence, leads to reduced AMP or ADP hydrolysis but does not affect the binding of these substrates. Conclusion Collectively, these results provide insight into the unique ability of AdsA to produce adenosine through the consecutive hydrolysis of ATP, ADP and AMP, thereby endowing S. aureus with the ability to modulate host immune responses. PMID:22035583

  15. Detrimental effects of adenosine signaling in sickle cell disease

    Science.gov (United States)

    Zhang, Yujin; Dai, Yingbo; Wen, Jiaming; Zhang, Weiru; Grenz, Almut; Sun, Hong; Tao, Lijian; Lu, Guangxiu; Alexander, Danny C; Milburn, Michael V; Carter-Dawson, Louvenia; Lewis, Dorothy E; Zhang, Wenzheng; Eltzschig, Holger K; Kellems, Rodney E; Blackburn, Michael R; Juneja, Harinder S; Xia, Yang

    2016-01-01

    Hypoxia can act as an initial trigger to induce erythrocyte sickling and eventual end organ damage in sickle cell disease (SCD). Many factors and metabolites are altered in response to hypoxia and may contribute to the pathogenesis of the disease. Using metabolomic profiling, we found that the steady-state concentration of adenosine in the blood was elevated in a transgenic mouse model of SCD. Adenosine concentrations were similarly elevated in the blood of humans with SCD. Increased adenosine levels promoted sickling, hemolysis and damage to multiple tissues in SCD transgenic mice and promoted sickling of human erythrocytes. Using biochemical, genetic and pharmacological approaches, we showed that adenosine A2B receptor (A2BR)-mediated induction of 2,3-diphosphoglycerate, an erythrocyte-specific metabolite that decreases the oxygen binding affinity of hemoglobin, underlies the induction of erythrocyte sickling by excess adenosine both in cultured human red blood cells and in SCD transgenic mice. Thus, excessive adenosine signaling through the A2BR has a pathological role in SCD. These findings may provide new therapeutic possibilities for this disease. PMID:21170046

  16. Interstitial adenosine concentration is increased by dipyridamole

    International Nuclear Information System (INIS)

    Gorman, M.W.; Wangler, R.D.; DeWitt, D.F.; Wang, C.Y.; Bassingthwaighte, J.B.; Sparks, H.V.

    1986-01-01

    The authors used the multiple indicator dilution technique to observe the capillary transport of adenosine (ADO) in isolated guinea pig hearts. Radiolabelled albumin, sucrose and ADO were injected on the arterial side and measured in venous samples collected during the following 20 seconds. Transport parameters calculated from these data include permeability-surface area products (PS) for transendothelial diffusion, endothelial cell (EC) uptake at the lumenal and ablumenal membranes, and EC metabolism. With simultaneous measurements of arterial and venous ADO concentrations and flow, the authors calculated the steady-state interstitial fluid (ISF) ADO concentration. Under control conditions the venous ADO concentration was 7.1 +/- 2.8 nM. The calculated ISF concentration depends on whether they assume the venous ADO comes from the ISF, or directly from ECs. These ISF concentrations are 25 +/- 12 nM and 9.8 +/- 4.0 nM, respectively. During dipyridamole infusion (10 uM) the EC transport parameters became nearly zero. Venous and ISF ADO concentrations increased to 33 +/- 8.9 nM and 169 +/- 42 nM, respectively. The authors conclude that the ISF ADO concentration is 1.5-4 fold higher than the venous concentration at rest, and the ISF concentration increases greatly with dipyridamole

  17. Skeletal muscle expresses the extracellular cyclic AMP–adenosine pathway

    Science.gov (United States)

    Chiavegatti, T; Costa, V L; Araújo, M S; Godinho, R O

    2007-01-01

    Background and purpose: cAMP is a key intracellular signalling molecule that regulates multiple processes of the vertebrate skeletal muscle. We have shown that cAMP can be actively pumped out from the skeletal muscle cell. Since in other tissues, cAMP efflux had been associated with extracellular generation of adenosine, in the present study we have assessed the fate of interstitial cAMP and the existence of an extracellular cAMP-adenosine signalling pathway in skeletal muscle. Experimental approach: cAMP efflux and/or its extracellular degradation were analysed by incubating rat cultured skeletal muscle with exogenous cAMP, forskolin or isoprenaline. cAMP and its metabolites were quantified by radioassay or HPLC, respectively. Key results: Incubation of cells with exogenous cAMP was followed by interstitial accumulation of 5′-AMP and adenosine, a phenomenon inhibited by selective inhibitors of ecto-phosphodiesterase (DPSPX) and ecto-nucleotidase (AMPCP). Activation of adenylyl cyclase (AC) in cultured cells with forskolin or isoprenaline increased cAMP efflux and extracellular generation of 5′-AMP and adenosine. Extracellular cAMP-adenosine pathway was also observed after direct and receptor-dependent stimulation of AC in rat extensor muscle ex vivo. These events were attenuated by probenecid, an inhibitor of ATP binding cassette family transporters. Conclusions and implications: Our results show the existence of an extracellular biochemical cascade that converts cAMP into adenosine. The functional relevance of this extracellular signalling system may involve a feedback modulation of cellular response initiated by several G protein-coupled receptor ligands, amplifying cAMP influence to a paracrine mode, through its metabolite, adenosine. PMID:18157164

  18. Activation of Adenylyl Cyclase Causes Stimulation of Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Thomas Pleli

    2018-03-01

    Full Text Available Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA and Epac, and an efflux of cAMP, the function of which is still unclear. Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2 inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA. Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors. In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors. Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.

  19. Extracellular adenosine controls NKT-cell-dependent hepatitis induction.

    Science.gov (United States)

    Subramanian, Meenakshi; Kini, Radhika; Madasu, Manasa; Ohta, Akiko; Nowak, Michael; Exley, Mark; Sitkovsky, Michail; Ohta, Akio

    2014-04-01

    Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR deficiency results in much exaggerated acute hepatitis, indicating nonredundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by concanavalin A (Con A) or α-galactosylceramide in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-galactosylceramide induced more severe hepatitis in A2AR-deficient mice than in WT controls. Transfer of A2AR-deficient NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT-cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Liposome-encapsulated chemotherapy

    DEFF Research Database (Denmark)

    Børresen, B.; Hansen, A. E.; Kjær, A.

    2018-01-01

    Cytotoxic drugs encapsulated into liposomes were originally designed to increase the anticancer response, while minimizing off-target adverse effects. The first liposomal chemotherapeutic drug was approved for use in humans more than 20years ago, and the first publication regarding its use...... to inherent issues with the enhanced permeability and retention effect, the tumour phenomenon which liposomal drugs exploit. This effect seems very heterogeneously distributed in the tumour. Also, it is potentially not as ubiquitously occurring as once thought, and it may prove important to select patients...... not resolve the other challenges that liposomal chemotherapy faces, and more work still needs to be done to determine which veterinary patients may benefit the most from liposomal chemotherapy....

  1. Combined radiotherapy-chemotherapy

    International Nuclear Information System (INIS)

    Steel, G.G.

    1989-01-01

    This paper presents the clinically confirmed benefits of combined chemotherapy-radiotherapy. They have been found in a small group of diseases that respond to chemotherapy alone. According to the author, only when a drug or drug combination has the ability to eradicate occult disease or substantially to reduce the size of objectively measurable disease is there likely to be an demonstrable benefit from its use in conjunction with radiotherapy. It is the author's belief that the immediate future lies in selecting drugs and patients in which a good chemotherapeutic response can be expected, avoiding drugs that seriously enhance radiation damage to normal tissues and keeping drug and radiation treatments far enough apart in time to minimize interactions

  2. Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression

    Science.gov (United States)

    Headrick, John P; Willems, Laura; Ashton, Kevin J; Holmgren, Kirsten; Peart, Jason; Matherne, G Paul

    2003-01-01

    The genesis of the ischaemia intolerant phenotype in aged myocardium is poorly understood. We tested the hypothesis that impaired adenosine-mediated protection contributes to ischaemic intolerance, and examined whether this is countered by A1 adenosine receptor (A1AR) overexpression. Responses to 20 min ischaemia and 45 min reperfusion were assessed in perfused hearts from young (2–4 months) and moderately aged (16–18 months) mice. Post-ischaemic contractility was impaired by ageing with elevated ventricular diastolic (32 ± 2 vs. 18 ± 2 mmHg in young) and reduced developed (37 ± 3 vs. 83 ± 6 mmHg in young) pressures. Lactate dehydrogenase (LDH) loss was exaggerated (27 ± 2 vs. 16 ± 2 IU g−1in young) whereas the incidence of tachyarrhythmias was similar in young (15 ± 1 %) and aged hearts (16 ± 1 %). Functional analysis confirmed equipotent effects of 50 μm adenosine at A1 and A2 receptors in young and aged hearts. Nonetheless, while 50 μm adenosine improved diastolic (5 ± 1 mmHg) and developed pressures (134 ± 7 mmHg) and LDH loss (6 ± 2 IU g−1) in young hearts, it did not alter these variables in the aged group. Adenosine did attenuate arrhythmogenesis for both ages (to ∼10 %). In contrast to adenosine, 50 μm diazoxide reduced ischaemic damage and arrhythmogenesis for both ages. Contractile and anti-necrotic effects of adenosine were limited by 100 μm 5-hydroxydecanoate (5-HD) and 3 μm chelerythrine. Anti-arrhythmic effects were limited by 5-HD but not chelerythrine. Non-selective (100 μm 8-sulfophenyltheophylline) and A1-selective (150 nm 8-cyclopentyl-1,3-dipropylxanthine) adenosine receptor antagonism impaired ischaemic tolerance in young but not aged hearts. Quantitative real-time PCR and radioligand analysis indicated that impaired protection is unrelated to changes in A1AR mRNA transcription, or receptor density (∼8 fmol mg−1 protein in both age groups). However, A1AR overexpression improved tolerance for both ages, restoring

  3. Prevent Infections During Chemotherapy

    Centers for Disease Control (CDC) Podcasts

    2011-10-24

    This podcast discusses the importance of preventing infections in cancer patients who are undergoing chemotherapy. Dr. Lisa Richardson, CDC oncologist, talks about a new Web site for cancer patients and their caregivers.  Created: 10/24/2011 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP), Division of Cancer Prevention and Control (DCPC).   Date Released: 10/24/2011.

  4. Full dose CHOP chemotherapy

    International Nuclear Information System (INIS)

    Tominaga, Shinichi; Kondo, Makoto; Ando, Yutaka; Yamashita, Shoji; Uematsu, Minoru; Shigematsu, Naoyuki; Nishiguchi, Iku; Hashimoto, Shozo

    1985-01-01

    Since 1982, we have performed 125 courses of CHOP chemotherapy for 27 patients of malignancy, adhering to the original regimen as strictly as possible. CHOP chemotherapy consisted of Cyclophosphamide 750 mg/m 2 , iv, on day 1; Adriamycin 50 mg/m 2 , iv, on day 1; Vincristine 1.4 mg/m 2 , iv, on day 1 (maximum single dose 2.0 mg) and Prednisolone 50 mg/m 2 , po, day 1 through 5. The cycle was repeated every 21 days. As side effects, myelosuppression, hair loss, fever, nausea, vomiting, liver dysfunction, stomatitis, neuropathy, herpes zoster, arrhythmia and hemorrhagic cystitis were seen. Due to myelosuppression, twenty patients experienced febrile episodes at each nadir of WBC counts on 40 courses. However, any febrile patient did not have life threatening infection. Other side effects were also reversible. The radiotherapy of most patients was carried out as initially scheduled, except for 3 patients in whom irradiation was interrupted due to severe stomatitis or herpes zoster. We consider that CHOP chemotherapy is excellent in feasibility even when combined with radiotherapy. (author)

  5. Concurrent radiotherapy and chemotherapy

    International Nuclear Information System (INIS)

    Fu, K.K.

    1985-01-01

    The principal objective of combining chemotherapy with radiotherapy (XRT) for the treatment of advanced head and neck cancer is to improve the therapeutic ratio through the enhancement of local control and reduction of distant metastases without excessively enhancing normal tissue effects. Improved tumour control can result from sole additivity of either therapy or direct interactions between drug and radiation leading to increased tumour cell kill. Chemotherapy may sensitize the cells to radiation, interfere with repair of sublethal or potentially lethal radiation damage, induce cell synchrony, and reduce tumour mass leading to reoxygenation and decreased fraction of resistant hypoxic cells. Radiation may improve drug accessibility to tumour cells and reduce tumour volume leading to increased cell proliferation and chemosensitivity. If the enhanced effects of combined therapy are purely additive, then the two modalities can be administered either sequentially or concurrently with the same results. However, if the enhanced effects result from the direct interaction between drug and radiation, it is necessary that the two modalities be administered concurrently and in close temporal proximity. This review summarizes the results of clinical studies in which chemotherapy was administered concurrently during the course of radiotherapy for patients with previously untreated advanced squamous cell carcinoma in the head and neck

  6. The crystal structure of the hexameric purine nucleoside phosphorylase from Bacillus subtilis in complex with adenosine

    Energy Technology Data Exchange (ETDEWEB)

    Giuseppe, P.O.; Meza, A.N.; Martins, N.H.; Santos, C.R.; Murakami, M.T. [Laboratorio Nacional de Luz Sincrotron (LNLS), Campinas, SP (Brazil)

    2012-07-01

    Full text: Purine nucleoside phosphorylases (PNPs) play a key role in the purine-salvage pathway in both prokaryotes and eukaryotes. Its ribosyltransferase activity is of great biotechnological interest due to potential application in the synthesis of nucleoside analogues used in the treatment of antiviral infections and in anticancer chemotherapy. Trimeric PNPs are found mainly in vertebrates and are specific for 6-oxo-purines whereas hexameric PNPs are prevalent in prokaryotes and exhibit a broad range of substrates including 6-oxo and 6-amino purines. BsPNP233, the hexameric PNP from B. subtilis, is able to catalyze the bioconversion of ribavirin, an anti-viral drug, and is relatively thermostable, being a good target for industrial use. Here we report the crystal structures of BsPNP233 in the apo form and in complex with adenosine solved at 2.65 and 1.91 resolution, respectively. The apo and ligand-bound BsPNP233 subunits superposed with an overall r.m.s. deviation of 0.31 for all C{alpha} atoms, which suggests that no major conformational changes occur upon substrate binding. Based on the crystal structure of BsPNP233 in complex with adenosine we have defined the active site residues implicated in binding the ribose (H4{sup *}, R43{sup *}, M64, R87, E178, M179, E180) and the nitrogenous base (S90, C91, G92, S202, V177, F159). These residues are highly conserved among the bacterial hexameric PNPs, suggesting they share the same mode of interaction with the substrates. This work will probably contribute to a better understanding of the molecular basis for the broad substrate specificity of hexameric PNPs and to projects aiming the rational design of PNPs for industrial purposes. (author)

  7. Regioselective 1-N-Alkylation and Rearrangement of Adenosine Derivatives.

    Science.gov (United States)

    Oslovsky, Vladimir E; Drenichev, Mikhail S; Mikhailov, Sergey N

    2015-01-01

    Several methods for the preparation of some N(6)-substituted adenosines based on selective 1-N-alkylation with subsequent Dimroth rearrangement were developed. The proposed methods seem to be effective for the preparation of natural N(6)-isopentenyl- and N(6)-benzyladenosines, which are known to possess pronounced biological activities. Direct 1-N-alkylation of 2',3',5'-tri-O-acetyladenosine and 3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides in N,N-dimethylformamide (DMF) in the presence of BaCO3 and KI gave 1-N-substituted derivatives with quantitative yields, whereas 1-N-alkylation of adenosine was accompanied by significant O-alkylation. Moreover, the reaction of trimethylsilyl derivatives of N(6)-acetyl-2',3',5'-tri-O-acetyladenosine and N(6)-acetyl-3',5'-di-O-acetyl-2'-deoxyadenosine with alkyl halides leads to the formation of the stable 1-N-substituted adenosines. Dimroth rearrangement of 1-N-substituted adenosines in aqueous ammonia yields pure N(6)-substituted adenosines.

  8. TOR induced resistance to toxic adenosine analogs in Leishmania brought about by the internalization and degradation of the adenosine permease

    Science.gov (United States)

    Detke, Siegfried

    2007-01-01

    TOR is an atypical multidrug resistance protein present in the human protozoan parasite, Leishmania. Resistance to the toxic adenosine analog tubercidin was brought about by redirecting the adenosine permease from the plasma membrane to the multivesicular tubule lysosome. The cells became resistant to tubercidin because they were unable to take up and accumulate this toxic purine. The domain which was recognized by TOR in this internalization pathway was identified by expressing portions of this transporter in Leishmania and assessing whether they were capable of hindering the multidrug resistance capability of TOR. This approach identified the adenosine permease region spanning Met289 to Trp305. This region was also the epitope recognized by the internalization mechanism. An internal deletion mutant lacking Met289-Trp305 was functionally active but could no longer be internalized in cells with high TOR levels. The internalization and altered trafficking of the adenosine permease by TOR was observed in yeast and human embryonic kidney cells co-expressing these two Leishmania proteins indicating that the internalization process was conserved in evolutionary diverse organisms. The inability of Saccharomyces with a temperature sensitive ubiquitin ligase to internalize adenosine permease suggested that ubiquitination was involved in this altered trafficking. PMID:17428463

  9. Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Schwarzschild, Michael A; Xu, Kui

    2008-01-01

    ...) that are leading candidate modulators of PD risk. In Year 4 we have obtained and reported evidence that the adenosine receptor blocker caffeine as well as specific genetic depletion of the A2A subtype of adenosine receptor...

  10. Fractional Flow Reserve: Intracoronary versus intravenous adenosine induced maximal coronary hyperemia

    Directory of Open Access Journals (Sweden)

    P.S. Sandhu

    2013-03-01

    Conclusions: This study suggests that IC adenosine is equivalent to IV infusion for the determination of FFR. The administration of IC adenosine is easy to use, cost effective, safe and associated with fewer systemic events.

  11. Role of adenosine as adjunctive therapy in acute myocardial infarction.

    Science.gov (United States)

    Forman, Mervyn B; Stone, Gregg W; Jackson, Edwin K

    2006-01-01

    Although early reperfusion and maintained patency is the mainstay therapy for ST elevation myocardial infarction, experimental studies demonstrate that reperfusion per se induces deleterious effects on viable ischemic cells. Thus "myocardial reperfusion injury" may compromise the full potential of reperfusion therapy and may account for unfavorable outcomes in high-risk patients. Although the mechanisms of reperfusion injury are complex and multifactorial, neutrophil-mediated microvascular injury resulting in a progressive decrease in blood flow ("no-reflow" phenomenon) likely plays an important role. Adenosine is an endogenous nucleoside found in large quantities in myocardial and endothelial cells. It activates four well-characterized receptors producing various physiological effects that attenuate many of the proposed mechanisms of reperfusion injury. The cardio-protective effects of adenosine are supported by its role as a mediator of pre- and post-conditioning. In experimental models, administration of adenosine in the peri-reperfusion period results in a marked reduction in infarct size and improvement in ventricular function. The cardioprotective effects in the canine model have a narrow time window with the drug losing its effect following three hours of ischemia. Several small clinical studies have demonstrated that administration of adenosine with reperfusion therapy reduces infarct size and improves ventricular function. In the larger AMISTAD and AMISTAD II trials a 3-h infusion of adenosine as an adjunct to reperfusion resulted in a striking reduction in infarct size (55-65%). Post hoc analysis of AMISTAD II showed that this was associated with significantly improved early and late mortality in patients treated within 3.17 h of symptoms. An intravenous infusion of adenosine for 3 h should be considered as adjunctive therapy in high risk-patients undergoing reperfusion therapy.

  12. Purification and properties of adenosine kinase from rat brain.

    Science.gov (United States)

    Yamada, Y; Goto, H; Ogasawara, N

    1980-12-04

    Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) has been purified to apparent homogeneity from rat brain by (NH4)2SO4 fractionation, affinity chromatography on AMP-Sepharose 4B, gel filtration with Sephadex G-100, and DE-52 cellulose column chromatography. The yield was 56% of the initial activity with a final specific activity of 7.8 mumol/min per mg protein. The molecular weight was estimated as 38 000 by gel filtration with Sephadex G-100 and 41 000 by acrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS). The enzyme catalyzed the phosphorylation of adenosine, deoxyadenosine, arabinoadenosine, inosine and ribavirin. The activity of deoxyadenosine phosphorylation was 20% that of adenosine phosphorylation. The pH optimum profile was biphasic; a sharp pH optimum at pH 5.5 and a broad pH optimum at pH 7.5-8.5. The Km value for adenosine was 0.2 microM and the maximum activity was observed at 0.5 microM. At higher concentrations of adenosine, the activity was strongly inhibited. The Km value for ATP was 0.02 mM and that for Mg2+ was 0.1 mM. GTP, dGTP, dATP and UTP were also proved to be effective phosphate donors. Co2+ was as effective as Mg2+, and Ca2+, Mn2+ or Ni2+ showed about 50% of the activity for Mg2+. The kinase is quite unstable, but stable in the presence of a high concentration of salt; e.g., 0.15 M KCl.

  13. Tween 20-stabilized gold nanoparticles combined with adenosine triphosphate-BODIPY conjugates for the fluorescence detection of adenosine with more than 1000-fold selectivity

    Energy Technology Data Exchange (ETDEWEB)

    Hung, Szu-Ying; Shih, Ya-Chen [Department of Chemistry, National Sun Yat-sen University, Taiwan (China); Tseng, Wei-Lung, E-mail: tsengwl@mail.nsysu.edu.tw [Department of Chemistry, National Sun Yat-sen University, Taiwan (China); School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Taiwan (China); Center for Nanoscience and Nanotechnology, National Sun Yat-sen University, Taiwan (China); Center for Stem Cell Research, Kaohsiung Medical University, Taiwan (China)

    2015-02-01

    Graphical abstract: A simple, enzyme-free, label-free, sensitive and selective system was developed for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles as an efficient quencher for boron dipyrromethene-conjugated adenosine 5′-triphosphate and as a recognition element for adenosine. - Highlights: • The proposed method can detect adenosine with more than 1000-fold selectivity. • The analysis of adenosine is rapid (∼6 min) using the proposed method. • This method provided better sensitivity for adenosine as compared to aptamer-based sensors. • This method can be applied for the determination of adenosine in urine. - Abstract: This study describes the development of a simple, enzyme-free, label-free, sensitive, and selective system for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles (Tween 20-AuNPs) as an efficient fluorescence quencher for boron dipyrromethene-conjugated adenosine 5′-triphosphate (BODIPY-ATP) and as a recognition element for adenosine. BODIPY-ATP can interact with Tween 20-AuNPs through the coordination between the adenine group of BODIPY-ATP and Au atoms on the NP surface, thereby causing the fluorescence quenching of BODIPY-ATP through the nanometal surface energy transfer (NSET) effect. When adenosine attaches to the NP surface, the attached adenosine exhibits additional electrostatic attraction to BODIPY-ATP. As a result, the presence of adenosine enhances the efficiency of AuNPs in fluorescence quenching of BODIPY-ATP. The AuNP-induced fluorescence quenching of BODIPY-ATP progressively increased with an increase in the concentration of adenosine; the detection limit at a signal-to-noise ratio of 3 for adenosine was determined to be 60 nM. The selectivity of the proposed system was more than 1000-fold for adenosine over any adenosine analogs and other nucleotides. The proposed system combined with a phenylboronic acid-containing column was successfully applied to the

  14. Tween 20-stabilized gold nanoparticles combined with adenosine triphosphate-BODIPY conjugates for the fluorescence detection of adenosine with more than 1000-fold selectivity

    International Nuclear Information System (INIS)

    Hung, Szu-Ying; Shih, Ya-Chen; Tseng, Wei-Lung

    2015-01-01

    Graphical abstract: A simple, enzyme-free, label-free, sensitive and selective system was developed for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles as an efficient quencher for boron dipyrromethene-conjugated adenosine 5′-triphosphate and as a recognition element for adenosine. - Highlights: • The proposed method can detect adenosine with more than 1000-fold selectivity. • The analysis of adenosine is rapid (∼6 min) using the proposed method. • This method provided better sensitivity for adenosine as compared to aptamer-based sensors. • This method can be applied for the determination of adenosine in urine. - Abstract: This study describes the development of a simple, enzyme-free, label-free, sensitive, and selective system for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles (Tween 20-AuNPs) as an efficient fluorescence quencher for boron dipyrromethene-conjugated adenosine 5′-triphosphate (BODIPY-ATP) and as a recognition element for adenosine. BODIPY-ATP can interact with Tween 20-AuNPs through the coordination between the adenine group of BODIPY-ATP and Au atoms on the NP surface, thereby causing the fluorescence quenching of BODIPY-ATP through the nanometal surface energy transfer (NSET) effect. When adenosine attaches to the NP surface, the attached adenosine exhibits additional electrostatic attraction to BODIPY-ATP. As a result, the presence of adenosine enhances the efficiency of AuNPs in fluorescence quenching of BODIPY-ATP. The AuNP-induced fluorescence quenching of BODIPY-ATP progressively increased with an increase in the concentration of adenosine; the detection limit at a signal-to-noise ratio of 3 for adenosine was determined to be 60 nM. The selectivity of the proposed system was more than 1000-fold for adenosine over any adenosine analogs and other nucleotides. The proposed system combined with a phenylboronic acid-containing column was successfully applied to the

  15. Adjuvant chemotherapy for osteosarcoma.

    Science.gov (United States)

    Eilber, F R; Rosen, G

    1989-08-01

    From this review of chemotherapy trials, several observations can be made. Osteosarcoma is a complex disease involving multiple histologies, each with a different prognosis. Prognostic factors that have been shown to be important include anatomic location of the primary tumor, stage at presentation (patients with metastatic or local recurrent disease fair far worse than those with primary disease), age at onset (children fair worse than the teenager with osteosarcoma), and location within the extremity (patients with more distal tumors fairing better than patients with more proximal tumors). There is convincing evidence for the efficacy of chemotherapeutic agents such as methotrexate in high doses (at least 8 g/m2 for adults, 12 g/m2 for children), Adriamycin, and cisplatin. The combination of Adriamycin and cisplatin appears to be more beneficial relative to either one of these agents alone. The efficacy of the combination of BCD as a triple-drug regimen, although useful in several different trials, has not been convincingly shown. Finally, from several of the recent randomized trials, it appears, that chemotherapeutic regimens containing an Adriamycin and cisplatin combination appear to be superior to those that do not include this combination. However, these observations are made from a historical perspective and have not been conclusively proven by randomized prospective investigations. The observations concerning the natural history of the disease and the activity of various chemotherapeutic agents suggest certain clinical practice algorithms. Essential staging procedures would include a bone scan looking for multifocal or metastatic disease, and CT scans of the chest looking for metastases to the lung. From all studies, it is apparent that surgery is mandatory for the primary tumor and should be an integral portion of all treatment methods. Chemotherapy should be considered for all patients with osteosarcoma, and the essential drugs in the regimen appear at

  16. Why do premature newborn infants display elevated blood adenosine levels?

    Science.gov (United States)

    Panfoli, Isabella; Cassanello, Michela; Bruschettini, Matteo; Colella, Marina; Cerone, Roberto; Ravera, Silvia; Calzia, Daniela; Candiano, Giovanni; Ramenghi, Luca

    2016-05-01

    Our preliminary data show high levels of adenosine in the blood of very low birth weight (VLBW) infants, positively correlating to their prematurity (i.e. body weight class). This prompted us to look for a mechanism promoting such impressive adenosine increase. We hypothesized a correlation with oxygen challenge. In fact, it is recognized that either oxygen lack or its excess contribute to the pathogenesis of the injuries of prematurity, such as retinopathy (ROP) and periventricular white matter lesions (PWMI). The optimal concentration of oxygen for resuscitation of VLBW infants is currently under revision. We propose that the elevated adenosine blood concentrations of VLBW infants recognizes two sources. The first could be its activity-dependent release from unmyelinated brain axons. Adenosine in this respect would be an end-product of the hypometabolic VLBW newborn unmyelinated axon intensely firing in response to the environmental stimuli consequent to premature birth. Adenosine would be eventually found in the blood due to blood-brain barrier immaturity. In fact, adenosine is the primary activity-dependent signal promoting differentiation of premyelinating oligodendrocyte progenitor cells (OPC) into myelinating cells in the Central Nervous System, while inhibiting their proliferation and inhibiting synaptic function. The second, would be the ecto-cellular ATP synthesized by the endothelial cell plasmalemma exposed to ambient oxygen concentrations due to premature breathing, especially in lung. ATP would be rapidly transformed into adenosine by the ectonucleotidase activities such as NTPDase I (CD39), and NT5E (CD73). An ectopic extra-mitochondrial aerobic ATP synthetic ability was reported in many cell plasma-membranes, among which endothelial cells. The potential implications of the cited hypotheses for the neonatology area would be great. The amount of oxygen administration for reviving of newborns would find a molecular basis for its assessment. VLBW

  17. Regulation of adenosine deaminase (ADA) on induced mouse experimental autoimmune uveitis (EAU) ?

    OpenAIRE

    Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan; Shao, Hui; Kaplan, Henry J.; Sun, Deming

    2016-01-01

    Adenosine is an important regulator of the immune response and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies have shown that adenosine receptor (AR) agonists can be either anti- or pro-inflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoim...

  18. Role of Adenosine Receptor A2A in Traumatic Optic Neuropathies (Addendum)

    Science.gov (United States)

    2016-03-01

    diabetic retinopathy . Life Sci. 2013 Jul 30;93(2-3):78-88. doi: 10.1016/j.lfs.2013.05.024. Epub 2013 Jun 12.PMID:23770229 7 AIMS: This study was...undertaken to determine the effect of an adenosine kinase inhibitor (AKI) in diabetic retinopathy (DR). We have shown previously that adenosine signaling...reported recently that adenosine kinase upregulated in retinal tissue of diabetic retinopathy (Elsherbiny et al., 2013). Adenosine kinase (ADK) converts

  19. DMPD: Shaping of monocyte and macrophage function by adenosine receptors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17056121 Shaping of monocyte and macrophage function by adenosine receptors. Hasko ...tml) (.csml) Show Shaping of monocyte and macrophage function by adenosine receptors. PubmedID 17056121 Titl...e Shaping of monocyte and macrophage function by adenosine receptors. Authors Has

  20. Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia.

    Science.gov (United States)

    Huang, Aji; Wu, Hongyu; Iriyama, Takayuki; Zhang, Yujin; Sun, Kaiqi; Song, Anren; Liu, Hong; Peng, Zhangzhe; Tang, Lili; Lee, Minjung; Huang, Yun; Ni, Xin; Kellems, Rodney E; Xia, Yang

    2017-07-01

    Preeclampsia is a prevalent pregnancy hypertensive disease with both maternal and fetal morbidity and mortality. Emerging evidence indicates that global placental DNA hypomethylation is observed in patients with preeclampsia and is linked to altered gene expression and disease development. However, the molecular basis underlying placental epigenetic changes in preeclampsia remains unclear. Using 2 independent experimental models of preeclampsia, adenosine deaminase-deficient mice and a pathogenic autoantibody-induced mouse model of preeclampsia, we demonstrate that elevated placental adenosine not only induces hallmark features of preeclampsia but also causes placental DNA hypomethylation. The use of genetic approaches to express an adenosine deaminase minigene specifically in placentas, or adenosine deaminase enzyme replacement therapy, restored placental adenosine to normal levels, attenuated preeclampsia features, and abolished placental DNA hypomethylation in adenosine deaminase-deficient mice. Genetic deletion of CD73 (an ectonucleotidase that converts AMP to adenosine) prevented the elevation of placental adenosine in the autoantibody-induced preeclampsia mouse model and ameliorated preeclampsia features and placental DNA hypomethylation. Immunohistochemical studies revealed that elevated placental adenosine-mediated DNA hypomethylation predominantly occurs in spongiotrophoblasts and labyrinthine trophoblasts and that this effect is independent of A2B adenosine receptor activation in both preeclampsia models. Extending our mouse findings to humans, we used cultured human trophoblasts to demonstrate that adenosine functions intracellularly and induces DNA hypomethylation without A2B adenosine receptor activation. Altogether, both mouse and human studies reveal novel mechanisms underlying placental DNA hypomethylation and potential therapeutic approaches for preeclampsia. © 2017 American Heart Association, Inc.

  1. The role of glial adenosine receptors in neural resilience and the neurobiology of mood disorders

    NARCIS (Netherlands)

    Calker, D; Biber, K

    2005-01-01

    Adenosine receptors were classified into A(1)- and A(2)-receptors in the laboratory of Bernd Hamprecht more than 25 years ago. Adenosine receptors are instrumental to the neurotrophic effects of glia cells. Both microglia and astrocytes release after stimulation via adenosine receptors factors that

  2. Physical exercise during adjuvant chemotherapy

    NARCIS (Netherlands)

    van Waart, H.

    2017-01-01

    This thesis evaluates the effect of physical exercise during chemotherapy. In chapter two the study design, rationale and methods of the Physical exercise during Adjuvant Chemotherapy Study (PACES) are described. Chapter three presents the effects of the randomized controlled trial evaluating a

  3. Gene expression profiles in adenosine-treated human mast cells ...

    African Journals Online (AJOL)

    Gene expression profiles in adenosine-treated human mast cells. ... SW Kang, JE Jeong, CH Kim, SH Choi, SH Chae, SA Jun, HJ Cha, JH Kim, YM Lee, YS ... beta 4, ring finger protein, high-mobility group, calmodulin 2, RAN binding protein, ...

  4. PET imaging of adenosine A2A receptors

    NARCIS (Netherlands)

    Zhou, Xiaoyun

    2017-01-01

    This thesis describes the development and evaluation of [11C]preladenant as a novel radioligand for in vivo imaging of adenosine A2A receptors in the brain with positron-emission tomography (PET). The 11C-labeled drug [11C]preladenant was produced with high radiochemical yield and specific activity.

  5. Spectral studies of lanthanide-nucleic acid component interaction: complexes of adenine, adenosine, adenosine 5'-mono-, adenosine 5'-di- and adenosine 5' tri-phosphates with praseodymium(III)

    International Nuclear Information System (INIS)

    Joseph, George; Anjaiah, K.; Misra, S.N.

    1990-01-01

    The interactions of adenine, adenosine, adenosine 5'-mono-, adenosine 5'-di-and adenosine 5'-tri-phosphates with praseodymium(III) have been studied in different stoichiometries and at varying hydrogen ion concentrations by absorption spectral studies. The sharp bands in the spectra have been individually analysed by Gaussian curve analysis, and various spectral parameters have been computed using partial and multiple regression methods on an HP-1000/45 computer. The changes in and the magnitudes of these parameters have been correlated with the degrees of outer- and inner-sphere coordination around praseodymium(III). Crystalline complexes of the type: Pr(nucleotide) 2 (H 2 O) 2 (where nucleotide = AMP, ADP and ATP) have been characterized on the basis of analytical, IR and 1 H NMR spectral data. These studies indicate that the binding of the nucleotide is through phosphoric oxygen. These complexes in aqueous medium show significant ionization which supports the observed weak 4f-4f bands, lower values of nephelauxetic effect and the parameters derived from coulombic and spin-orbit interactions. (author). 3 t abs., 28 refs

  6. Plasma Adenosine Deaminase Enzyme Reduces with Treatment of ...

    African Journals Online (AJOL)

    olayemitoyin

    Plasma Adenosine Deaminase Enzyme Reduces with Treatment of Pulmonary Tuberculosis in Nigerian Patients: Indication for. Diagnosis and Treatment Monitoring. Ige O.a, Edem V.F.b and Arinola O.G.b,*. aDepartment of Medicine, University of Ibadan, Ibadan, Nigeria b Department of Chemical Pathology,. University of ...

  7. Contributory role of adenosine deaminase in metabolic syndrome ...

    African Journals Online (AJOL)

    Adenosine deaminase (ADA) is an enzyme of purine metabolism commonly associated with severe combined immunodeficiency disease and believed to modulate bioactivity of insulin. Its contributory role in patients with metabolic syndrome (having features such as obesity, insulin resistance, fasting hyperglycaemia, lipid ...

  8. Adenosine receptor modulation of seizure susceptibility in rats

    International Nuclear Information System (INIS)

    Szot, P.

    1987-01-01

    Adenosine is considered to be a neuromodulator or cotransmitter in the periphery and CNS. This neuromodulatory action of adenosine may be observed as an anticonvulsant effect. Dose-response curves for R-phenylisopropyladenosine (PIA), cycohexyladenosine (CHA), 2-chloroadenosine (2-ClAdo), N-ethylcarboxamidoadenosine (NECA) and S-PIA were generated against PTZ seizure thresholds in the rat. The rank order of potency for adenosine agonists to elevate PTZ seizure threshold was R-PIA > 2-ClAdo > NECA > CHA > S-PIA. R-PIA was approximately 80-fold more potent than S-PIA. This 80-fold difference in potency between the diasteriomers of PIA was consistent with an A 1 adenoise receptor-mediated response. The anticonvulsant action of 2-ClAdo was reversed by pretreatment with theoplylline. Chronic administration of theophylline significantly increased the specific binding of 3 H-cyclohexyladenosine in membranes of the cerebral cortex and cerebellum of the rat. Chronic exposure to theophylline produced a significant increase in the densities of both the high- and low-affinity forms of A 1 adenosine receptors in the cerebral cortex

  9. Cerebral adenosine A1 receptors are upregulated in rodent encephalitis

    NARCIS (Netherlands)

    Paul, Souman; Khanapur, Shivashankar; Boersma, Wytske; Sijbesma, Jurgen W.; Ishiwata, Kiichi; Elsinga, Philip H.; Meerlo, Peter; Doorduin, Janine; Dierckx, Rudi A.; van Waarde, Aren

    2014-01-01

    Adenosine A(1) receptors (A(1) Rs) are implied in the modulation of neuroinflammation. Activation of cerebral A(1) Rs acts as a brake on the microglial response after traumatic brain injury and has neuroprotective properties in animal models of Parkinson's disease and multiple sclerosis.

  10. Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

    Directory of Open Access Journals (Sweden)

    Sergi Ferré

    2007-01-01

    Full Text Available By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS. Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit, where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

  11. Contributory role of adenosine deaminase in metabolic syndrome

    African Journals Online (AJOL)

    olayemitoyin

    Cytokine balance was also changed in diet induced obese mice (Mito and Hiyosin, 2002). Although Mito et al (2000) ... immunity in man (Sadasivudu et al, 1982) adenosine deaminase modulates cell growth (Lelieuve et al, .... Colgiuri, S. (2002) The Carnivore Connection- evolution aspect of insulin resistance. Eur. J. Clin.

  12. 21 CFR 864.7040 - Adenosine triphosphate release assay.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Adenosine triphosphate release assay. 864.7040 Section 864.7040 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES HEMATOLOGY AND PATHOLOGY DEVICES Hematology Kits and Packages § 864.7040...

  13. The role of adenosine receptor agonists in regulation of hematopoiesis

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Weiterová, Lenka; Hoferová, Zuzana

    2011-01-01

    Roč. 16, č. 1 (2011), s. 675-685 ISSN 1420-3049 R&D Projects: GA MO OVBIOFYZ20101; GA ČR(CZ) GA305/08/0158 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : adenosine receptors * hematopoiesis * myelosuppression Subject RIV: BO - Biophysics Impact factor: 2.386, year: 2011

  14. A comparison of adenosine and arbutamine for myocardial perfusion imaging

    International Nuclear Information System (INIS)

    Anagnostopoulos, C.; Pennell, D.; Francis, J.; Serup-Hansen, K.; Davies, G.; Underwood, R.

    1998-01-01

    We have compared our standard stress protocol (adenosine combined with exercise) with the new stress agent arbutamine, for thallium-201 myocardial perfusion imaging (MPI) in order to assess the comparative value of arbutamine. We studied 23 patients referred for MPI, and each patient had two studies (18 males, median age 66 years, five with previous myocardial infarction). Uptake scores were assigned to each of nine segments, and the extent and severity of defects were measured using a polar plot. Haemodynamic changes were greater with arbutamine (rate-pressure product increase 78% vs 51%, P = 0.003). Symptoms were experienced by 21 patients with arbutamine and 16 with adenosine (P = 0.07). Agreement between the techniques for classification of patients as normal or as having reversible, fixed or mixed defects was good (19 of 23 studies, 83%, κ = 0.76). Agreement for similar classification of segments was also good (82%, κ = 0.71). Segmental agreement for stress scores was good (86%, κ = 0.77). However, mean size of stress defect was larger with adenosine (83±52 pixels vs 65±48 pixels, P<0.05), though severity and reversibility were similar (P = NS). We conclude that arbutamine provides comparable results to those obtained with adenosine and exercise and that the observed differences are not clinically significant. (orig.)

  15. Safety of adenosine in stress cerebral perfusion imaging

    International Nuclear Information System (INIS)

    Hu Pengcheng; Gu Yushen; Liu Wenguan; Xiu Yan; Zhu Weimin; Chen Shuguang; Shi Hongcheng

    2009-01-01

    Objective: To evaluate the safety of adenosine as pharmacological stress agents in stress cerebral perfusion imaging. Methods: Eighty patients under investigation for suspected cerebral vessel disease were recruited. Each had a resting scan and a stress scan on different days. The adenosine stress protocol was as same as the protocol used in adenosine stress myocardial perfusion imaging. Subjective and objective side-effects were investigated during pharmacological stress procedure. Results: All patients completed the 6 min infusion protocol without premature termination on safety criteria or due to intolerable symptoms. 46 patients had mild side effects. 20 patients (25%) had dizziness, 12 patients (15%) had palpitation, 1 patient (1%) was hypotensive, 7 patients (9%) had dyspnoea, 4 patients (5%) felt hot, 3 patients (4%) had sweat, 4 patients (5%) had nausea, 6 patients (8%) had flushing, 19 patients (24%) had chest pain, 6 patients (8%) had abdomen pain, 3 patients (4%) had abnormal taste and 1 patient (1%) were thirsty. Transient ST change occurred in only 1 patient. Conclusion: Adenosine stress cerebral perfusion imaging is a safe diagnostic method with mild side effects. (authors)

  16. Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine

    Science.gov (United States)

    Naguib, Fardos N. M.; Rais, Reem H.; Al Safarjalani, Omar N.; el Kouni, Mahmoud H.

    2015-01-01

    Toxoplasma gondii has an extraordinarily ability to utilize adenosine (Ado) as the primary source of all necessary purines in this parasite which lacks de novo purine biosynthesis. The activity of T. gondii adenosine kinase (TgAK, EC 2.7.1.20) is responsible for this efficient salvage of Ado in T. gondii. To fully understand this remarkable efficiency of TgAK in the utilization of Ado, complete kinetic parameters of this enzyme are necessary. Initial velocity and product inhibition studies of TgAK demonstrated that the basic mechanism of this enzyme is a hybrid random bi-uni ping-pong uni-bi. Initial velocity studies showed an intersecting pattern, consistent with substrate-enzyme-co-substrate complex formation and a binding pattern indicating that binding of the substrate interferes with the binding of the co-substrate and vice versa. Estimated kinetic parameters were KAdo = 0.002 ± 0.0002 mM, KATP = 0.05 ± 0.008 mM, and Vmax = 920 ± 35 μmol/min/mg protein. Ado exhibited substrate inhibition suggesting the presence of more than one binding site for Ado on the enzyme. ATP relieved substrate inhibition by Ado. Thus, Ado also binds to the ATP binding site. AMP was competitive with ATP, inferring that AMP binds to the same site as ATP. AMP, ADP and ATP were non-competitive with Ado, therefore, none of these nucleotides binds to the Ado binding site. Combining ATP with ADP was additive. Therefore, the binding of either ATP or ADP does not interfere with the binding of the other. It is concluded that for every ATP consumed, TgAK generates three new AMPs. These findings along with the fact that a wide range of nucleoside 5′-mono, di, and triphosphates could substitute for ATP as phosphate donors in this reaction may explain the efficient and central role played by TgAK in the utilization of Ado as the major source from which all other purines can be synthesized in T. gondii. PMID:26112826

  17. Chromonychia Secondary to Chemotherapy

    Directory of Open Access Journals (Sweden)

    Marien Lopes

    2013-06-01

    Full Text Available Chemotherapy drugs can affect the skin and its appendages. Several clinical presentations can be observed, depending on the affected structure. The most common dermatological side effect is chromonychia. The main causative agents are: (1 cyclophosphamide, which can provoke a diffuse, black pigmentation, longitudinal striae and dark grey pigmentation located proximally on the nails; (2 doxorubicin, which promotes dark brown bands alternating with white striae and dark brown pigmentation in transverse bands, and (3 hydroxyurea, which produces a distal, diffuse, dark brown pigmentation. In the majority of cases, the effects are reversible after the suspension of the causative agent for a few months. We report a patient who developed chromonychia while undergoing treatment with cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine for acute lymphocytic leukemia.

  18. Feed-Forward Inhibition of CD73 and Upregulation of Adenosine Deaminase Contribute to the Loss of Adenosine Neuromodulation in Postinflammatory Ileitis

    Directory of Open Access Journals (Sweden)

    Cátia Vieira

    2014-01-01

    Full Text Available Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the “purinome” may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on A2A excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5′-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from released ATP, thus contributing to the prolonged inhibition of muscle-bound ecto-5′-nucleotidase/CD73 and to the delay of adenosine formation at the inflamed neuromuscular synapse. On the other hand, depression of endogenous adenosine accumulation may also occur due to enhancement of adenosine deaminase activity. Both membrane-bound and soluble forms of ecto-5′-nucleotidase/CD73 and adenosine deaminase were detected in the inflamed myenteric plexus. These findings provide novel therapeutic targets for inflammatory gut motility disorders.

  19. Mechanism of A2 adenosine receptor activation. I. Blockade of A2 adenosine receptors by photoaffinity labeling

    International Nuclear Information System (INIS)

    Lohse, M.J.; Klotz, K.N.; Schwabe, U.

    1991-01-01

    It has previously been shown that covalent incorporation of the photoreactive adenosine derivative (R)-2-azido-N6-p-hydroxy-phenylisopropyladenosine [(R)-AHPIA] into the A1 adenosine receptor of intact fat cells leads to a persistent activation of this receptor, resulting in a reduction of cellular cAMP levels. In contrast, covalent incorporation of (R)-AHPIA into human platelet membranes, which contain only stimulatory A2 adenosine receptors, reduces adenylate cyclase stimulation via these receptors. This effect of (R)-AHPIA is specific for the A2 receptor and can be prevented by the adenosine receptor antagonist theophylline. Binding studies indicate that up to 90% of A2 receptors can be blocked by photoincorporation of (R)-AHPIA. However, the remaining 10-20% of A2 receptors are sufficient to mediate an adenylate cyclase stimulation of up to 50% of the control value. Similarly, the activation via these 10-20% of receptors occurs with a half-life that is only 2 times longer than that in control membranes. This indicates the presence of a receptor reserve, with respect to both the extent and the rate of adenylate cyclase stimulation. These observations require a modification of the models of receptor-adenylate cyclase coupling

  20. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism.

    Science.gov (United States)

    Eltzschig, Holger K; Thompson, Linda F; Karhausen, Jorn; Cotta, Richard J; Ibla, Juan C; Robson, Simon C; Colgan, Sean P

    2004-12-15

    Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A(2A) and A(2B) receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5'-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation.

  1. Metabolic changes of cultured DRG neurons induced by adenosine using confocal microscopy imaging

    Science.gov (United States)

    Zheng, Liqin; Huang, Yimei; Chen, Jiangxu; Wang, Yuhua; Yang, Hongqin; Zhang, Yanding; Xie, Shusen

    2012-12-01

    Adenosine exerts multiple effects on pain transmission in the peripheral nervous system. This study was performed to use confocal microscopy to evaluate whether adenosine could affect dorsal root ganglia (DRG) neurons in vitro and test which adenosine receptor mediates the effect of adenosine on DRG neurons. After adding adenosine with different concentration, we compared the metabolic changes by the real time imaging of calcium and mitochondria membrane potential using confocal microscopy. The results showed that the effect of 500 μM adenosine on the metabolic changes of DRG neurons was more significant than others. Furthermore, four different adenosine receptor antagonists were used to study which receptor mediated the influences of adenosine on the cultured DRG neurons. All adenosine receptor antagonists especially A1 receptor antagonist (DPCPX) had effect on the Ca2+ and mitochondria membrane potential dynamics of DRG neurons. The above studies demonstrated that the effect of adenosine which may be involved in the signal transmission on the sensory neurons was dose-dependent, and all the four adenosine receptors especially the A1R may mediate the transmission.

  2. Heterogeneity of tumor chemosensitivity in ovarian epithelial cancer revealed using the adenosine triphosphate-tumor chemosensitivity assay.

    Science.gov (United States)

    Zhang, Jin; Li, Hongxia

    2015-05-01

    Ovarian cancer has a poor prognosis, primarily due to the heterogeneity in chemosensitivity among patients. In the present study, this heterogeneity was evaluated in ovarian epithelial cancer (OEC) using an in vitro adenosine triphosphate tumor chemosensitivity assay (ATP-TCA). Specimens were collected from 80 patients who underwent cytoreductive surgery. Viable ovarian cancer cells obtained from malignant tissues were tested for sensitivity to paclitaxel (PTX), carboplatin (CBP), topotecan (TPT), gemcitabine (GEM), docetaxel (TXT), etoposide, bleomycin and 4-hydroperoxycyclophosphamide using ATP-TCA. The sensitivity, specificity, positive predictive value and negative predictive value for the clinical chemotherapy sensitivity of OEC were 88.6, 77.8, 83 and 84.8%, respectively. PTX demonstrated the highest sensitivity of all agents tested (82.5% in all specimens, 85.7% in recurrent specimens), followed by CBP (58.8 and 60.7%, respectively). The sensitivities to PTX and docetaxel (PIII) or low-differentiated specimens, respectively. The present study indicated that ATP-TCA is an effective method for guiding the choice of chemotherapy drugs. Notable heterogeneity of chemosensitivity was observed in the OEC specimens.

  3. Acute emesis: moderately emetogenic chemotherapy

    DEFF Research Database (Denmark)

    Herrstedt, Jørn; Rapoport, Bernardo; Warr, David

    2011-01-01

    This paper is a review of the recommendations for the prophylaxis of acute emesis induced by moderately emetogenic chemotherapy as concluded at the third Perugia Consensus Conference, which took place in June 2009. The review will focus on new studies appearing since the Second consensus conference...... receiving multiple cycles of moderately emetogenic chemotherapy will be reviewed. Consensus statements are given, including optimal dose and schedule of serotonin(3) receptor antagonists, dexamethasone, and neurokinin(1) receptor antagonists. The most significant recommendations (and changes since the 2004...... version of the guidelines) are as follows: the best prophylaxis in patients receiving moderately emetogenic chemotherapy (not including a combination of an anthracycline plus cyclophosphamide) is the combination of palonosetron and dexamethasone on the day of chemotherapy, followed by dexamethasone...

  4. Uterine/Endometrial Cancer: Chemotherapy

    Science.gov (United States)

    ... with Your Treatment Team Treatment Surgery Surgical Staging Pathology of Ovarian Cancer Chemotherapy Radiation Therapy Hormone Therapy ... 20, 2016 January 17, 2017 February 21, 2017 March 22, 2017 April 18, 2017 May 16, 2017 ...

  5. The Role of Adenosine A2BR in Metastatic Melanoma

    Science.gov (United States)

    2017-07-01

    burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense...would like to interrogate the role of adenosine receptor (A2BR) in regulating primary tumor growth and metastasis in experimental models of melanoma...The positive control was a triple negative breast cancer cell line, E0771. To interrogate the role of A2BR in aiding tumor metastasis, we used VeCad

  6. Synthesis of adenosine triphosphate tritiated in position 2 and 8

    International Nuclear Information System (INIS)

    Cossery, Jean-Michel

    1986-01-01

    Adenosine triphosphate or ATP is an important molecule present at the cellular level in many fundamental biochemical mechanism, and the study of its metabolism is therefore of particular interest. In this thesis for pharmacy graduation, the author first describes the different steps of synthesis and purification leading to chloride-2-ATP, a precursor of the final tritiated molecule. Then, the author explains the tritiation of this molecule to obtain an ATP tritiated in position 2 and in position 8 [fr

  7. The emerging role of adenosine deaminases in insects

    Czech Academy of Sciences Publication Activity Database

    Doleželová, Eva; Žurovec, Michal; Doležal, T.; Šimek, Petr; Bryant, P. J.

    2005-01-01

    Roč. 35, č. 5 (2005), s. 381-389 ISSN 0965-1748 R&D Projects: GA ČR(CZ) GA204/04/1205; GA AV ČR(CZ) IAA5007107 Grant - others:United States National Science Foundation(US) 440860-21565 Institutional research plan: CEZ:AV0Z50070508 Keywords : adenosine deaminase * ADA * growth factor Subject RIV: ED - Physiology Impact factor: 2.733, year: 2005

  8. 5' adenosine monophosphate-activated protein kinase, metabolism and exercise.

    Science.gov (United States)

    Aschenbach, William G; Sakamoto, Kei; Goodyear, Laurie J

    2004-01-01

    The 5' adenosine monophosphate-activated protein kinase (AMPK) is a member of a metabolite-sensing protein kinase family that functions as a metabolic 'fuel gauge' in skeletal muscle. AMPK is a ubiquitous heterotrimeric protein, consisting of an alpha catalytic, and beta and gamma regulatory subunits that exist in multiple isoforms and are all required for full enzymatic activity. During exercise, AMPK becomes activated in skeletal muscle in response to changes in cellular energy status (e.g. increased adenosine monophosphate [AMP]/adenosine triphosphate [ATP] and creatine/phosphocreatine ratios) in an intensity-dependent manner, and serves to inhibit ATP-consuming pathways, and activate pathways involved in carbohydrate and fatty-acid metabolism to restore ATP levels. Recent evidence shows that although AMPK plays this key metabolic role during acute bouts of exercise, it is also an important component of the adaptive response of skeletal muscles to endurance exercise training because of its ability to alter muscle fuel reserves and expression of several exercise-responsive genes. This review discusses the putative roles of AMPK in acute and chronic exercise responses, and suggests avenues for future AMPK research in exercise physiology and biochemistry.

  9. Moonlighting adenosine deaminase: a target protein for drug development.

    Science.gov (United States)

    Cortés, Antoni; Gracia, Eduard; Moreno, Estefania; Mallol, Josefa; Lluís, Carme; Canela, Enric I; Casadó, Vicent

    2015-01-01

    Interest in adenosine deaminase (ADA) in the context of medicine has mainly focused on its enzymatic activity. This is justified by the importance of the reaction catalyzed by ADA not only for the intracellular purine metabolism, but also for the extracellular purine metabolism as well, because of its capacity as a regulator of the concentration of extracellular adenosine that is able to activate adenosine receptors (ARs). In recent years, other important roles have been described for ADA. One of these, with special relevance in immunology, is the capacity of ADA to act as a costimulator, promoting T-cell proliferation and differentiation mainly by interacting with the differentiation cluster CD26. Another role is the ability of ADA to act as an allosteric modulator of ARs. These receptors have very general physiological implications, particularly in the neurological system where they play an important role. Thus, ADA, being a single chain protein, performs more than one function, consistent with the definition of a moonlighting protein. Although ADA has never been associated with moonlighting proteins, here we consider ADA as an example of this family of multifunctional proteins. In this review, we discuss the different roles of ADA and their pathological implications. We propose a mechanism by which some of their moonlighting functions can be coordinated. We also suggest that drugs modulating ADA properties may act as modulators of the moonlighting functions of ADA, giving them additional potential medical interest. © 2014 Wiley Periodicals, Inc.

  10. ADENOSINE DEAMINASE ACTIVITY IN TYPE 2 DIABETES MELLITUS

    Directory of Open Access Journals (Sweden)

    Farija Peruvankuzhiyil

    2017-01-01

    Full Text Available BACKGROUND Altered blood levels of adenosine deaminase may help in predicting immunological dysfunction in diabetic individuals. But very few studies exist on ADA activity in type 2 diabetes mellitus. Aim of this study is to compare serum adenosine deaminase activity in type 2 diabetic patients with non-diabetic control. MATERIALS AND METHODS A comparative study design was used in data collection process. The study was conducted in 40 type 2 diabetes mellitus patients attending diabetic clinic or admitted in the medicine ward for metabolic control of diabetes in medical college, Calicut from January 2011 to January 2012. The adenosine deaminase (ADA level in the serum is measured by endpoint method in these patients. The results were expressed as mean and standard deviation. The statistical significance of the differences between the values was assessed by ANOVA. RESULTS Among 40 diabetic patients, mean ADA level in the serum is 38.56, SD±6.72 (min 30, max 53. Mean ADA level in the serum in the control group is 22.04±4.625 (min 13, max 29. CONCLUSION ADA level in the serum is found to be increased indicating its role as an important immunoenzyme marker in the aetiopathology of type 2 diabetes mellitus.

  11. The impact of adenosine pharmacologic stress combined with low-level exercise in patients undergoing myocardial perfusion imaging (BIWAKO adenosine-Ex trial)

    International Nuclear Information System (INIS)

    Monzen, Hajime; Hara, Masatake; Hirata, Makoto

    2011-01-01

    The combination of adenosine infusion with low-level exercise has become a common approach for inducing stress during stress myocardial perfusion imaging (MPI). We investigated stress MPI performed by combined low-level exercise and adenosine infusion. This combined protocol can decrease adverse reactions and reduce the effect of scattered rays from the liver. Subjects were clinically referred for a 53-min rest-stress Tc-99m Sestamibi MPI procedure using BIWAKO PROTOCOL. Ninety-eight patients (44.5%) underwent adenosine infusion with ergometer exercise testing and 122 patients (55.5%) underwent adenosine infusion without exercise testing. We evaluated the liver/heart (L/H) uptake ratio, background activity in the upper mediastinum, and adverse reactions. The L/H ratio and background activity were lower in the adenosine-exercise group than in the adenosine-non-exercise group (1.8±0.54 vs. 2.1±0.62, P<0.0056; 43.1±12.2 vs. 61.5±15.4, P<0.0001). The adenosine-exercise group had fewer adverse reactions than the adenosine-non-exercise group (11.2 vs. 19.7%). All of the adverse reactions were minor, with the exception of severe back pain in one case. The incidence of adverse reactions in our study was lower than that in previous studies for unknown reason. Adenosine infusion in combination with low-level exercise seems to result in higher-quality images and fewer adverse reactions than adenosine infusion without exercise. The combined protocol decreases adverse reactions and improves the quality of myocardial perfusion images by decreasing background activity. (author)

  12. Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes.

    Science.gov (United States)

    Morrison, R Ray; Teng, Bunyen; Oldenburg, Peter J; Katwa, Laxmansa C; Schnermann, Jurgen B; Mustafa, S Jamal

    2006-10-01

    To examine ischemic tolerance in the absence of A(1) adenosine receptors (A(1)ARs), isolated wild-type (WT) and A(1)AR knockout (A(1)KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A(1)AR deletion and/or ischemia-reperfusion. A(1)KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A(1)AR deletion. After 20 min of ischemia, CF was attenuated in A(1)KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A(1)KO hearts (54.4 +/- 5.1 vs. WT 81.1 +/- 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Postischemic efflux of LDH was greater in A(1)KO compared with WT hearts. Real-time RT-PCR demonstrated the absence of A(1)AR transcript in A(1)KO hearts, and the message for A(2A), A(2B), and A(3) adenosine receptors was similar in uninstrumented A(1)KO and WT hearts. Ischemia-reperfusion increased A(2B) mRNA expression 2.5-fold in both WT and A(1)KO hearts without changing A(1) or A(3) expression. In WT hearts, ischemia transiently doubled A(2A) mRNA, which returned to preischemic level upon reperfusion, a pattern not observed in A(1)KO hearts. Together, these data affirm the cardioprotective role of A(1)ARs and suggest that induced expression of other adenosine receptor subtypes may participate in the response to ischemia-reperfusion in isolated murine hearts.

  13. Acute hyperammonemia and systemic inflammation is associated with increased extracellular brain adenosine in rats

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Dale, Nicholas; Larsen, Fin Stolze

    2015-01-01

    ) and cerebral blood flow (CBF). We measured the adenosine concentration with biosensors in rat brain slices exposed to ammonia and in a rat model with hyperammonemia and systemic inflammation. Exposure to ammonia in concentrations from 0.15-10 mM led to increases in the cortical adenosine concentration up to 18......Acute liver failure (ALF) can lead to brain edema, cerebral hyperperfusion and intracranial hypertension. These complications are thought to be mediated by hyperammonemia and inflammation leading to altered brain metabolism. As increased levels of adenosine degradation products have been found...... in brain tissue of patients with ALF we investigated whether hyperammonemia could induce adenosine release in brain tissue. Since adenosine is a potent vasodilator and modulator of cerebral metabolism we furthermore studied the effect of adenosine receptor ligands on intracranial pressure (ICP...

  14. Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

    Directory of Open Access Journals (Sweden)

    Xia Hu

    2016-06-01

    Full Text Available The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here, we report that mice lacking adenosine deaminase (ADA, an enzyme necessary for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada−/− mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models: sickle cell disease mice, a model of severe pain with limited treatment, and complete Freund’s adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain. Mechanistically, we revealed that activation of adenosine A2B receptors on myeloid cells caused nociceptor hyperexcitability and promoted chronic pain via soluble IL-6 receptor trans-signaling, and our findings determined that prolonged accumulated circulating adenosine contributes to chronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets.

  15. Contraction induced secretion of VEGF from skeletal muscle cells is mediated by adenosine

    DEFF Research Database (Denmark)

    Høier, Birgitte; Olsen, Karina; Nyberg, Michael Permin

    2010-01-01

    and that the contraction induced secretion of VEGF is partially mediated via adenosine acting on A(2B) adenosine receptors. Moreover, the contraction induced secretion of VEGF protein from muscle is dependent on both PKA and MAPK activation, but only the MAPK pathway appears to be adenosine dependent.......The role of adenosine and contraction for secretion of VEGF in skeletal muscle was investigated in human subjects and rat primary skeletal muscle cells. Microdialysis probes were inserted into the thigh muscle of seven male subjects and dialysate was collected at rest, during infusion of adenosine...... and contraction caused secretion of VEGF (pcontraction induced secretion of VEGF protein was abolished by the A(2B) antagonist enprofyllin and markedly reduced by inhibition of PKA or MAPK. The results demonstrate that adenosine causes secretion of VEGF from human skeletal muscle cells...

  16. Cyclic adenosine 3:5-monophosphate binding proteins in Hartmannella culbertsoni

    International Nuclear Information System (INIS)

    Verma, A.K.; Krishna Murti, C.R.

    1976-01-01

    When 100, 000 g supernatant fractions of homogenates of Hartmannella culbertsoni were incubated with ('- 3 H)-cyclic adenosine 3 : 5 monophosphate and passed through a sephadex G-100 column, radioactivity appeared with protein fractions eluted after the void colume. About 75% radioactivity bound to these fractions was recovered as cyclic adenosine 3 : 5 monophosphate. Unlabelled cAMP diluted the amount of radioactivity bound. Adenosine, deoxyadenosine, 5-AMP, 3-AMP, ADP and ATP did not inhibit binding. (author)

  17. Traditional Acupuncture Triggers a Local Increase in Adenosine in Human Subjects

    OpenAIRE

    Takano, Takahiro; Chen, Xiaolin; Luo, Fang; Fujita, Takumi; Ren, Zeguang; Goldman, Nanna; Zhao, Yuanli; Markman, John D.; Nedergaard, Maiken

    2012-01-01

    Acupuncture is a form of Eastern medicine that has been practiced for centuries. Despite its long history and worldwide application, the biological mechanisms of acupuncture in relieving pain have been poorly defined. Recent studies in mice, however, demonstrate that acupuncture triggers increases in interstitial adenosine, which reduces the severity of chronic pain through adenosine A1 receptors, suggesting that adenosine-mediated antinociception contributes to the clinical benefits of acupu...

  18. Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

    OpenAIRE

    Chee, Hyun Keun; Oh, S. June

    2013-01-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine ...

  19. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells.

    Science.gov (United States)

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R Douglas

    2004-02-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2(A) adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

  20. A rapid enzymatic assay for high-throughput screening of adenosine-producing strains

    Science.gov (United States)

    Dong, Huina; Zu, Xin; Zheng, Ping; Zhang, Dawei

    2015-01-01

    Adenosine is a major local regulator of tissue function and industrially useful as precursor for the production of medicinal nucleoside substances. High-throughput screening of adenosine overproducers is important for industrial microorganism breeding. An enzymatic assay of adenosine was developed by combined adenosine deaminase (ADA) with indophenol method. The ADA catalyzes the cleavage of adenosine to inosine and NH3, the latter can be accurately determined by indophenol method. The assay system was optimized to deliver a good performance and could tolerate the addition of inorganic salts and many nutrition components to the assay mixtures. Adenosine could be accurately determined by this assay using 96-well microplates. Spike and recovery tests showed that this assay can accurately and reproducibly determine increases in adenosine in fermentation broth without any pretreatment to remove proteins and potentially interfering low-molecular-weight molecules. This assay was also applied to high-throughput screening for high adenosine-producing strains. The high selectivity and accuracy of the ADA assay provides rapid and high-throughput analysis of adenosine in large numbers of samples. PMID:25580842

  1. Adenosine A(2A) receptor dynamics studied with the novel fluorescent agonist Alexa488-APEC.

    Science.gov (United States)

    Brand, Frank; Klutz, Athena M; Jacobson, Kenneth A; Fredholm, Bertil B; Schulte, Gunnar

    2008-08-20

    G protein-coupled receptors, such as the adenosine A(2A) receptor, are dynamic proteins, which undergo agonist-dependent redistribution from the cell surface to intracellular membranous compartments, such as endosomes. In order to study the kinetics of adenosine A(2A) receptor redistribution in living cells, we synthesized a novel fluorescent agonist, Alexa488-APEC. Alexa488-APEC binds to adenosine A(2A) (K(i)=149+/-27 nM) as well as A(3) receptors (K(i)=240+/-160 nM) but not to adenosine A(1) receptors. Further, we characterized the dose-dependent increase in Alexa488-APEC-induced cAMP production as well as cAMP response element binding (CREB) protein phosphorylation, verifying the ligand's functionality at adenosine A(2A) but not A(2B) receptors. In live-cell imaging studies, Alexa488-APEC-induced adenosine A(2A) receptor internalization, which was blocked by the competitive reversible antagonist ZM 241385 and hyperosmolaric sucrose. Further, internalized adenosine A(2A) receptors co-localized with clathrin and Rab5, indicating that agonist stimulation promotes adenosine A(2A) receptor uptake through a clathrin-dependent mechanism to Rab5-positive endosomes. The basic characterization of Alexa488-APEC described here showed that it provides a useful tool for tracing adenosine A(2A) receptors in vitro.

  2. Molecular vibration-activity relationship in the agonism of adenosine receptors.

    Science.gov (United States)

    Chee, Hyun Keun; Oh, S June

    2013-12-01

    The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

  3. Molecular Vibration-Activity Relationship in the Agonism of Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Hyun Keun Chee

    2013-12-01

    Full Text Available The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands.

  4. Chemotherapy for carcinoma of stomach

    International Nuclear Information System (INIS)

    Salek, T.

    2011-01-01

    Of all patients with gastric cancer 80 % to 90 % are either diagnosed at an advanced stage when the tumour is inoperable, or develop a recurrence within five years after surgery. Chemotherapy clearly improves survival in comparison to best supportive care only. No chemotherapy regimen showed a survival benefit better than 5-fluorouracil alone in a phase III trial for advanced gastric cancer in 1990s, and several new cytotoxic agents became available in late 1990s. Thereafter, a couple of phase III trials supported the substitution of infusional 5-fluorouracil by orally administered agents and the replacement of cisplatin by oxaliplatin in early 2000s. Trastuzumab has succeeded in showing a survival benefit for patients with Her-2 positive gastric cancer which accounts for about 10 - 20 % of the cancer. This means that the door is opened to the new era of chemotherapy with molecular target agents and with individualization for advanced gastric cancer. (author)

  5. Adjuvant chemotherapy and cancer cure

    International Nuclear Information System (INIS)

    Bertino, J.R.

    1983-01-01

    The use of chemotherapy as an adjuvant to surgery and/or radiotherapy is well founded in experimental tumor systems and appears to be effective in patients in some circumstances. It is clear from both clinical and experimental studies that (1) the dose is important, (2) the earlier chemotherapy is started after primary therapy the better, and (3) combination chemotherapy may be more effective than single-agent treatment. The better the estimation of risk of recurrence, the better the assessment of the risk-benefit ratio with adjuvant therapy. Salvage therapy as well as relative risk of recurrence are considerations in the choice of patients to be treated. Finally, some evidence is presented to indicate that alkylating agents may not be necessary in combination regimens for adjuvant therapy if effective antimetabolite combinations are available

  6. Inosine Released from Dying or Dead Cells Stimulates Cell Proliferation via Adenosine Receptors

    Directory of Open Access Journals (Sweden)

    Yi Zhao

    2017-04-01

    Full Text Available IntroductionMany antitumor therapies induce apoptotic cell death in order to cause tumor regression. Paradoxically, apoptotic cells are also known to promote wound healing, cell proliferation, and tumor cell repopulation in multicellular organisms. We aimed to characterize the nature of the regenerative signals concentrated in the micromilieu of dead and dying cells.MethodsCultures of viable melanoma B16F10 cells, mouse fibroblasts, and primary human fibroblast-like synoviocytes (FLS in the presence of dead and dying cells, their supernatants (SNs, or purified agonists and antagonists were used to evaluate the stimulation of proliferation. Viable cell quantification was performed by either flow cytometry of harvested cells or by crystal violet staining of adherent cells. High-performance liquid chromatography and liquid chromatography coupled with mass spectrometry of cell SNs were deployed to identify the nature of growth-promoting factors. Coimplantation of living cells in the presence of SNs collected from dead and dying cells and specific agonists was used to evaluate tumor growth in vivo.ResultsThe stimulation of proliferation of few surviving cells by bystander dead cells was confirmed for melanoma cells, mouse fibroblasts, and primary FLS. We found that small soluble molecules present in the protein-free fraction of SNs of dead and dying cells were responsible for the promotion of proliferation. The nucleoside inosine released by dead and dying cells acting via adenosine receptors was identified as putative inducer of proliferation of surviving tumor cells after irradiation and heat treatment.ConclusionInosine released by dead and dying cells mediates tumor cell proliferation via purinergic receptors. Therapeutic strategies surmounting this pathway may help to reduce the rate of recurrence after radio- and chemotherapy.

  7. Adenosine Inhibits the Excitatory Synaptic Inputs to Basal Forebrain Cholinergic, GABAergic and Parvalbumin Neurons in mice

    Directory of Open Access Journals (Sweden)

    Chun eYang

    2013-06-01

    Full Text Available Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV neurons to determine the effect of adenosine. Whole-cell recordings were made BF cholinergic neurons and from BF GABAergic & PV neurons with the size (>20 µm and intrinsic membrane properties (prominent H-currents corresponding to cortically projecting neurons. A brief (2 min bath application of adenosine (100 μM decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents in all groups of BF cholinergic, GABAergic and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM. Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1-receptor mediated inhibition of glutamatergic inputs to cortically-projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for

  8. Age-dependent changes of presynaptic neuromodulation via A1-adenosine receptors in rat hippocampal slices.

    Science.gov (United States)

    Sperlágh, B; Zsilla, G; Baranyi, M; Kékes-Szabó, A; Vizi, E S

    1997-10-01

    The presynaptic neuromodulation of stimulation-evoked release of [3H]-acetylcholine by endogenous adenosine, via A1-adenosine receptors, was studied in superfused hippocampal slices taken from 4-, 12- and 24-month-old rats. 8-Cyclopentyl-1,3-dimethylxanthine (0.25 microM), a selective A1-receptor antagonist, increased significantly the electrical field stimulation-induced release of [3H]-acetylcholine in slices prepared from 4- and 12-month-old rats, showing a tonic inhibitory action of endogenous adenosine via stimulation of presynaptic A1-adenosine receptors. In contrast, 8-cyclopentyl-1,3-dimethylxanthine had no effect in 24-month-old rats. 2-Chloroadenosine (10 microM), an adenosine receptor agonist decreased the release of [3H]-acetylcholine in slices taken from 4- and 12-month-old rats, and no significant change was observed in slices taken from 24-month-old rats. In order to show whether the number/or affinity of the A1-receptors was affected in aged rats, [3H]-8-cyclopentyl-1,3-dimethylxanthine binding was studied in hippocampal membranes prepared from rats of different ages. Whereas the Bmax value was significantly lower in 2-year-old rats than in younger counterparts, the dissociation constant (Kd) was not affected by aging, indicating that the density rather than the affinity of adenosine receptors was altered. Endogenous adenosine levels present in the extracellular space were also measured in the superfusate by high performance liquid chromatography (HPLC) coupled with ultraviolet detection, and an age-related increase in the adenosine level was found. In summary, our results indicate that during aging the level of adenosine in the extracellular fluid is increased in the hippocampus. There is a downregulation and reduced responsiveness of presynaptic adenosine A1-receptors, and it seems likely that these changes are due to the enhanced adenosine level in the extracellular space.

  9. An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep.

    Science.gov (United States)

    Bjorness, Theresa E; Dale, Nicholas; Mettlach, Gabriel; Sonneborn, Alex; Sahin, Bogachan; Fienberg, Allen A; Yanagisawa, Masashi; Bibb, James A; Greene, Robert W

    2016-03-30

    Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis. The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to

  10. Differential response of Drosophila cell lines to extracellular adenosine

    Czech Academy of Sciences Publication Activity Database

    Fleischmannová, J.; Kučerová, Lucie; Šandová, Kateřina; Steinbauerová, Veronika; Brož, Václav; Šimek, Petr; Žurovec, Michal

    2012-01-01

    Roč. 42, č. 5 (2012), s. 321-331 ISSN 0965-1748 R&D Projects: GA MŠk(CZ) LC06077 Grant - others:AV ČR(CZ) KJB501410801; European Community´s Seventh Framwork Programme (FP7/2007-2013)(CZ) 229518 Institutional research plan: CEZ:AV0Z50070508 Institutional support: RVO:60077344 Keywords : adenosine recycling * nucleoside transport * Mbn2 Subject RIV: CE - Biochemistry Impact factor: 3.234, year: 2012 http://www.sciencedirect.com/science/article/pii/S0965174812000033

  11. The Role of Adenosine Receptors in Psychostimulant Addiction

    Directory of Open Access Journals (Sweden)

    Inmaculada Ballesteros-Yáñez

    2018-01-01

    Full Text Available Adenosine receptors (AR are a family of G-protein coupled receptors, comprised of four members, named A1, A2A, A2B, and A3 receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system (CNS, adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In terms of molecular pathways and second messengers involved, A1 and A3 receptors inhibit adenylyl cyclase (AC, through Gi/o proteins, while A2A and A2B receptors stimulate it through Gs proteins. In the CNS, A1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A2A receptors are localized mainly in the striatum and olfactory bulb, while A2B and A3 receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves (e.g., A1/A2A, as well as with other subtypes (e.g., A2A/D2, opening a whole range of possibilities in the field of the pharmacology of AR. Nowadays, we know that adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A1 receptors colocalized in heteromeric complexes with D1 receptors, and A2A receptors with D2 receptors. This review documents the present state of knowledge of the contribution of AR, particularly A1 and A2A, to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A1 agonists as an effective strategy to counteract psychostimulant-induced effects. Furthermore, different experimental data support the hypothesis that A2A/D2 heterodimers are

  12. Managing Chemotherapy Side Effects: Bleeding Problems

    Science.gov (United States)

    ... C ancer I nstitute Managing Chemotherapy Side Effects Bleeding Problems “My nurse said that chemotherapy could make ... with a clean cloth. Keep pressing until the bleeding stops. If you bruise: Put ice on the ...

  13. Fertility preservation after chemotherapy for Hodgkin lymphoma

    NARCIS (Netherlands)

    van der Kaaij, Marleen A. E.; van Echten-Arends, Jannie; Simons, Arnold H. M.; Kluin-Nelemans, Hanneke C.

    2010-01-01

    Treatment for Hodgkin lymphoma can negatively affect fertility. This review summarizes data on fertility after chemotherapy in adult patients. Alkylating chemotherapy, especially if containing procarbazine and/or cyclophosphamide, is most harmful to gonadal functioning. Alkylating regimens cause

  14. Chemotherapy-associated recurrent pneumothoraces in lymphangioleiomyomatosis.

    LENUS (Irish Health Repository)

    Kelly, Emer

    2012-02-01

    Lymphangioleiomyomatosis is a rare cause of pneumothorax in women. We present the case of a 48-year-old woman with lymphangioleiomyomatosis, who had never had a pneumothorax prior to commencing chemotherapy for breast cancer. During chemotherapy she developed 3 pneumothoraces and 2 episodes of pneumomediastinum. We suggest that the pneumothoraces were caused by the chemotherapy. To our knowledge, this is the first reported case of chemotherapy triggering pneumothoraces in a woman with lymphangioleiomyomatosis.

  15. Managing Chemotherapy Side Effects: Constipation

    Science.gov (United States)

    N ational C ancer I nstitute Managing Chemotherapy Side Effects Constipation Take these steps: Eat high-fiber foods such as: ● ● Whole-grain breads and cereals ● ● Fruits and vegetables ● ● Nuts and seeds Turn this ...

  16. Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity

    DEFF Research Database (Denmark)

    Heinonen, Ilkka H.A.; Kemppainen, Jukka; Kaskinoro, Kimmo

    2010-01-01

    Adenosine is a widely used pharmacological agent to induce a 'high flow' control condition to study the mechanisms of exercise hyperemia, but it is not known how well adenosine infusion depicts exercise-induced hyperemia especially in terms of blood flow distribution at the capillary level in hum...

  17. Lack of adenosine A(3) receptors causes defects in mouse peripheral blood parameters

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Dušek, L.; Hoferová, Zuzana; Komůrková, Denisa

    2014-01-01

    Roč. 10, č. 3 (2014), s. 509-514 ISSN 1573-9538 R&D Projects: GA ČR(CZ) GAP303/11/0128 Institutional support: RVO:68081707 Keywords : Adenosine A(3) receptor * Adenosine A(3) receptor knockout mice * Hematopoiesis Subject RIV: BO - Biophysics Impact factor: 3.886, year: 2014

  18. Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

    Directory of Open Access Journals (Sweden)

    Hui-Ling Diao

    2017-11-01

    Full Text Available The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

  19. Transient Delivery of Adenosine as a Novel Therapy to Prevent Epileptogenesis

    Science.gov (United States)

    2015-10-01

    Chemother 6:98–101. Bukoski RD, Sparks HV, and Mela -Riker LM (1986) A role for mitochondria in myocardial adenosine production. Adv Exp Med Biol 194:157–167...Bukoski RD, Sparks HV, and Mela LM (1983) Rat heart mitochondria release adenosine. Biochem Biophys Res Commun 113:990–995. Burnstock G, Fredholm BB

  20. Arterial occlusion precipitated by cisplatinbased chemotherapy

    OpenAIRE

    Joseph, D.; Dubashi, B.; Karthikeyan, B.; Jain, A.

    2010-01-01

    Cisplatin-based therapy is curative in testicular cancer. Adverse effects of cisplatin-based chemotherapy include dose-dependent myelosuppression, nephrotoxicity, neurotoxicity, and ototoxicity. By contrast, chemotherapy-associated vascular complications are unpredictable. Few incidents of digital gangrene with cisplatin have been reported. Here, we present a patient who developed arterial occlusion leading to gangrene of the toe after cisplatinbased chemotherapy.

  1. Small-animal PET study of adenosine A(1) receptors in rat brain: blocking receptors and raising extracellular adenosine.

    Science.gov (United States)

    Paul, Soumen; Khanapur, Shivashankar; Rybczynska, Anna A; Kwizera, Chantal; Sijbesma, Jurgen W A; Ishiwata, Kiichi; Willemsen, Antoon T M; Elsinga, Philip H; Dierckx, Rudi A J O; van Waarde, Aren

    2011-08-01

    Activation of adenosine A(1) receptors (A(1)R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A(1)R can be visualized using 8-dicyclopropylmethyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX) and PET. This study aims to test whether (11)C-MPDX can be used for quantitative studies of cerebral A(1)R in rodents. (11)C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A(1)R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A(1)R, whereas ethanol and ABT-702 increase extracellular adenosine. In groups 1 and 3, the brain was clearly visualized. High uptake of (11)C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2-tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K(1)/k(2) from the model fit) was not altered under the study conditions. (11)C-MPDX shows a regional distribution in rat brain consistent with binding to A(1)R. Tracer binding is blocked by the selective A

  2. A continuous spectrophotometric assay for monitoring adenosine 5'-monophosphate production.

    Science.gov (United States)

    First, Eric A

    2015-08-15

    A number of biologically important enzymes release adenosine 5'-monophosphate (AMP) as a product, including aminoacyl-tRNA synthetases, cyclic AMP (cAMP) phosphodiesterases, ubiquitin and ubiquitin-like ligases, DNA ligases, coenzyme A (CoA) ligases, polyA deadenylases, and ribonucleases. In contrast to the abundance of assays available for monitoring the conversion of adenosine 5'-triphosphate (ATP) to ADP, there are relatively few assays for monitoring the conversion of ATP (or cAMP) to AMP. In this article, we describe a homogeneous assay that continuously monitors the production of AMP. Specifically, we have coupled the conversion of AMP to inosine 5'-monophosphate (IMP) (by AMP deaminase) to the oxidation of IMP (by IMP dehydrogenase). This results in the reduction of oxidized nicotine adenine dinucleotide (NAD(+)) to reduced nicotine adenine dinucleotide (NADH), allowing AMP formation to be monitored by the change in the absorbance at 340 nm. Changes in AMP concentrations of 5 μM or more can be reliably detected. The ease of use and relatively low expense make the AMP assay suitable for both high-throughput screening and kinetic analyses. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Diagnostic significance of adenosine deaminase in pleural tuberculosis

    International Nuclear Information System (INIS)

    Khurshid, R.; Shore, N.; Saleem, M.; Zameer, N.

    2009-01-01

    Tuberculosis (TB) is a major cause of pleural effusion, which in TB usually has lymphocytic and exudative characteristics. Analysis of adenosine deaminase (ADA) activity is a very useful diagnostic approach to achieve a more rapid and precise diagnosis in cases of Pleural TB (pTB). Fifty male and fifty female patients presenting with tuberculosis pleural effusion was included in the study. The patients were taken from the medical ward of Sir Ganga Ram Hospital between September 2001 and September 2002. Activity of Adenosine Deaminase (ADA) was estimated by the technique of Sodium dodecyl sulphate electrophoresis (SDS-EF) using 10% polyacrylamide gel. Mean age of males was 45.72+-19.22 years and of female was 43.74+-16.09 years. Mean protein level was 3.39+-0.24 g/dl in males, and it was 3.02+-0.26 g/dl in females. Mean specific gravity both in males and females was 1.020+-0.01. The results show an increased level of enzyme ADA in patients as compared to normal subjects. Estimation of ADA activity may provide basis for rapid and efficient diagnosis of pleural TB in different clinical settings. However study should be extended to larger number of patients to reach a better conclusion. (author)

  4. Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum*

    Science.gov (United States)

    Cassera, María B.; Hazleton, Keith Z.; Riegelhaupt, Paul M.; Merino, Emilio F.; Luo, Minkui; Akabas, Myles H.; Schramm, Vern L.

    2008-01-01

    Plasmodium falciparum is a purine auxotroph, salvaging purines from erythrocytes for synthesis of RNA and DNA. Hypoxanthine is the key precursor for purine metabolism in Plasmodium. Inhibition of hypoxanthine-forming reactions in both erythrocytes and parasites is lethal to cultured P. falciparum. We observed that high concentrations of adenosine can rescue cultured parasites from purine nucleoside phosphorylase and adenosine deaminase blockade but not when erythrocyte adenosine kinase is also inhibited. P. falciparum lacks adenosine kinase but can salvage AMP synthesized in the erythrocyte cytoplasm to provide purines when both human and Plasmodium purine nucleoside phosphorylases and adenosine deaminases are inhibited. Transport studies in Xenopus laevis oocytes expressing the P. falciparum nucleoside transporter PfNT1 established that this transporter does not transport AMP. These metabolic patterns establish the existence of a novel nucleoside monophosphate transport pathway in P. falciparum. PMID:18799466

  5. Determination of adenosine phosphates in rat gastrocnemius at various postmortem intervals using high performance liquid chromatography.

    Science.gov (United States)

    Huang, Hong; Yan, Youyi; Zuo, Zhong; Yang, Lin; Li, Bin; Song, Yu; Liao, Linchuan

    2010-09-01

    Although the change in adenosine phosphate levels in muscles may contribute to the development of rigor mortis, the relationship between their levels and the onset and development of rigor mortis has not been well elucidated. In the current study, levels of the adenosine phosphates including adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) in gastrocnemius at various postmortem intervals of 180 rats from different death modes were detected by high performance liquid chromatography. The results showed that the levels of ATP and ADP significantly decreased along with the postmortem period of rats from different death mode whereas the AMP level remained the same. In addition, it was found that changes in the ATP levels in muscles after death correlated well with the development of rigor mortis. Therefore, the ATP level could serve as a reference parameter for the deduction of rigor mortis in forensic science.

  6. Evaluation of usefulness of pleural fluid adenosine deaminase in diagnosing tuberculous pleural effusion from empyema

    Directory of Open Access Journals (Sweden)

    Vijetha Shenoy

    2014-02-01

    Full Text Available Objective: To evaluate the utility of adenosine deaminase activity in the pleural fluid for the diagnosis of tuberculous pleural effusion from empyema of non-tubercular origin. Method: A retrospective analysis of data was performed on patients who were diagnosed to have tuberculous pleural effusion and empyema of non tubercular origin. Among 46 patients at Kasturba Hospital, Manipal University, Manipal, Karnataka, India, from November 201 2 to February 2013 who underwent pleural fluid adenosine deaminase estimation, 25 patients with tuberculous pleural effusion and 21 patients with empyema were diagnosed respectively. Adenosine deaminase in pleural fluid is estimated using colorimetric, Galanti and Guisti method. Results: Pleural fluid Adenosine Deaminase levels among tuberculous pleural effusion(109.38依 53.83 , empyema (141.20依71.69 with P=0.27. Conclusion: Pleural fluid adenosine deaminase alone cannot be used as a marker for the diagnosis of tuberculous pleural effusion.

  7. Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer

    DEFF Research Database (Denmark)

    Sternberg, Cora N; Donat, S Machele; Bellmunt, Joaquim

    2007-01-01

    To determine the optimal use of chemotherapy in the neoadjuvant, adjuvant, and metastatic setting in patients with advanced urothelial cell carcinoma, a consensus conference was convened by the World Health Organization (WHO) and the Société Internationale d'Urologie (SIU) to critically review...

  8. Overexpression, purification and crystallographic analysis of a unique adenosine kinase from Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yimin; Long, Mary C.; Ranganathan, Senthil; Escuyer, Vincent; Parker, William B.; Li, Rongbao, E-mail: li@sri.org [Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35205 (United States)

    2005-06-01

    Adenosine kinase from M. tuberculosis has been overexpressed, purified and crystallized in the presence of adenosine. Structure determination using molecular replacement with diffraction data collected at 2.2 Å reveals a dimeric structure. Adenosine kinase from Mycobacterium tuberculosis is the only prokaryotic adenosine kinase that has been isolated and characterized. The enzyme catalyzes the phosphorylation of adenosine to adenosine monophosphate and is involved in the activation of 2-methyladenosine, a compound that has demonstrated selective activity against M. tuberculosis. The mechanism of action of 2-methyladenosine is likely to be different from those of current tuberculosis treatments and this compound (or other adenosine analogs) may prove to be a novel therapeutic intervention for this disease. The M. tuberculosis adenosine kinase was overexpressed in Escherichia coli and the enzyme was purified with activity comparable to that reported previously. The protein was crystallized in the presence of adenosine using the vapour-diffusion method. The crystals diffracted X-rays to high resolution and a complete data set was collected to 2.2 Å using synchrotron radiation. The crystal belonged to space group P3{sub 1}21, with unit-cell parameters a = 70.2, c = 111.6 Å, and contained a single protein molecule in the asymmetric unit. An initial structural model of the protein was obtained by the molecular-replacement method, which revealed a dimeric structure. The monomers of the dimer were related by twofold crystallographic symmetry. An understanding of how the M. tuberculosis adenosine kinase differs from the human homolog should aid in the design of more potent and selective antimycobacterial agents that are selectively activated by this enzyme.

  9. Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

    Science.gov (United States)

    Xia, J X; Xiong, J X; Wang, H K; Duan, S M; Ye, J N; Hu, Z A

    2012-01-10

    Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin

  10. Adenosine-loaded dissolving microneedle patches to improve skin wrinkles, dermal density, elasticity and hydration.

    Science.gov (United States)

    Kang, G; Tu, T N T; Kim, S; Yang, H; Jang, M; Jo, D; Ryu, J; Baek, J; Jung, H

    2018-04-01

    Although dissolving microneedle patches have been widely studied in the cosmetics field, no comparisons have been drawn with the topical applications available for routine use. In this study, two wrinkle-improving products, adenosine-loaded dissolving microneedle patches and an adenosine cream, were evaluated for efficacy, with respect to skin wrinkling, dermal density, elasticity, and hydration, and safety in a clinical test on the crow's feet area. Clinical efficacy and safety tests were performed for 10 weeks on 22 female subjects with wrinkles around their eyes. The adenosine-loaded dissolving microneedle patch was applied once every 3 days, in the evening, for 8 weeks to the designated crow's feet area. The adenosine cream was applied two times per day, in the morning and evening, for 8 weeks to the other crow's feet area. Skin wrinkling, dermal density, elasticity, and hydration were measured by using PRIMOS ® premium, Dermascan ® C, Cutometer ® MPA580, and Corneometer ® CM 825, respectively. In addition, subjective skin irritation was evaluated by self-observation, and objective skin irritation was assessed through expert interviews. The adenosine-loaded dissolving microneedle patches had a similar or better efficacy than the adenosine cream. Both groups showed statistically significant efficacy for almost all parameters (P hydration efficacy (P skin-improvement parameters, adenosine-loaded dissolving microneedle patches showed the same or better effect than the adenosine cream, although the weekly adenosine dose was 140 times lower. The dissolving microneedle patches caused no adverse reactions. These adenosine-loaded dissolving microneedle patches are expected to be safe, effective, and novel cosmetics for skin improvement. © 2018 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  11. Overexpression, purification and crystallographic analysis of a unique adenosine kinase from Mycobacterium tuberculosis

    International Nuclear Information System (INIS)

    Wang, Yimin; Long, Mary C.; Ranganathan, Senthil; Escuyer, Vincent; Parker, William B.; Li, Rongbao

    2005-01-01

    Adenosine kinase from M. tuberculosis has been overexpressed, purified and crystallized in the presence of adenosine. Structure determination using molecular replacement with diffraction data collected at 2.2 Å reveals a dimeric structure. Adenosine kinase from Mycobacterium tuberculosis is the only prokaryotic adenosine kinase that has been isolated and characterized. The enzyme catalyzes the phosphorylation of adenosine to adenosine monophosphate and is involved in the activation of 2-methyladenosine, a compound that has demonstrated selective activity against M. tuberculosis. The mechanism of action of 2-methyladenosine is likely to be different from those of current tuberculosis treatments and this compound (or other adenosine analogs) may prove to be a novel therapeutic intervention for this disease. The M. tuberculosis adenosine kinase was overexpressed in Escherichia coli and the enzyme was purified with activity comparable to that reported previously. The protein was crystallized in the presence of adenosine using the vapour-diffusion method. The crystals diffracted X-rays to high resolution and a complete data set was collected to 2.2 Å using synchrotron radiation. The crystal belonged to space group P3 1 21, with unit-cell parameters a = 70.2, c = 111.6 Å, and contained a single protein molecule in the asymmetric unit. An initial structural model of the protein was obtained by the molecular-replacement method, which revealed a dimeric structure. The monomers of the dimer were related by twofold crystallographic symmetry. An understanding of how the M. tuberculosis adenosine kinase differs from the human homolog should aid in the design of more potent and selective antimycobacterial agents that are selectively activated by this enzyme

  12. Chemotherapy-induced Spontaneous Pneumothorax: Case Series

    Directory of Open Access Journals (Sweden)

    Een Hendarsih

    2016-09-01

    The mechanism of pneumothorax following chemotherapy is not clearly understood yet, however, several hypotheses have been considered: 1 the rupture of a subpleural bulla after chemotherapy; 2 the rupture of an emphysematous bulla in an over expanded portion of the lung which is partially obstructed by a neoplasm; 3 tumor lyses or necrosis due to cytotoxic chemotherapy directly induces the formation of fistula. Dyspnea and chest pain suddenly appear during successful chemotherapy for metastatic chemosensitive tumors should alert the physician to the possibility of SP. The treatment is directed toward lung re-expansion. Chemotherapy induced pneumothorax should be considered as oncologic emergency.

  13. Cancer cell adaptation to chemotherapy

    International Nuclear Information System (INIS)

    Di Nicolantonio, Federica; Johnson, Penny; Somers, Shaw S; Toh, Simon; Higgins, Bernie; Lamont, Alan; Gulliford, Tim; Hurren, Jeremy; Yiangou, Constantinos; Cree, Ian A; Mercer, Stuart J; Knight, Louise A; Gabriel, Francis G; Whitehouse, Pauline A; Sharma, Sanjay; Fernando, Augusta; Glaysher, Sharon; Di Palma, Silvana

    2005-01-01

    Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors. Cells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels. In 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors. This study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation

  14. Mechanism of adenylate kinase. Dose adenosine 5'-triphosphate bind to the adenosine 5'-monophosphate site

    Energy Technology Data Exchange (ETDEWEB)

    Shyy, Y.J.; Tian, G.; Tsai, M.D.

    1987-10-06

    Although the subtrate binding properties of adenylate kinase (AK) have been studied extensively by various biochemical and biophysical techniques, it remains controversial whether uncomplexed adenosine 5'-triphosphate (ATP) binds to the adenosine 5'-monophosphate (AMP) site of AK. The authors present two sets of experiments which argue against binding of ATP to the AMP site. (a) /sup 31/P nuclear magnetic resonance titration of ATP with AK indicated a 1:1 stoichiometry on the basis of changes in coupling constants and line widths. This ruled out binding of ATP to both sites. (b) ATP and MgATP were found to behave similarly by protecting AK from spontaneous inactivation while AMP showed only a small degree of protection. Such inactivation could also be protected or reversed by dithioerythritol and is most likely due to oxidation of sulfhydryl groups, one of which (cysteine-25) is located near the MgATP site. The results support binding of ATP to the MgATP site predominantly, instead of the AMP site, in the absence of Mg/sup 2 +/.

  15. A Bulky Rhodium Complex Bound to an Adenosine-Adenosine DNA Mismatch: General Architecture of the Metalloinsertion Binding Mode†

    Science.gov (United States)

    Zeglis, Brian M.; Pierre, Valérie C.; Kaiser, Jens T.; Barton, Jacqueline K.

    2009-01-01

    Two crystal structures are determined for Δ-Rh(bpy)2(chrysi)3+ (chrysi = 5,6-chrysenequinone diimine) bound to the oligonucleotide duplex 5′-CGGAAATTACCG-3′ containing two adenosine-adenosine mismatches (italics) through metalloinsertion. Diffraction quality crystals with two different space groups (P3221 and P43212) were obtained under very similar crystallization conditions. In both structures, the bulky rhodium complex inserts into the two mismatched sites from the minor groove side, ejecting the mismatched bases into the major groove. The conformational changes are localized to the mismatched site; the metal complex replaces the mismatched base pair without an increase in base pair rise. The expansive metal complex is accommodated in the duplex by a slight opening in the phosphodiester backbone; all sugars retain a C2′-endo puckering, and flanking base pairs neither stretch nor shear. The structures differ, however, in that in one of the structures, an additional metal complex is bound by intercalation from the major groove at the central 5′-AT-3′ step. We conclude that this additional metal complex is intercalated into this central step because of crystal packing forces. The structures described here of Δ-Rh(bpy)2(chrysi)3+ bound to thermodynamically destabilized AA mismatches share critical features with binding by metalloinsertion in two other oligonucleotides containing different single base mismatches. These results underscore the generality of the metalloinsertion as a new mode of non-covalent binding by small molecules with a DNA duplex. PMID:19374348

  16. Experimental studies on cancer chemotherapy

    International Nuclear Information System (INIS)

    1976-08-01

    The further development of the chemotherapy of cancer in the experimental and clinical fields necessitates a profound knowledge of its chemical, biochemical and pharmacological fundamentals and the mechanism of physiological and pathological growth processes. The 'Arbeitsgemeinschaft Zytostatika' includes chemists, biochemists, pharmacologists, molecular biologists, physicians and immunologists of various scientific institutes and clinics in the Federal Republic of Germany and in West Berlin. It is their aim to carry out basic research as well as clinical-orientated research in the field of the chemotherapy of cancer. In the 15 years of cooperation, fundamental knowledge was gained, especially in the field of the cytotoxic specificity and cancerotoxic selectivity of alkylating cytostatics. New cytostatics with a greater oncostatic selectivity and an altered spectrum of activity were tested and greater knowledge was won on the molecular-biological prerequisites of a rational drug design. (orig.) [de

  17. [Chemotherapy and women fertility preservation].

    Science.gov (United States)

    Gauthier, Tristan; Piver, Pascal; Durand, Lise-Marie; Donadel, Lorène; Pech, Jean-Christophe; Roux, Christophe; Aubard, Yves

    2010-01-01

    Agressive chemotherapy can lead to premature ovarian failure and loss of fertility in women and children. Embryo cryopreservation is an established clinical procedure of fertility preservation but with several limitations. Others options are available. Cryopreservation ovarian cortex tissu have to be suggested in case of high gonadotoxic treatment. It doesn't require puberty and delay in initiation of chemotherapy. The first birth in France after orthotopic graft of ovarian tissu thawed have been recently described with a promising process. Oocyte cryopreservation is available for women without partner but the experience is limited. Gonadotrophin-releasing hormone (GnRH) agonist therapy as ovarian protectants seem interesting. Follicular growth and maturation in vitro are still experimental. Copyright 2010 Elsevier Masson SAS. All rights reserved.

  18. Chemotherapy for advanced gastric cancer.

    Science.gov (United States)

    Wagner, Anna Dorothea; Syn, Nicholas Lx; Moehler, Markus; Grothe, Wilfried; Yong, Wei Peng; Tai, Bee-Choo; Ho, Jingshan; Unverzagt, Susanne

    2017-08-29

    Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen. To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer. We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs). We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer. Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is

  19. Metastatic hidradenocarcinoma: Surgery and chemotherapy.

    Science.gov (United States)

    Amel, Trabelsi; Olfa, Gharbi; Faten, Hammedi; Makrem, Hochlef; Slim, Ben Ahmed; Moncef, Mokni

    2009-12-01

    Hidradenocarcinoma is a rare carcinoma of high malignant potential. It most metastasizes to regional lymph nodes and distant viscera. We report a case of 52-year-old woman who presented with an invasive hidradenocarcinoma of the finger, treated with surgical excision. The patient presented with skin and lymph node metastases four years after, treated by chemotherapy. Hidradenocarcinoma is an aggressive tumor. It seems important to use adjuvant therapies particularly for recurrent and metastatic forms.

  20. Metastatic hidradenocarcinoma: Surgery and chemotherapy

    OpenAIRE

    Trabelsi Amel; Gharbi Olfa; Hammedi Faten; Hochlef Makrem; Ben Ahmed Slim; Mokni Moncef

    2009-01-01

    Context: Hidradenocarcinoma is a rare carcinoma of high malignant potential. It most metastasizes to regional lymph nodes and distant viscera. Case report: We report a case of 52-year-old woman who presented with an invasive hidradenocarcinoma of the finger, treated with surgical excision. The patient presented with skin and lymph node metastases four years after, treated by chemotherapy. Conclusion: Hidradenocarcinoma is an aggressive tumor. It seems important to use adjuvant therapies parti...

  1. Extracellular adenosine generation in the regulation of pro-inflammatory responses and pathogen colonization.

    Science.gov (United States)

    Alam, M Samiul; Costales, Matthew G; Cavanaugh, Christopher; Williams, Kristina

    2015-05-05

    Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine's control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis). Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen. The role of adenosine in dampening inflammation has been an area of active research, but the relevance of the CD39/CD73-axis and adenosine receptor signaling in host defense against infection has received less attention. Here, we review our recent knowledge regarding CD73 expression during murine Salmonellosis and Helicobacter-induced gastric infection and its role in disease pathogenesis and bacterial persistence. We also explored a possible role for the CD73/adenosine pathway in regulating innate host defense function during infection.

  2. Effects of adenosine on pressure-flow relationships in an in vitro model of compartment syndrome.

    Science.gov (United States)

    Shrier, I; Baratz, A; Magder, S

    1997-03-01

    Blood flow through skeletal muscle is best modeled with a vascular waterfall at the arteriolar level. Under these conditions, flow is determined by the difference between perfusion pressure (Pper) and the waterfall pressure (Pcrit), divided by the arterial resistance (Ra). By pump perfusing an isolated canine gastrocnemius muscle (n = 6) after it was placed within an airtight box, with and without adenosine infusion, we observed an interaction between the pressure surrounding a muscle (as occurs in compartment syndrome) and baseline vascular tone. We titrated adenosine concentration to double baseline flow. We measured Pcrit and Ra at box pressures (Pbox), which resulted in 100 (Pbox = 0), 90, 75, and 50% flow without adenosine; and 200, 180, 150, 100, and 50% flow with adenosine. Without adenosine, each 10% decline in flow was associated with a 5.7 mmHg increase in Pcrit (P 0.9). We conclude that increases in pressure surrounding a muscle limit flow primarily through changes in Pcrit with and without adenosine-induced vasodilation. The interaction between Pbox and adenosine with respect to Pcrit but not Ra suggests that Pbox affects the tone of the vessels responsible for Pcrit but not Ra.

  3. Role of adenosine signalling and metabolism in β-cell regeneration

    Energy Technology Data Exchange (ETDEWEB)

    Andersson, Olov, E-mail: olov.andersson@ki.se

    2014-02-01

    Glucose homeostasis, which is controlled by the endocrine cells of the pancreas, is disrupted in both type I and type II diabetes. Deficiency in the number of insulin-producing β cells – a primary cause of type I diabetes and a secondary contributor of type II diabetes – leads to hyperglycemia and hence an increase in the need for insulin. Although diabetes can be controlled with insulin injections, a curative approach is needed. A potential approach to curing diabetes involves regenerating the β-cell mass, e.g. by increasing β-cell proliferation, survival, neogenesis or transdifferentiation. The nucleoside adenosine and its cognate nucleotide ATP have long been known to affect insulin secretion, but have more recently been shown to increase β-cell proliferation during homeostatic control and regeneration of the β-cell mass. Adenosine is also known to have anti-inflammatory properties, and agonism of adenosine receptors can promote the survival of β-cells in an inflammatory microenvironment. In this review, both intracellular and extracellular mechanisms of adenosine and ATP are discussed in terms of their established and putative effects on β-cell regeneration. - Highlights: • A potential way to cure diabetes is to regenerate the β-cell mass by promoting cell survival, proliferation or neogenesis. • Adenosine may promote β-cell regeneration through several cellular mechanisms. • Adenosine and its cognate nucleotide ATP can each promote β-cell proliferation. • Do adenosine and ATP interact in promoting β-cell proliferation?.

  4. Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

    Science.gov (United States)

    Tang, Z; Diamond, M A; Chen, J-M; Holly, T A; Bonow, R O; Dasgupta, A; Hyslop, T; Purzycki, A; Wagner, J; McNamara, D M; Kukulski, T; Wos, S; Velazquez, E J; Ardlie, K; Feldman, A M

    2007-10-01

    The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

  5. Evidence for evoked release of adenosine and glutamate from cultured cerebellar granule cells

    International Nuclear Information System (INIS)

    Schousboe, A.; Frandsen, A.; Drejer, J.

    1989-01-01

    Evoked release of [ 3 H]-D-aspartate which labels the neurotransmitter glutamate pool in cultured cerebellar granule cells was compared with evoked release of adenosine from similar cultures. It was found that both adenosine and [3H]-D-aspartate could be released from the neurons in a calcium dependent manner after depolarization of the cells with either 10-100 microM glutamate or 50 mM KCl. Cultures of cerebellar granule cells treated with 50 microM kainate to eliminate GABAergic neurons behaved in the same way. This together with the observation that cultured astrocytes did not exhibit a calcium dependent, potassium stimulated adenosine release strongly suggest that cerebellar granule cells release adenosine in a neurotransmitter-like fashion together with glutamate which is the classical neurotransmitter of these neurons. Studies of the metabolism of adenosine showed that in the granule cells adenosine is rapidly metabolized to ATP, ADP, and AMP, but in spite of this, adenosine was found to be released preferential to ATP

  6. Adenosine for postoperative analgesia: A systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Xin Jin

    Full Text Available Perioperative infusion of adenosine has been suggested to reduce the requirement for inhalation anesthetics, without causing serious adverse effects in humans. We conducted a meta-analysis of randomized controlled trials evaluating the effect of adenosine on postoperative analgesia.We retrieved articles in computerized searches of Scopus, Web of Science, PubMed, EMBASE, and Cochrane Library databases, up to July 2016. We used adenosine, postoperative analgesia, and postoperative pain(s as key words, with humans, RCT, and CCT as filters. Data of eligible studies were extracted, which included pain scores, cumulative opioid consumption, adverse reactions, and vital signs. Overall incidence rates, relative risk (RR, and 95% confidence intervals (CI were calculated employing fixed-effects or random-effects models, depending on the heterogeneity of the included trials.In total, 757 patients from 9 studies were included. The overall effect of adenosine on postoperative VAS/VRS scores and postoperative opioid consumption was not significantly different from that of controls (P >0.1. The occurrence of PONV and pruritus was not statistically significantly different between an adenosine and nonremifentanil subgroup (P >0.1, but the rate of PONV occurrence was greater in the remifentanil subgroup (P 0.1.Adenosine has no analgesic effect or prophylactic effect against PONV, but reduce systolic blood pressure and heart rates. Adenosine may benefit patients with hypertension, ischemic heart disease, and tachyarrhythmia, thereby improving cardiac function.

  7. Tolerance and diagnostic accuracy of an abbreviated adenosine infusion for myocardial scintigraphy: a randomized, prospective study.

    Science.gov (United States)

    Treuth, M G; Reyes, G A; He, Z X; Cwajg, E; Mahmarian, J J; Verani, M S

    2001-01-01

    The objectives of this study were 2-fold: (1) to determine the tolerance of adenosine perfusion tomography with the use of an abbreviated (3-minute) infusion in comparison to the standard (6-minute) infusion, and (2) to assess the relative diagnostic accuracy of a 3-minute adenosine infusion in patients referred for arteriography. An abbreviated adenosine infusion may decrease the frequency and duration of side effects and be a more cost-effective alternative. We prospectively randomized 599 patients undergoing adenosine myocardial perfusion tomography to either a 3-minute or 6-minute adenosine infusion at 140 microg/kg per minute. Among the 599 enrolled patients, 142 subsequently underwent coronary angiography. Patients randomized to the 3-minute adenosine infusion tolerated the procedure better than those randomized to the standard infusion (P <.01). Flushing, headache, neck pain, and atrioventricular block were all significantly less frequent (P <.01) with the abbreviated infusion. Moreover, patients receiving the abbreviated infusion had less hypotension and tachycardia (P <.05). The sensitivity of the test for detection of coronary artery disease was 88% for both the 3- and 6-minute infusions. In patients with abnormal scan results, perfusion defect size was slightly larger in those receiving a 6-minute infusion versus those receiving a 3-minute infusion (P =.05). An abbreviated 3-minute adenosine infusion, in combination with perfusion tomography, has similar sensitivity for detection of coronary artery disease and is better tolerated than the standard 6-minute infusion.

  8. Alterations in electrocardiogram of adenosine test for 99Tcm-MIBI myocardial perfusion imaging

    International Nuclear Information System (INIS)

    Xie Boqia; Tian Yueqin; Zheng Lihui

    2011-01-01

    Objective: To analyze alterations in electrocardiogram (ECG) of adenosine test in 99 Tc m -MIBI myocardial perfusion imaging(MPI)SPECT study. Methods: A total of 641 patients were included in the study. The patients each underwent 99 Tc m -MIBI MPI with adenosine test. The ECGs were taken before, during, and after adenosine infusion. Results: In all, abnormal ECGs were found in 205(32.0%) patients. During adenosine infusion, 20.6%(132/641) of patients suffered from arrhythmia, 29.5%(39/132) had atrial premature beats, 34.1% (45/132) had premature ventricular beats, and 6.1% (8/132) had sinoatrial block. In addition, 5.3% (7/132) had first-, 24.2% (32/132) had second-, and 0.8% (1/132) had third-degree atrioventricular block (AVB). After adenosine infusion, 4.4%( 28/641) of patients suffered from arrhythmia, 57.1% (16/28) had atrial premature beats, 39.3% (11/28) had premature ventricular beats, and 3.6% (1/28) had sinoatrial block. The perfusion images showed ischemia in 36 patients and infarction in 8 patients. Adenosine infusion was terminated in 39 patients (6.1%) because of poorly tolerated side effects. However, no death or acute myocardial infarction occurred in the study. Conclusions: Adenosine pharmacologic test for 99 Tc m -MIBI MPI may result in relatively high incidence of arrhythmia in ECG monitoring. (authors)

  9. Role of adenosine signalling and metabolism in β-cell regeneration

    International Nuclear Information System (INIS)

    Andersson, Olov

    2014-01-01

    Glucose homeostasis, which is controlled by the endocrine cells of the pancreas, is disrupted in both type I and type II diabetes. Deficiency in the number of insulin-producing β cells – a primary cause of type I diabetes and a secondary contributor of type II diabetes – leads to hyperglycemia and hence an increase in the need for insulin. Although diabetes can be controlled with insulin injections, a curative approach is needed. A potential approach to curing diabetes involves regenerating the β-cell mass, e.g. by increasing β-cell proliferation, survival, neogenesis or transdifferentiation. The nucleoside adenosine and its cognate nucleotide ATP have long been known to affect insulin secretion, but have more recently been shown to increase β-cell proliferation during homeostatic control and regeneration of the β-cell mass. Adenosine is also known to have anti-inflammatory properties, and agonism of adenosine receptors can promote the survival of β-cells in an inflammatory microenvironment. In this review, both intracellular and extracellular mechanisms of adenosine and ATP are discussed in terms of their established and putative effects on β-cell regeneration. - Highlights: • A potential way to cure diabetes is to regenerate the β-cell mass by promoting cell survival, proliferation or neogenesis. • Adenosine may promote β-cell regeneration through several cellular mechanisms. • Adenosine and its cognate nucleotide ATP can each promote β-cell proliferation. • Do adenosine and ATP interact in promoting β-cell proliferation?

  10. A simplified radioimmunoassay of adenosine-3':5'-monophosphate

    International Nuclear Information System (INIS)

    Katoh, Yoshiki; Takezawa, Junichi; Suzuki, Morio; Kuninaka, Akira; Yoshino, Hiroshi

    1975-01-01

    Dextran-coated charcoal was proved to be able to separate free adenosine-3':5'monophosphate (cAMP) from antibody-bound cAMP. Only free cAMO was adsorbed on dextran-coated charcoal within 1 min after contacting the charcoal. In a reaction mixture of cAMP and anti-cAMP-plasma, most of antibody-bound cAMP had not been adsorbed 4 min after contacting. The data obtained were found to be almost the same as the data of another experiment using cellulose ester filter separation technique. Thus, dextran-coated charcoal could be employed to simplify the radioimmunoassay of cAMP. (author)

  11. N6-adenosine methylation in MiRNAs.

    Directory of Open Access Journals (Sweden)

    Tea Berulava

    Full Text Available Methylation of N6-adenosine (m6A has been observed in many different classes of RNA, but its prevalence in microRNAs (miRNAs has not yet been studied. Here we show that a knockdown of the m6A demethylase FTO affects the steady-state levels of several miRNAs. Moreover, RNA immunoprecipitation with an anti-m6A-antibody followed by RNA-seq revealed that a significant fraction of miRNAs contains m6A. By motif searches we have discovered consensus sequences discriminating between methylated and unmethylated miRNAs. The epigenetic modification of an epigenetic modifier as described here adds a new layer to the complexity of the posttranscriptional regulation of gene expression.

  12. The Adverse Events and Hemodynamic Effects of Adenosine-Based Cardiac MRI

    International Nuclear Information System (INIS)

    Voigtlander, Thomas; Magedanz, Annett; Schmermund, Axel; Bramlage, Peter; Elsaesser, Amelie; Kauczor, Hans-Ulrich; Mohrs, Oliver K.

    2011-01-01

    We wanted to prospectively assess the adverse events and hemodynamic effects associated with an intravenous adenosine infusion in patients with suspected or known coronary artery disease and who were undergoing cardiac MRI. One hundred and sixty-eight patients (64 ± 9 years) received adenosine (140 μg/kg/min) during cardiac MRI. Before and during the administration, the heart rate, systemic blood pressure, and oxygen saturation were monitored using a MRI-compatible system. We documented any signs and symptoms of potential adverse events. In total, 47 out of 168 patients (28%) experienced adverse effects, which were mostly mild or moderate. In 13 patients (8%), the adenosine infusion was discontinued due to intolerable dyspnea or chest pain. No high grade atrioventricular block, bronchospasm or other life-threatening adverse events occurred. The hemodynamic measurements showed a significant increase in the heart rate during adenosine infusion (69.3 ± 11.7 versus 82.4 ± 13.0 beats/min, respectively; p < 0.001). A significant but clinically irrelevant increase in oxygen saturation occurred during adenosine infusion (96 ± 1.9% versus 97 ± 1.3%, respectively; p < 0.001). The blood pressure did not significantly change during adenosine infusion (systolic: 142.8 ± 24.0 versus 140.9 ± 25.7 mmHg; diastolic: 80.2 ± 12.5 mmHg versus 78.9 ± 15.6, respectively). This study confirms the safety of adenosine infusion during cardiac MRI. A considerable proportion of all patients will experience minor adverse effects and some patients will not tolerate adenosine infusion. However, all adverse events can be successfully managed by a radiologist. The increased heart rate during adenosine infusion highlights the need to individually adjust the settings according to the patient, e.g., the number of slices of myocardial perfusion imaging.

  13. Novel approaches for targeting the adenosine A2A receptor.

    Science.gov (United States)

    Yuan, Gengyang; Gedeon, Nicholas G; Jankins, Tanner C; Jones, Graham B

    2015-01-01

    The adenosine A2A receptor (A2AR) represents a drug target for a wide spectrum of diseases. Approaches for targeting this membrane-bound protein have been greatly advanced by new stabilization techniques. The resulting X-ray crystal structures and subsequent analyses provide deep insight to the A2AR from both static and dynamic perspectives. Application of this, along with other biophysical methods combined with fragment-based drug design (FBDD), has become a standard approach in targeting A2AR. Complementarities of in silico screening based- and biophysical screening assisted- FBDD are likely to feature in future approaches in identifying novel ligands against this key receptor. This review describes evolution of the above approaches for targeting A2AR and highlights key modulators identified. It includes a review of: adenosine receptor structures, homology modeling, X-ray structural analysis, rational drug design, biophysical methods, FBDD and in silico screening. As a drug target, the A2AR is attractive as its function plays a role in a wide spectrum of diseases including oncologic, inflammatory, Parkinson's and cardiovascular diseases. Although traditional approaches such as high-throughput screening and homology model-based virtual screening (VS) have played a role in targeting A2AR, numerous shortcomings have generally restricted their applications to specific ligand families. Using stabilization methods for crystallization, X-ray structures of A2AR have greatly accelerated drug discovery and influenced development of biophysical-in silico hybrid screening methods. Application of these new methods to other ARs and G-protein-coupled receptors is anticipated in the future.

  14. Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation.

    Science.gov (United States)

    Frøbert, Ole; Haink, Gesine; Simonsen, Ulf; Gravholt, Claus H; Levin, Max; Deussen, Andreas

    2006-01-15

    We tested whether hypoxia-induced coronary artery dilatation could be mediated by an increase in adenosine concentration within the coronary artery wall or by an increase in adenosine sensitivity. Porcine left anterior descendent coronary arteries, precontracted with prostaglandin F(2alpha) (10(-5) M), were mounted in a pressure myograph and microdialysis catheters were inserted into the tunica media. Dialysate adenosine concentrations were analysed by HPLC. Glucose, lactate and pyruvate were measured by an automated spectrophotometric kinetic enzymatic analyser. The exchange fraction of [(14)C]adenosine over the microdialysis membrane increased from 0.32 +/- 0.02 to 0.46 +/- 0.02 (n = 4, P lactate/pyruvate ratio was significantly increased in hypoxic arteries but did not correlate with adenosine concentration. We conclude that hypoxia-induced coronary artery dilatation is not mediated by increased adenosine produced within the artery wall but might be facilitated by increased adenosine sensitivity at the A(2A) receptor level.

  15. Adenosine receptors in rat and human pancreatic ducts stimulate chloride transport

    DEFF Research Database (Denmark)

    Novak, Ivana; Hede, Susanne; Hansen, Mette

    2007-01-01

    , it was found that 58% of PANC-1 cells responded to adenosine, whereas only 9% of CFPAC-1 cells responded. Adenosine elicited Ca(2+) signals only in a few rat and human duct cells, which did not seem to correlate with Cl(-) signals. A(2A) receptors were localized in the luminal membranes of rat pancreatic ducts......, plasma membrane of many PANC-1 cells, but only a few CFPAC-1 cells. Taken together, our data indicate that A(2A) receptors open Cl(-) channels in pancreatic ducts cells with functional CFTR. We propose that adenosine can stimulate pancreatic secretion and, thereby, is an active player in the acini...

  16. Intracellular signalling pathways in the vasoconstrictor response of mouse afferent arterioles to adenosine

    DEFF Research Database (Denmark)

    Hansen, Pernille B. Lærkegaard; Friis, Ulla Glenert; Uhrenholt, Torben Rene

    2007-01-01

    of calcium from the sarcoplasmic reticulum (SR), stimulated presumably by IP(3), is involved in the adenosine contraction mechanism of the afferent arteriole. In agreement with this notion is the observation that 2 aminoethoxydiphenyl borate (100 microM) blocked the adenosine-induced constriction whereas...... was abolished by IAA-94. Furthermore, the vasoconstriction caused by adenosine was significantly inhibited by 5 microM nifedipine (control 8.3 +/- 0.2 microM, ado 3.6 +/- 0.6 microM, ado + nifedipine 6.8 +/- 0.2 microM) suggesting involvement of voltage-dependent calcium channels. CONCLUSION: We conclude...

  17. Adenosine formation in contracting primary rat skeletal muscle cells and endothelial cells in culture

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Frandsen, Ulrik

    1997-01-01

    1. The present study examined the capacity for adenosine formation, uptake and metabolism in contracting primary rat muscle cells and in microvascular endothelial cells in culture. 2. Strong and moderate electrical simulation of skeletal muscle cells led to a significantly greater increase....... 3. Addition of microvascular endothelial cells to the cultured skeletal muscle cells enhanced the contraction-induced accumulation of extracellular adenosine (P Skeletal muscle cells were...... in the extracellular adenosine concentration (421 +/- 91 and 235 +/- 30 nmol (g protein)-1, respectively; P muscle cells (161 +/- 20 nmol (g protein)-1). The ATP concentration was lower (18%; P contracted, but not in the moderately contracted muscle cells...

  18. Characteristics of high affinity and low affinity adenosine binding sites in human cerebral cortex

    International Nuclear Information System (INIS)

    John, D.; Fox, I.V.

    1986-01-01

    The binding characteristics of human brain cortical membrane fractions were evaluated to test the hypothesis that there are A 1 and A 2 adenosine binding sites. The ligands used were 2-chloro(8- 3 H) adenosine and N 6 -(adenine-2, 8- 3 H) cyclohexayladenosine. Binding of chloroadenosine to human brain cortical membranes was time dependent, reversible and concentration dependent. The kinetic constant determinations from binding studies of the adenosine receptor are presented. Utilizing tritium-cyclohexyladenosine as ligand the authors observed evidence for a high affinity binding site in human brain cortical membranes with a kd of 5 nM

  19. Alteration of sodium, potassium-adenosine triphosphatase activity in rabbit ciliary processes by cyclic adenosine monophosphate-dependent protein kinase

    International Nuclear Information System (INIS)

    Delamere, N.A.; Socci, R.R.; King, K.L.

    1990-01-01

    The response of sodium, potassium-adenosine triphosphatase (Na,K-ATPase) to cyclic adenosine monophosphate (cAMP)-dependent protein kinase was examined in membranes obtained from rabbit iris-ciliary body. In the presence of the protein kinase together with 10(-5) M cAMP, Na,K-ATPase activity was reduced. No change in Na,K-ATPase activity was detected in response to the protein kinase without added cAMP. Likewise cAMP alone did not alter Na,K-ATPase activity. Reduction of Na,K-ATPase activity was also observed in the presence of the cAMP-dependent protein kinase catalytic subunit. The response of the enzyme to the kinase catalytic subunit was also examined in membranes obtained from rabbit ciliary processes. In the presence of 8 micrograms/ml of the catalytic subunit, ciliary process Na,K-ATPase activity was reduced by more than 50%. To examine whether other ATPases were suppressed by the protein kinase, calcium-stimulated ATPase activity was examined; its activity was stimulated by the catalytic subunit. To test whether the response of the ciliary process Na,K-ATPase is unique, experiments were also performed using membrane preparations from rabbit lens epithelium or rabbit kidney; the catalytic subunit significantly reduced the activity of Na,K-ATPase from the kidney but not the lens. These Na,K-ATPase studies suggest that in the iris-ciliary body, cAMP may alter sodium pump activity. In parallel 86Rb uptake studies, we observed that ouabain-inhibitable potassium uptake by intact pieces of iris-ciliary body was reduced by exogenous dibutryl cAMP or by forskolin

  20. Nanotechnology for Cancer Therapy Based on Chemotherapy

    OpenAIRE

    Chen-Yang Zhao; Rui Cheng; Zhe Yang; Zhong-Min Tian

    2018-01-01

    Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover,...

  1. Overview, prevention and management of chemotherapy extravasation

    OpenAIRE

    Kreidieh, Firas Y; Moukadem, Hiba A; El Saghir, Nagi S

    2016-01-01

    Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, prevention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracycl...

  2. Combined radiotherapy and chemotherapy for head and neck cancer

    International Nuclear Information System (INIS)

    Inuyama, Yukio; Fujii, Masato; Tanaka, Juichi; Takaoka, Tetsuro; Hosoda, Hyonosuke; Kawaura, Mitsuhiro; Toji, Masao

    1988-01-01

    There are 4 modalities of combined radiotherapy and chemotherapy which include (1) concurrent radiotherapy and chemotherapy, (2) sequential use of radiotherapy and chemotherapy (pre-radiation chemotherapy), (3) pre-radiation chemotherapy followed by concurrent radiation and chemotherapy, and (4) alternating use of radiotherapy and chemotherapy based upon Looney's hypothesis. We studied concurrent use of radiotherapy and UFT by means of animal experimentation and clinical trials. The results obtained revealed that UFT was a most suitable agent together with 5-fluorouracil for concurrent application of radiotherapy and chemotherapy. Neo-adjuvant chemotherapy including pre-radiation chemotherapy was also studied in cases of maxillary sinus carcinoma and nasopharyngeal carcinoma. From the results, it seemed desirable to use cisplatin and bleomycin analogs sequentially in combined chemotherapy and radiotherapy. Neo-adjuvant chemotherapy should be studied successively to improve local tumor control rates and prevent distant metastases. For future perspectives, new trials of alternating radiotherapy and chemotherapy based upon Looney's hypothesis seem necessary. (author)

  3. [Oral complications of chemotherapy of malignant neoplasms].

    Science.gov (United States)

    Obralić, N; Tahmiscija, H; Kobaslija, S; Beslija, S

    1999-01-01

    Function and integrity disorders of the oral cavity fall into the most frequent complication of the chemotherapy of leucemias, malignant lymphomas and solid tumors. Complications associated with cancer chemotherapy can be direct ones, resulting from the toxic action of antineoplastic agents on the proliferative lining of the mouth, or indirect, as a result of myelosuppression and immunosuppression. The most frequent oral complications associated with cancer chemotherapy are mucositis, infection and bleeding. The principles of prevention and management of oral complications during cancer chemotherapy are considered in this paper.

  4. Chemotherapy in combined and multimodality treatment

    International Nuclear Information System (INIS)

    Anon.

    1989-01-01

    It is shown that chemotherapy of tumors of various localizations developes intensively in the last few years. It is connected with discovery and adoption of new active antitumoral preparations, such as alkylating preparations, antimetabolites, antitumoral antibiotics, hormonal preparations. To create the rational effective conditions of chemotherapy a study was made on kinetics of tumor gowth, molecular mechanisms of interaction of cytostatics and cells of malignant tumor. Main factors of chemotherapy combination with radiotherapy when treating numerous malignant tumors were considered. Effectiveness of using chemotherapy in combination with other methods of treatment was shown

  5. Chemotherapy

    Science.gov (United States)

    ... Central venous catheter Central venous catheter with a port Percutaneously inserted central catheter (PICC) A central line ... pain or numbness from nerve damage Have a dry mouth , mouth sores, or swelling in the mouth ...

  6. Chemotherapy

    Science.gov (United States)

    ... cause nerve problems and burning, numbness, tingling, or shooting pain in the fingers and toes. Certain types ... more comfortable wearing hats, scarves, or wigs to school or other events. Or, you may look great ...

  7. Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Schwarzschild, Michael A; Xu, Kui

    2008-01-01

    Continued progress has been made toward each of the Specific Aims (SAs) 1 and 2 (SA 3 completed) of our research project, Caffeine, adenosine receptors and estrogen in toxin models of Parkinson's disease...

  8. Catalytic dephosphorylation of adenosine monophosphate (AMP) to form supramolecular nanofibers/hydrogels.

    Science.gov (United States)

    Du, Xuewen; Li, Junfeng; Gao, Yuan; Kuang, Yi; Xu, Bing

    2012-02-18

    The use of enzyme to instruct the self-assembly of the nucleoside of adenosine in water provides a new class of molecular nanofibers/hydrogels as functional soft materials. This journal is © The Royal Society of Chemistry 2012

  9. Time Window Is Important for Adenosine Preventing Cold-induced Injury to the Endothelium.

    Science.gov (United States)

    Li, Yan; Hu, Xiao-Xia; Fu, Li; Chen, Jing; Lu, Li-He; Liu, Xiang; Xu, Zhe; Zhou, Li; Wang, Zhi-Ping; Zhang, Xi; Ou, Zhi-Jun; Ou, Jing-Song

    2017-06-01

    Cold cardioplegia is used to induce heart arrest during cardiac surgery. However, endothelial function may be compromised after this procedure. Accordingly, interventions such as adenosine, that mimic the effects of preconditioning, may minimize endothelial injury. Herein, we investigated whether adenosine prevents cold-induced injury to the endothelium. Cultured human cardiac microvascular endothelial cells were treated with adenosine for different durations. Phosphorylation and expression of endothelial nitric oxide synthase (eNOS), p38MAPK, ERK1/2, and p70S6K6 were measured along with nitric oxide (NO) production using diaminofluorescein-2 diacetate (DAF-2DA) probe. Cold-induced injury by hypothermia to 4°C for 45 minutes to mimic conditions of cold cardioplegia during open heart surgery was induced in human cardiac microvascular endothelial cells. Under basal conditions, adenosine stimulated NO production, eNOS phosphorylation at serine 1177 from 5 minutes to 4 hours and inhibited eNOS phosphorylation at threonine 495 from 5 minutes to 6 hours, but increased phosphorylation of ERK1/2, p38MAPK, and p70S6K only after exposure for 5 minutes. Cold-induced injury inhibited NO production and the phosphorylation of the different enzymes. Importantly, adenosine prevented these effects of hypothermic injury. Our data demonstrated that adenosine prevents hypothermic injury to the endothelium by activating ERK1/2, eNOS, p70S6K, and p38MAPK signaling pathways at early time points. These findings also indicated that 5 minutes after administration of adenosine or release of adenosine is an important time window for cardioprotection during cardiac surgery.

  10. Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury

    OpenAIRE

    Winerdal, Max; Winerdal, Malin E.; Wang, Ying-Qing; Fredholm, Bertil B.; Winqvist, Ola; Ådén, Ulrika

    2015-01-01

    Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R−/−) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction siz...

  11. Treatment of out-of-hospital supraventricular tachycardia: adenosine vs verapamil.

    Science.gov (United States)

    Brady, W J; DeBehnke, D J; Wickman, L L; Lindbeck, G

    1996-06-01

    To compare the use of adenosine and the use of verapamil as out-of-hospital therapy for supraventricular tachycardia (SVT). A period of prospective adenosine use (March 1993 to February 1994) was compared with a historical control period of verapamil use (March 1990 to February 1991) for SVT. Data were obtained for SVT patients treated in a metropolitan, fire-department-based paramedic system serving a population of approximately 1 million persons. Standard drug protocols were used and patient outcomes (i.e., conversion rates, complications, and recurrences) were monitored. During the adenosine treatment period, 105 patients had SVT; 87 (83%) received adenosine, of whom 60 (69%) converted to a sinus rhythm (SR). Vagal maneuvers (VM) resulted in restoration of SR in 8 patients (7.6%). Some patients received adenosine for non-SVT rhythms: 7 sinus tachycardia, 18 atrial fibrilation, 7 wide-complex tachycardia (WCT), and 2 ventricular tachycardia; no non-SVT rhythm converted to SR and none of these patients experienced an adverse effect. Twenty-five patients were hemodynamically unstable (systolic blood pressure fibrillation). Recurrence of SVT was noted in 2 adenosine patients and 2 verapamil patients in the out-of-hospital setting and in 23 adenosine patients and 15 verapamil patients after ED arrival, necessitating additional therapy (p = 0.48 and 0.88, for recurrence rates and types of additional therapies, respectively). Hospital diagnoses, outcomes, and ED dispositions were similar for the 2 groups. Adenosine and verapamil were equally successful in converting out-of-hospital SVT in patients with similar etiologies responsible for the SVT. Recurrence of SVT occurred at similar rates for the 2 medications. Rhythm misidentification remains a common issue in out-of-hospital cardiac care in this emergency medical services system.

  12. No Effect of Nutritional Adenosine Receptor Antagonists on Exercise Performance in the Heat

    Science.gov (United States)

    2008-11-01

    358–363, 1996. 11. Cook NC, Samman S. Flavonoids —chemistry, metabolism, cardiopro- tective effects, and dietary sources. Nutr Biochem 7: 66–76, 1996...metabolism and health effects of dietary flavonoids in man. Biomed Pharmacother 51: 305–310, 1997. R400 ADENOSINE RECEPTOR ANTAGONISM AND EXERCISE IN THE HEAT...Interactions of flavonoids with adenosine receptors. J Med Chem 39: 781–788, 1996. 35. MacRae HS, Mefferd KM. Dietary antioxidant supplementation com

  13. Human adenosine deaminase: properties and turnover in cultured T and B lymphoblasts

    International Nuclear Information System (INIS)

    Daddona, P.E.

    1981-01-01

    In this study, the properties and rate of turnover of adenosine deaminase are compared in cultured human T and B lymphoblast cell lines. 1) Relative to B lymphoblasts, the level of adenosine deaminase activity in extracts of T lymphoblast cell lines (MOLT-4, RPMI-8402, CCRF-CEM, and CCRF-HSB-2) is elevated 7-14-fold and differs by 2-fold between the C cell lines. 2) In both T and B lymphoblast extracts, the enzyme is apparently identical, based on K/sub m/ for adenosine and deoxyadenosine, K/sub i/ for inosine, V/sub max/ for adenosine, /sub S20,w/, isoelectric pH, and heat stability. Furthermore, by radioimmunoassay, the quantity of adenosine deaminase-immunocreative protein is proportional to the level of enzyme activity in all cell lines studies. 3) Using a purification and selective immunoprecipitation technique, the enzyme turnover could be assessed in cell lines labeled with [ 35 S]methionine. The apparent rate of adenosine deaminase synthesis, relative to total protein, is 2-fold faster in both T cell lines (RPMI-8402 and CCRF-CEM) than in the B cell lines (MGL-8 and GM-130). The apparent half-life (tsub1/2) for the enzyme degradation is 19 and 39 h, respectively, in CCFR-CEM and RPMI-8402, while the tsub1/2 in both B cell lines is 7-9 h. From the net rate of synthesis and degradation, the T cell lines, respectively, exhibit approximately a 6- and 12-fold difference in adenosine deaminase turnover relative to B cells, consistent with the observed differences in enzyme activity. This study suggests that while adenosine deaminase is apparently identical in both T and B lymphoblast cell lines, alterations in both the rate of enzyme synthesis and degradation contribute to its high steady state level in T cells

  14. Radio-chromatographic determination of plasmatic adenosine deaminase (A.D.)

    International Nuclear Information System (INIS)

    Chivot, J.J.; Depernet, D.; Caen, J.

    1970-01-01

    We were able, by using a radio-chromatographic method, to measure an adenosine deaminase activity in normal human heparinized platelet-poor plasma, which can degrade 0.016 μM adenosine. This activity suppressed by heating 56 C for 30 minutes is inhibited by high concentrations of urea and is proportional to the amount of plasma, source of enzyme, in the systems. (authors) [fr

  15. The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology

    Science.gov (United States)

    2016-09-01

    not be cited for purposes of advertisement . REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this...survivability. That was an important step to clinical relevancy as it was feared that ADO’s depression of cardiovascular output would exacerbate...kainate, adenosine and neuropeptide Y receptors. Neurochemical Research. 28: 1501-1515. 23. Bjorness, T. E. & R. W. Greene . 2009. Adenosine and sleep

  16. Effects of adenosine on the organ injury and dysfunction caused by hemorrhagic shock

    International Nuclear Information System (INIS)

    Soliman, M.M.

    2009-01-01

    Objectives: Adenosine has been shown in animal and human studies to decrease the post-ischemic myocardial injury by lowering the levels of tumor necrosis factor-a. The objectives of the study was to examine the protective effects of adenosine on the organ injury (liver, kidney, pancreas) associated with hemorrhagic shock in rats. Methodology: The study was conducted at Cardiovascular Physiology laboratory, King Saud University, Riyadh in 2007-2008. Anesthetized male Sprague- Dawley rats were assigned to hemorrhage and resuscitation treated with 20mM adenosine , untreated, or similar time matched control groups (n=6 per group). Rats were hemorrhaged for one hour using a reservoir model. Arterial blood pressure was monitored for one hour, and maintained at a mean arterial blood pressure of 40 mmHg. Adenosine 20mM was injected intra-arterially, before resuscitation in the adenosine treated group. Resuscitation was performed by re infusion of the sheded blood for 30 minutes. Arterial blood samples were analyzed for biochemical indicators of multiple organ injury: 1) liver function: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 2) renal function: urea and creatinine, 3) pancreatic function: amylase. Results: In the control group there was no significant rise in the serum levels of (i) urea and creatinine, (ii) aspartate aminotransferase (AST) and alanine aminotransferase (ALT), (iii) amylase. While in the adenosine treated group, resuscitation from one hour of hemorrhagic shock resulted in significant rises in the serum levels of (i) urea and creatinine, (ii) aspartate aminotransferase (AST) and alanine aminotransferase (ALT), (iii) amylase. Treatment of rats with 20mM adenosine before resuscitation following one hour of hemorrhagic shock decreased the multiple organ injury and dysfunction caused by hemorrhagic shock. Conclusion: Adenosine attenuated the renal, liver and pancreatic injury caused by hemorrhagic shock and resuscitation in rats. Thus

  17. The Neuroprotective Benefits of Central Adenosine Receptor Stimulation in a Soman Nerve Agent Rat Model

    Science.gov (United States)

    2014-04-01

    where treatment is delayed and nerve agent-induced status epilepticus develops. New therapeutic targets are required to improve survivability and...Exp Ther 304(3): 1307-1313. Compton, J. R. (2004). Adenosine Receptor Agonist Pd 81,723 Protects Against Seizure/ Status Epilepticus and...Dragunow (1994). " Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms." Neuroscience 58(2): 245-261. Youssef, A. F. and B. W

  18. Actinides and rare earths complexation with adenosine phosphate nucleotides

    International Nuclear Information System (INIS)

    Mostapha, Sarah

    2013-01-01

    Organophosphorus compounds are important molecules in both nuclear industry and living systems fields. Indeed, several extractants of organophosphorus compounds (such as TBP, HDEHP) are used in the nuclear fuel cycle reprocessing and in the biological field. For instance, the nucleotides are organophosphates which play a very important role in various metabolic processes. Although the literature on the interactions of actinides with inorganic phosphate is abundant, published studies with organophosphate compounds are generally limited to macroscopic and / or physiological approaches. The objective of this thesis is to study the structure of several organophosphorus compounds with actinides to reach a better understanding and develop new specific buildings blocks. The family of the chosen molecules for this procedure consists of three adenine nucleotides mono, bi and triphosphate (AMP, adenosine monophosphate - ADP, adenosine diphosphate - ATP, adenosine triphosphate) and an amino-alkylphosphate (AEP O-phosphoryl-ethanolamine). Complexes synthesis was conducted in aqueous and weakly acidic medium (2.8-4) for several lanthanides (III) (Lu, Yb, Eu) and actinides (U (VI), Th (IV) and Am (III)). Several analytical and spectroscopic techniques have been used to describe the organization of the synthesized complexes: spectrometric analysis performed by FTIR and NMR were used to identify the functional groups involved in the complexation, analysis by ESI-MS and pH-metric titration were used to determine the solution speciation and EXAFS analyzes were performed on Mars beamline of the SOLEIL synchrotron, have described the local cation environment, for both solution and solid compounds. Some theoretical approaches of DFT were conducted to identify stable structures in purpose of completing the experimental studies. All solid complexes (AMP, ADP, ATP and AEP) have polynuclear structures, while soluble ATP complexes are mononuclear. For all synthesized complexes, it has been

  19. Ethanol-induced increase in portal blood glow: Role of adenosine

    International Nuclear Information System (INIS)

    Orrego, H.; Carmichael, F.J.; Saldivia, V.; Giles, H.G.; Sandrin, S.; Israel, Y.

    1988-01-01

    The mechanism by which ethanol induces an increase in portal vein blood flow was studied in rats using radiolabeled microspheres. Ethanol by gavage resulted in an increase of 50-70% in portal vein blood flow. The ethanol-induced increase in portal blood flow was suppressed by the adenosine receptor blocker 8-phenyltheophylline. By itself, 8-phenyltheophylline was without effect on cardiac output or portal blood flow. Adenosine infusion resulted in a dose-dependent increase in portal blood flow. This adenosine-induced increase in portal blood flow was inhibited by 8-phenyltheophylline in a dose-dependent manner. Both alcohol and adenosine significantly reduced preportal vascular resistance by 40% and 60%, respectively. These effects were fully suppressed by 8-phenyltheophylline. It is concluded that adenosine is a likely candidate to mediate the ethanol-induced increase in portal vein blood flow. It is suggested that an increase in circulating acetate and liver hypoxia may mediate the effects of alcohol by increasing tissue and interstitial adenosine levels

  20. Suppression of adenosine-activated chloride transport by ethanol in airway epithelia.

    Directory of Open Access Journals (Sweden)

    Sammeta V Raju

    Full Text Available Alcohol abuse is associated with increased lung infections. Molecular understanding of the underlying mechanisms is not complete. Airway epithelial ion transport regulates the homeostasis of airway surface liquid, essential for airway mucosal immunity and lung host defense. Here, air-liquid interface cultures of Calu-3 epithelial cells were basolaterally exposed to physiologically relevant concentrations of ethanol (0, 25, 50 and 100 mM for 24 hours and adenosine-stimulated ion transport was measured by Ussing chamber. The ethanol exposure reduced the epithelial short-circuit currents (I(SC in a dose-dependent manner. The ion currents activated by adenosine were chloride conductance mediated by cystic fibrosis transmembrane conductance regulator (CFTR, a cAMP-activated chloride channel. Alloxazine, a specific inhibitor for A(2B adenosine receptor (A(2BAR, largely abolished the adenosine-stimulated chloride transport, suggesting that A(2BAR is a major receptor responsible for regulating the chloride transport of the cells. Ethanol significantly reduced intracellular cAMP production upon adenosine stimulation. Moreover, ethanol-suppression of the chloride secretion was able to be restored by cAMP analogs or by inhibitors to block cAMP degradation. These results imply that ethanol exposure dysregulates CFTR-mediated chloride transport in airways by suppression of adenosine-A(2BAR-cAMP signaling pathway, which might contribute to alcohol-associated lung infections.

  1. Topical adenosine increases thick hair ratio in Japanese men with androgenetic alopecia.

    Science.gov (United States)

    Watanabe, Y; Nagashima, T; Hanzawa, N; Ishino, A; Nakazawa, Y; Ogo, M; Iwabuchi, T; Tajima, M

    2015-12-01

    Hair thickness is more important than hair density in the appearance of baldness in male with androgenetic alopecia (AGA). Adenosine improves hair loss by stimulating hair growth and by thickening hair shafts in women. The objective of this study was to evaluate the hair growth efficacy and safety of topical adenosine in men with AGA. A lotion containing either adenosine or niacinamide was administered to the scalps of 102 Japanese men twice daily for 6 months in a double-blind, randomized study. Efficacy was evaluated by dermatologists who assessed the quality of the hair and by calculating the percentages of vellus-like and thick hairs among the vertex hairs, as well as hair density. Adenosine was significantly (P < 0.05) superior to niacinamide in terms of global improvement of AGA, increase in the percentage of thick hairs (at least 60 μm) and self-assessment of hair thickness by the study participants. No causal adverse event due to the adenosine lotion was observed. These data indicate that adenosine increases thick hair ratio in Japanese men with AGA, and this compound is useful for the improvement of AGA. © 2015 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  2. Safety of adenosine stress myocardial perfusion imaging by a one-route infusion protocol

    International Nuclear Information System (INIS)

    Kawai, Yuko; Kishino, Koh

    2006-01-01

    When adenosine stress testing is performed, a vein is generally accessed in each arm. To determine whether the one-route infusion protocol, that is, infusion via one upper arm vein, is safe, myocardial perfusion imaging was performed during adenosine stress testing in patients with angina pectoris. Sixty-six consecutive patients (43 men, 68±11 years of age) with suspected coronary artery disease were enrolled in this study. For the stress test, adenosine was injected at 120 μg/kg/min for 6 minutes. Systolic blood pressure, diastolic blood pressure, and heart rate did not show any significant changes after injection of the adenosine and radioisotope (RI) tracer. Adverse events during infusion of the adenosine were seen in 42 (64%) patients and included chest discomfort/oppression in 17 (26%) and dyspnea/throat discomfort in 15 (23%). On the other hand, adverse events just after infusion of the RI tracer occurred in 5 (8%) patients and included chest oppression in 2 (3%) and dyspnea in 1 (2%). Almost all adverse events disappeared quickly without treatment. Therefore, we concluded that adenosine stress myocardial perfusion imaging using a one-route infusion protocol is safe and useful to do for patients unable to secure veins in both arms. (author)

  3. Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation.

    Science.gov (United States)

    Delle Donne, K T; Sonsalla, P K

    1994-12-01

    Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A1 and A2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore, concurrent administration of cyclopentyladenosine, an adenosine A1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A1 receptor antagonist. These results indicate that activation of A1 receptors can protect against METH-induced neurotoxicity in mice.

  4. Oral sucrose for heel lance enhances adenosine triphosphate use in preterm neonates with respiratory distress.

    Science.gov (United States)

    Angeles, Danilyn M; Asmerom, Yayesh; Boskovic, Danilo S; Slater, Laurel; Bacot-Carter, Sharon; Bahjri, Khaled; Mukasa, Joseph; Holden, Megan; Fayard, Elba

    2015-01-01

    To examine the effects of oral sucrose on procedural pain, and on biochemical markers of adenosine triphosphate utilization and oxidative stress in preterm neonates with mild to moderate respiratory distress. Preterm neonates with a clinically required heel lance that met study criteria (n = 49) were randomized into three groups: (1) control (n = 24), (2) heel lance treated with placebo and non-nutritive sucking (n = 15) and (3) heel lance treated with sucrose and non-nutritive sucking (n = 10). Plasma markers of adenosine triphosphate degradation (hypoxanthine, xanthine and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the Premature Infant Pain Profile. Data were analyzed using repeated measures analysis of variance, chi-square and one-way analysis of variance. We found that in preterm neonates who were intubated and/or were receiving ⩾30% FiO2, a single dose of oral sucrose given before a heel lance significantly increased markers of adenosine triphosphate use. We found that oral sucrose enhanced adenosine triphosphate use in neonates who were intubated and/or were receiving ⩾30% FiO2. Although oral sucrose decreased pain scores, our data suggest that it also increased energy use as evidenced by increased plasma markers of adenosine triphosphate utilization. These effects of sucrose, specifically the fructose component, on adenosine triphosphate metabolism warrant further investigation.

  5. In vivo effects of adenosine 5´-triphosphate on rat preneoplastic liver

    Directory of Open Access Journals (Sweden)

    Ana V. Frontini

    2011-04-01

    Full Text Available The utilization of adenosine 5´-triphosphate (ATP infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation.

  6. Adenosine signaling promotes regeneration of pancreatic β-cells in vivo

    Science.gov (United States)

    Andersson, Olov; Adams, Bruce A.; Yoo, Daniel; Ellis, Gregory C.; Gut, Philipp; Anderson, Ryan M.; German, Michael S.; Stainier, Didier Y. R.

    2012-01-01

    Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing β-cells is still needed. Using a zebrafish model of diabetes, we screened ~7000 small molecules to identify enhancers of β-cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of β-cell regeneration was the adenosine agonist 5′-N-Ethylcarboxamidoadenosine (NECA), which acting through the adenosine receptor A2aa increased β-cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating β-cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in β-cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes. PMID:22608007

  7. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy

    Directory of Open Access Journals (Sweden)

    Khalid J.H. Alzahrani

    2017-08-01

    Full Text Available Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU and 5F,2′deoxyuridine (5F,2′dUrd, and was designated uridine-uracil transporter 1 (UUT1; the other transporter mediated uptake of adenosine, uridine, 5F,2′dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1. To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [3H]-uridine but not of [3H]-inosine. Conversely, the NT2-like genes mediated uptake of [3H]-inosine but not [3H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2′dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2′dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy. Keywords: Leishmania, Pyrimidine metabolism, Uracil

  8. A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.

    Science.gov (United States)

    Janes, Kali; Esposito, Emanuela; Doyle, Timothy; Cuzzocrea, Salvatore; Tosh, Dillip K; Jacobson, Kenneth A; Salvemini, Daniela

    2014-12-01

    Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. Copyright © 2014

  9. Comparison of chemotherapy and hematopoietic stem cell ...

    African Journals Online (AJOL)

    Aims: Chemotherapy is frequently used as a conditioning regimen to destroy malignant marrow cells before transplantation. Xerostomia, dysphagia, altered taste perception, mucositis, soft‑tissue ulceration, and infection are common adverse oral effects of chemotherapy. The study was aimed to compare decayed, missing, ...

  10. Paradox of Prescribing Late Chemotherapy: Oncologists Explain.

    Science.gov (United States)

    Bluhm, Minnie; Connell, Cathleen M; De Vries, Raymond G; Janz, Nancy K; Bickel, Kathleen E; Silveira, Maria J

    2016-12-01

    The value of chemotherapy for patients with cancer in the last weeks of life warrants examination. Late chemotherapy may not improve survival or quality of life but typically precludes hospice enrollment and may result in additional symptoms, increased use of other aggressive treatments, and worsening quality of life. Few studies have explored oncologists' rationales for administering chemotherapy near death. This study examines the self-reported factors that influence oncologists' decisions about late chemotherapy. In-depth individual interviews were conducted with 17 oncologists through a semistructured interview guide. Interviews were audio recorded and transcribed verbatim. Transcripts were coded and analyzed using conventional content analysis, a qualitative method that allows the detection and analysis of patterns in the data. Clinical factors take priority in determining late chemotherapy decisions when clear treatment choices exist. When clinical factors are ambiguous, emotion becomes a highly salient influence. Oncologists view late chemotherapy to be patient driven and use it to palliate emotional distress and maintain patient hope even when physical benefit is unexpected. Oncologists experience unique and difficult challenges when caring for dying patients, including emotionally draining communication, overwhelming responsibility for life/death, limitations of oncology to heal, and prognostic uncertainty. These challenges are also eased by offering late chemotherapy. The findings reveal a nuanced understanding of why oncologists find it difficult to refuse chemotherapy treatment for patients near death. Optimal end-of-life treatment decisions require supportive interventions and system change, both of which must take into account the challenges oncologists face.

  11. Adenosine diphosphate sugar pyrophosphatase prevents glycogen biosynthesis in Escherichia coli

    Science.gov (United States)

    Moreno-Bruna, Beatriz; Baroja-Fernández, Edurne; Muñoz, Francisco José; Bastarrica-Berasategui, Ainara; Zandueta-Criado, Aitor; Rodríguez-López, Milagros; Lasa, Iñigo; Akazawa, Takashi; Pozueta-Romero, Javier

    2001-01-01

    An adenosine diphosphate sugar pyrophosphatase (ASPPase, EC 3.6.1.21) has been characterized by using Escherichia coli. This enzyme, whose activities in the cell are inversely correlated with the intracellular glycogen content and the glucose concentration in the culture medium, hydrolyzes ADP-glucose, the precursor molecule of glycogen biosynthesis. ASPPase was purified to apparent homogeneity (over 3,000-fold), and sequence analyses revealed that it is a member of the ubiquitously distributed group of nucleotide pyrophosphatases designated as “nudix” hydrolases. Insertional mutagenesis experiments leading to the inactivation of the ASPPase encoding gene, aspP, produced cells with marginally low enzymatic activities and higher glycogen content than wild-type bacteria. aspP was cloned into an expression vector and introduced into E. coli. Transformed cells were shown to contain a dramatically reduced amount of glycogen, as compared with the untransformed bacteria. No pleiotropic changes in the bacterial growth occurred in both the aspP-overexpressing and aspP-deficient strains. The overall results pinpoint the reaction catalyzed by ASPPase as a potential step of regulating glycogen biosynthesis in E. coli. PMID:11416161

  12. On the structure of thorium and americium adenosine triphosphate complexes

    International Nuclear Information System (INIS)

    Mostapha, Sarah; Berton, Laurence; Boubals, Nathalie; Zorz, Nicole; Charbonnel, Marie-Christine; Fontaine-Vive, Fabien; Den Auwer, Christophe; Solari, Pier Lorenzo

    2014-01-01

    The actinides are chemical poisons and radiological hazards. One challenge to better appraise their toxicity and develop countermeasures in case of exposure of living organisms is to better assess pathways of contamination. Because of the high chemical affinity of those actinide elements for phosphate groups and the ubiquity of such chemical functions in biochemistry, nucleotides and in particular adenosine triphosphate nucleotide (ATP) may be considered critical target building blocks for actinides. Combinations of spectroscopic techniques (Fourier transformed Infra Red [FTIR], Electro-spray Ionization Mass Spectrometry [ESI-MS], and Extended X-ray Absorption Fine Structure [EXAFS]) with quantum chemical calculations have been implemented in order to assess the actinides coordination arrangement with ATP. We describe and compare herein the interaction of ATP with thorium and americium; thorium(IV) as a representative of actinide(IV) like plutonium(IV) and americium(III) as a representative of all heavier actinides. In the case of thorium, an insoluble complex is readily formed. In the case of americium, a behavior identical to that described previously for lutetium has been observed with insoluble and soluble complexes. The comparative study of ATP complexation with Th(IV) and Am(III) shows their ability to form insoluble complexes for which a structural model has been proposed by analogy with previously described Lu(III) complexes. (authors)

  13. On the structure of thorium and americium adenosine triphosphate complexes.

    Science.gov (United States)

    Mostapha, Sarah; Fontaine-Vive, Fabien; Berthon, Laurence; Boubals, Nathalie; Zorz, Nicole; Solari, Pier Lorenzo; Charbonnel, Marie Christine; Den Auwer, Christophe

    2014-11-01

    The actinides are chemical poisons and radiological hazards. One challenge to better appraise their toxicity and develop countermeasures in case of exposure of living organisms is to better assess pathways of contamination. Because of the high chemical affinity of those actinide elements for phosphate groups and the ubiquity of such chemical functions in biochemistry, nucleotides and in particular adenosine triphosphate nucleotide (ATP) may be considered critical target building blocks for actinides. Combinations of spectroscopic techniques (Fourier transformed Infra Red [FTIR], Electrospray Ionization Mass Spectrometry [ESI-MS], and Extended X-ray Absorption Fine Structure [EXAFS]) with quantum chemical calculations have been implemented in order to assess the actinides coordination arrangement with ATP. We describe and compare herein the interaction of ATP with thorium and americium; thorium(IV) as a representative of actinide(IV) like plutonium(IV) and americium(III) as a representative of all heavier actinides. In the case of thorium, an insoluble complex is readily formed. In the case of americium, a behavior identical to that described previously for lutetium has been observed with insoluble and soluble complexes. The comparative study of ATP complexation with Th(IV) and Am(III) shows their ability to form insoluble complexes for which a structural model has been proposed by analogy with previously described Lu(III) complexes.

  14. Distribution of adenosine deaminase complexing protein (ADCP) in human tissues.

    Science.gov (United States)

    Dinjens, W N; ten Kate, J; van der Linden, E P; Wijnen, J T; Khan, P M; Bosman, F T

    1989-12-01

    The normal distribution of adenosine deaminase complexing protein (ADCP) in the human body was investigated quantitatively by ADCP-specific radioimmunoassay (RIA) and qualitatively by immunohistochemistry. In these studies we used a specific rabbit anti-human ADCP antiserum. In all 19 investigated tissues, except erythrocytes, ADCP was found by RIA in the soluble and membrane fractions. From all tissues the membrane fractions contained more ADCP (expressed per mg protein) than the soluble fractions. High membrane ADCP concentrations were found in skin, renal cortex, gastrointestinal tract, and prostate. Immunoperoxidase staining confirmed the predominant membrane-associated localization of the protein. In serous sweat glands, convoluted tubules of renal cortex, bile canaliculi, gastrointestinal tract, lung, pancreas, prostate gland, salivary gland, gallbladder, mammary gland, and uterus, ADCP immunoreactivity was found confined to the luminal membranes of the epithelial cells. These data demonstrate that ADCP is present predominantly in exocrine glands and absorptive epithelia. The localization of ADCP at the secretory or absorptive apex of the cells suggests that the function of ADCP is related to the secretory and/or absorptive process.

  15. Adenosine deaminase complexing protein (ADCP) immunoreactivity in colorectal adenocarcinoma.

    Science.gov (United States)

    ten Kate, J; van den Ingh, H F; Khan, P M; Bosman, F T

    1986-04-15

    Immunoreactive adenosine deaminase complexing protein (ADCP) was studied in 91 human colorectal adenocarcinomas. The expression of ADCP was correlated with that of secretory component (SC) and carcinoembryonic antigen (CEA), with the histological grade and the Dukes' stage of the carcinomas. The histological grade was scored semi-quantitatively according to 5 structural and 4 cytological variables. ADCP expression was observed in 3 different staining patterns, namely: (1) diffuse cytoplasmic (77% of the carcinomas); (2) granular cytoplasmic (13%); and (3) membrane-associated (66%). These patterns were observed alone or in combination. Eleven percent of the carcinomas exhibited no ADCP immunoreactivity. Linear regression analysis showed that the expression of ADCP correlates with that of SC and CEA. However, no significant correlation emerged between the histological parameters or the Dukes' stage and any of the immunohistological parameters. Comparison of the histological characteristics of carcinomas exhibiting little or no ADCP immunoreactivity with those showing extensive immunoreactivity, showed that membranous ADCP immunoreactivity occurs more frequently in well-differentiated carcinomas. Structural parameters showed a better correlation with membranous ADCP expression than the cytological variables. It is concluded that membranous expression of ADCP and CEA are indicators of a high level of differentiation as reflected primarily in the structural characteristics of the tumor.

  16. Nanotechnology for Cancer Therapy Based on Chemotherapy

    Directory of Open Access Journals (Sweden)

    Chen-Yang Zhao

    2018-04-01

    Full Text Available Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.

  17. Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early stage Hodgkin lymphoma (Review)

    DEFF Research Database (Denmark)

    Blank, Oliver; von Tresckow, Bastian; Monsef, Ina

    2017-01-01

    BACKGROUND: Combined modality treatment consisting of chemotherapy followed by localised radiotherapy is the standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long- term adverse effects such as secondary malignancies the role of radiotherapy has been questioned...... recently and some clinical study groups advocate chemotherapy only for this indication. OBJECTIVES: To assess the effects of chemotherapy alone compared to chemotherapy plus radiotherapy in adults with early stage HL . SEARCH METHODS: For the or i ginal version of this review, we searched MEDLINE, Embase......-related mortality (RR 0.99; 95% CI 0.14 to 6.90; P = 0.99; low-quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. CRR rate was not reported. AUTHORS' CONCLUSIONS: This systematic review compared the effects of chemotherapy alone...

  18. The adenosine A2B receptor is involved in anion secretion in human pancreatic duct Capan-1 epithelial cells

    DEFF Research Database (Denmark)

    Hayashi, M.; Inagaki, A.; Novak, Ivana

    2016-01-01

    Adenosine modulates a wide variety of biological processes via adenosine receptors. In the exocrine pancreas, adenosine regulates transepithelial anion secretion in duct cells and is considered to play a role in acini-to-duct signaling. To identify the functional adenosine receptors and Cl......− channels important for anion secretion, we herein performed experiments on Capan-1, a human pancreatic duct cell line, using open-circuit Ussing chamber and gramicidin-perforated patch-clamp techniques. The luminal addition of adenosine increased the negative transepithelial potential difference (Vte......) in Capan-1 monolayers with a half-maximal effective concentration value of approximately 10 μM, which corresponded to the value obtained on whole-cell Cl− currents in Capan-1 single cells. The effects of adenosine on Vte, an equivalent short-circuit current (Isc), and whole-cell Cl− currents were inhibited...

  19. Altered sarco(endo)plasmic reticulum calcium adenosine triphosphatase 2a content: Targets for heart failure therapy.

    Science.gov (United States)

    Liu, Gang; Li, Si Qi; Hu, Ping Ping; Tong, Xiao Yong

    2018-05-01

    Sarco(endo)plasmic reticulum calcium adenosine triphosphatase is responsible for transporting cytosolic calcium into the sarcoplasmic reticulum and endoplasmic reticulum to maintain calcium homeostasis. Sarco(endo)plasmic reticulum calcium adenosine triphosphatase is the dominant isoform expressed in cardiac tissue, which is regulated by endogenous protein inhibitors, post-translational modifications, hormones as well as microRNAs. Dysfunction of sarco(endo)plasmic reticulum calcium adenosine triphosphatase is associated with heart failure, which makes sarco(endo)plasmic reticulum calcium adenosine triphosphatase a promising target for heart failure therapy. This review summarizes current approaches to ameliorate sarco(endo)plasmic reticulum calcium adenosine triphosphatase function and focuses on phospholamban, an endogenous inhibitor of sarco(endo)plasmic reticulum calcium adenosine triphosphatase, pharmacological tools and gene therapies.

  20. Splenic abscess in cancer chemotherapy.

    Science.gov (United States)

    Ismail, Essadi; El Barni, Rachid; Lahkim, Mohamed; Rokhsi, Redouane; Atmane, Elmehdi; El Fikri, Abdelghani; Bouchama, Rachid; Achour, Abdessamad; Zyani, Mohamed

    2015-11-11

    Splenic abcess is an uncommon complication for cancer treatment. It occurs more frequently in immunocompromised patients. They are characterized by high mortality. The classic triad (fever, pain of the left hypochondrium, and sensitive mass left) is only present in one-third of cases the clinical spectrum ranging from no symptoms to events such as fever, nausea, vomiting, weight loss, abdominal pain left, splenomegaly. Treatment options are limited, but must be discussed and adapted to the patient profile. We report the case of a 62-year-old Arabic male, diagnosed with metastatic lung adenocarcinoma, who, after several cycles of chemotherapy, presented symptoms and signs of splenic abcess. Splenic abcess is rare situation, which must be actively researched, to have access to an optimal therapeutic approach.

  1. Ecto-ATPase inhibition: ATP and adenosine release under physiological and ischemic in vivo conditions in the rat striatum.

    Science.gov (United States)

    Melani, Alessia; Corti, Francesca; Stephan, Holger; Müller, Christa E; Donati, Chiara; Bruni, Paola; Vannucchi, Maria Giuliana; Pedata, Felicita

    2012-01-01

    In the central nervous system (CNS) ATP and adenosine act as transmitters and neuromodulators on their own receptors but it is still unknown which part of extracellular adenosine derives per se from cells and which part is formed from the hydrolysis of released ATP. In this study extracellular concentrations of adenosine and ATP from the rat striatum were estimated by the microdialysis technique under in vivo physiological conditions and after focal ischemia induced by medial cerebral artery occlusion. Under physiological conditions, adenosine and ATP concentrations were in the range of 130 nmol/L and 40 nmol/L, respectively. In the presence of the novel ecto-ATPase inhibitor, PV4 (100 nmol/L), the extracellular concentration of ATP increased 12-fold to ~360 nmol/L but the adenosine concentration was not altered. This demonstrates that, under physiological conditions, adenosine is not a product of extracellular ATP. In the first 4h after ischemia, adenosine increased to ~690 nmol/L and ATP to ~50 nmol/L. In the presence of PV4 the extracellular concentration of ATP was in the range of 450 nmol/L and a significant decrease in extracellular adenosine (to ~270 nmol/L) was measured. The contribution of extracellular ATP to extracellular adenosine was maximal in the first 20 min after ischemia onset. Furthermore we demonstrated, by immunoelectron microscopy, the presence of the concentrative nucleoside transporter CNT2 on plasma and vesicle membranes isolated from the rat striatum. These results are in favor that adenosine is transported in vesicles and is released in an excitation-secretion manner under in vivo physiological conditions. Early after ischemia, extracellular ATP is hydrolyzed by ecto-nucleotidases which significantly contribute to the increase in extracellular adenosine. To establish the contribution of extracellular ATP to adenosine might constitute the basis for devising a correct putative purinergic strategy aimed at protection from ischemic damage

  2. Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents: an in vitro study.

    Directory of Open Access Journals (Sweden)

    Robert Edward Sims

    Full Text Available Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K(+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state.

  3. Radio-chromatographic determination of plasmatic adenosine deaminase (A.D.); Determination radiochromatographique de l'adenosine deaminase (A.D.)

    Energy Technology Data Exchange (ETDEWEB)

    Chivot, J J; Depernet, D; Caen, J [Commissariat a l' Energie Atomique, Bruyeres-le-Chatel (France). Centre d' Etudes

    1970-07-01

    We were able, by using a radio-chromatographic method, to measure an adenosine deaminase activity in normal human heparinized platelet-poor plasma, which can degrade 0.016 {mu}M adenosine. This activity suppressed by heating 56 C for 30 minutes is inhibited by high concentrations of urea and is proportional to the amount of plasma, source of enzyme, in the systems. (authors) [French] Nous avons pu, en utilisant une methode radiochromatographique, mesurer une activite adenosine deaminasique dans le plasma humain pauvre en plaquettes heparine qui peut degrader 0,016 {mu}M d'adenosine. Cette activite qui est supprimee par chauffage a 56 degres pendant 30 minutes, est reduite par conservation a -20 C pendant une semaine, est inhibee par d'importantes concentrations d'uree et ne l'est pas, ni par le dipyridamol, ni par le pHMB. Cette activite est proportionnelle a la quantite de plasma, source d'enzyme, mise dans les differents systemes reactifs. (auteur)

  4. Structural basis of the substrate specificity of Bacillus cereus adenosine phosphorylase

    Energy Technology Data Exchange (ETDEWEB)

    Dessanti, Paola [Cornell University, Ithaca, NY 14853-1301 (United States); Università di Sassari, (Italy); Zhang, Yang [Cornell University, Ithaca, NY 14853-1301 (United States); Allegrini, Simone [Università di Sassari, (Italy); Tozzi, Maria Grazia [Università di Pisa, (Italy); Sgarrella, Francesco [Università di Sassari, (Italy); Ealick, Steven E., E-mail: see3@cornell.edu [Cornell University, Ithaca, NY 14853-1301 (United States)

    2012-03-01

    Adenosine phosphorylase from B. cereus shows a strong preference for adenosine over other 6-oxopurine nucleosides. Mutation of Asp204 to asparagine reduces the efficiency of adenosine cleavage but does not affect inosine cleavage, effectively reversing the substrate specificity. The structures of D204N complexes explain these observations. Purine nucleoside phosphorylases catalyze the phosphorolytic cleavage of the glycosidic bond of purine (2′-deoxy)nucleosides, generating the corresponding free base and (2′-deoxy)ribose 1-phosphate. Two classes of PNPs have been identified: homotrimers specific for 6-oxopurines and homohexamers that accept both 6-oxopurines and 6-aminopurines. Bacillus cereus adenosine phosphorylase (AdoP) is a hexameric PNP; however, it is highly specific for 6-aminopurines. To investigate the structural basis for the unique substrate specificity of AdoP, the active-site mutant D204N was prepared and kinetically characterized and the structures of the wild-type protein and the D204N mutant complexed with adenosine and sulfate or with inosine and sulfate were determined at high resolution (1.2–1.4 Å). AdoP interacts directly with the preferred substrate through a hydrogen-bond donation from the catalytically important residue Asp204 to N7 of the purine base. Comparison with Escherichia coli PNP revealed a more optimal orientation of Asp204 towards N7 of adenosine and a more closed active site. When inosine is bound, two water molecules are interposed between Asp204 and the N7 and O6 atoms of the nucleoside, thus allowing the enzyme to find alternative but less efficient ways to stabilize the transition state. The mutation of Asp204 to asparagine led to a significant decrease in catalytic efficiency for adenosine without affecting the efficiency of inosine cleavage.

  5. Adenosine enhances sweet taste through A2B receptors in the taste bud.

    Science.gov (United States)

    Dando, Robin; Dvoryanchikov, Gennady; Pereira, Elizabeth; Chaudhari, Nirupa; Roper, Stephen D

    2012-01-04

    Mammalian taste buds use ATP as a neurotransmitter. Taste Receptor (type II) cells secrete ATP via gap junction hemichannels into the narrow extracellular spaces within a taste bud. This ATP excites primary sensory afferent fibers and also stimulates neighboring taste bud cells. Here we show that extracellular ATP is enzymatically degraded to adenosine within mouse vallate taste buds and that this nucleoside acts as an autocrine neuromodulator to selectively enhance sweet taste. In Receptor cells in a lingual slice preparation, Ca(2+) mobilization evoked by focally applied artificial sweeteners was significantly enhanced by adenosine (50 μM). Adenosine had no effect on bitter or umami taste responses, and the nucleoside did not affect Presynaptic (type III) taste cells. We also used biosensor cells to measure transmitter release from isolated taste buds. Adenosine (5 μM) enhanced ATP release evoked by sweet but not bitter taste stimuli. Using single-cell reverse transcriptase (RT)-PCR on isolated vallate taste cells, we show that many Receptor cells express the adenosine receptor, Adora2b, while Presynaptic (type III) and Glial-like (type I) cells seldom do. Furthermore, Adora2b receptors are significantly associated with expression of the sweet taste receptor subunit, Tas1r2. Adenosine is generated during taste stimulation mainly by the action of the ecto-5'-nucleotidase, NT5E, and to a lesser extent, prostatic acid phosphatase. Both these ecto-nucleotidases are expressed by Presynaptic cells, as shown by single-cell RT-PCR, enzyme histochemistry, and immunofluorescence. Our findings suggest that ATP released during taste reception is degraded to adenosine to exert positive modulation particularly on sweet taste.

  6. Three minute versus six minute adenosine infusion in myocardial perfusion scintigraphy

    International Nuclear Information System (INIS)

    Gopinath, G.; Naojee, S.A.; Croasdale, J.; Johnson, G.; Hilson, A.J.W.; Buscombe, J.R.

    2003-01-01

    Pharmacological stress imaging techniques are used widely in clinical nuclear cardiology for evaluation of ischemic heart disease. Adenosine is often used but is expensive and causes significant side effects .The aim of this retrospective review was to study the tolerance and efficacy, of adenosine infusion of a 3 minute (min) versus the conventional 6 min stress protocol and to assess the cost efficiency of the 3 min protocol. Three hundred thirty one patients had myocardial scintigraphy using adenosine as a stressing agent. Blood pressure, heart rate and ECG were recorded at baseline and during the test. Symptoms (flushing, headache, chest pain, dyspnoea, neck pain) were recorded throughout the adenosine infusion. All the patients had had either 6 min or 3 min adenosine infusion at 140 mg/kg per minute. 169 of them had side effects. Flushing (32% at 3 min vs 50 % at 6 min, p<0.05), headache (11.5% at 3 min vs 7 % at 6 min p-not significant-ns), chest pain (8% at 3 min vs 13 % at 6 min, ns), dyspnoea (7% at 3 min vs %10 at 6 min, ns), ECG changes (10% at 3 min vs 28% at 6 min, p<0.05), neck pain (4.5% at 3 min vs 9% at 6 min, ns), abdominal discomfort (3% at 3 min vs 3% at 6 min, ns) and fall in blood pressure (6% at 3 min vs 8.5% at 6 min, ns). The change in heart rate was not significant with either protocol. The 6 min and 3 min infusions of adenosine had similar accuracy (73% vs 70%) for the detection of coronary artery disease. The patients tolerated the 3 min protocol better with only 40% of the patients having minimal side effects compared with 60% for the 6 mon protocol. The 3 min protocol is also cost effective as it uses less adenosine and therefore reduces total costs by 40 US$ per patient. (author)

  7. Ethanol-induced increase in portal blood flow: Role of acetate and A1- and A2-adenosine receptors

    International Nuclear Information System (INIS)

    Carmichael, F.J.; Saldivia, V.; Varghese, G.A.; Israel, Y.; Orrego, H.

    1988-01-01

    The increase in portal blood flow induced by ethanol appears to be adenosine mediated. Acetate, which is released by the liver during ethanol metabolism, is known to increase adenosine levels in tissues and in blood. The effects of acetate on portal blood flow were investigated in rats using the microsphere technique. The intravenous infusion of acetate resulted in vasodilation of the preportal vasculature and in a dose-dependent increase in portal blood flow. This acetate-induced increase in portal blood flow was suppressed by the adenosine receptor blocker, 8-phenyltheophylline. Using the A 1 -adenosine receptor agonist N-6-cyclohexyl adenosine and the A 2 -agonist 5'-N-ethylcarboxamido adenosine, we demonstrate that the effect of adenosine on the preportal vasculature is mediated by the A 2 -subtype of adenosine receptors. In conclusion, these data support the hypothesis that the increase in portal blood flow after ethanol administration results from a preportal vasodilatory effect of adenosine formed from acetate metabolism in extrahepatic tissues

  8. Ability of γδ T cells to modulate the Foxp3 T cell response is dependent on adenosine.

    Directory of Open Access Journals (Sweden)

    Dongchun Liang

    Full Text Available Whether γδ T cells inhibit or enhance the Foxp3 T cell response depends upon their activation status. The critical enhancing effector in the supernatant is adenosine. Activated γδ T cells express adenosine receptors at high levels, which enables them to deprive Foxp3+ T cells of adenosine, and to inhibit their expansion. Meanwhile, cell-free supernatants of γδ T cell cultures enhance Foxp3 T cell expansion. Thus, inhibition and enhancement by γδ T cells of Foxp3 T cell response are a reflection of the balance between adenosine production and absorption by γδ T cells. Non-activated γδ T cells produce adenosine but bind little, and thus enhance the Foxp3 T cell response. Activated γδ T cells express high density of adenosine receptors and have a greatly increased ability to bind adenosine. Extracellular adenosine metabolism and expression of adenosine receptor A2ARs by γδ T cells played a major role in the outcome of γδ and Foxp3 T cell interactions. A better understanding of the functional conversion of γδ T cells could lead to γδ T cell-targeted immunotherapies for related diseases.

  9. Artificial oxygen carrier with pharmacologic actions of adenosine-5'-triphosphate, adenosine, and reduced glutathione formulated to treat an array of medical conditions.

    Science.gov (United States)

    Simoni, Jan; Simoni, Grace; Moeller, John F; Feola, Mario; Wesson, Donald E

    2014-08-01

    Effective artificial oxygen carriers may offer a solution to tackling current transfusion medicine challenges such as blood shortages, red blood cell storage lesions, and transmission of emerging pathogens. These products, could provide additional therapeutic benefits besides oxygen delivery for an array of medical conditions. To meet these needs, we developed a hemoglobin (Hb)-based oxygen carrier, HemoTech, which utilizes the concept of pharmacologic cross-linking. It consists of purified bovine Hb cross-linked intramolecularly with open ring adenosine-5'-triphosphate (ATP) and intermolecularly with open ring adenosine, and conjugated with reduced glutathione (GSH). In this composition, ATP prevents Hb dimerization, and adenosine promotes formation of Hb polymers as well as counteracts the vasoconstrictive and pro-inflammatory properties of Hb via stimulation of adenosine receptors. ATP also serves as a regulator of vascular tone through activation of purinergic receptors. GSH blocks Hb's extravasation and glomerular filtration by lowering the isoelectric point, as well as shields heme from nitric oxide and reactive oxygen species. HemoTech and its manufacturing technology have been broadly tested, including viral and prion clearance validation studies and various nonclinical pharmacology, toxicology, genotoxicity, and efficacy tests. The clinical proof-of-concept was carried out in sickle cell anemia subjects. The preclinical and clinical studies indicate that HemoTech works as a physiologic oxygen carrier and has efficacy in treating: (i) acute blood loss anemia by providing a temporary oxygen bridge while stimulating an endogenous erythropoietic response; (ii) sickle cell disease by counteracting vaso-occlusive/inflammatory episodes and anemia; and (iii) ischemic vascular diseases particularly thrombotic and restenotic events. The pharmacologic cross-linking of Hb with ATP, adenosine, and GSH showed usefulness in designing an artificial oxygen carrier for

  10. Cerebral adenosine A₁ receptors are upregulated in rodent encephalitis.

    Science.gov (United States)

    Paul, Soumen; Khanapur, Shivashankar; Boersma, Wytske; Sijbesma, Jurgen W; Ishiwata, Kiichi; Elsinga, Philip H; Meerlo, Peter; Doorduin, Janine; Dierckx, Rudi A; van Waarde, Aren

    2014-05-15

    Adenosine A1 receptors (A1Rs) are implied in the modulation of neuroinflammation. Activation of cerebral A1Rs acts as a brake on the microglial response after traumatic brain injury and has neuroprotective properties in animal models of Parkinson's disease and multiple sclerosis. Neuroinflammatory processes in turn may affect the expression of A1Rs, but the available data is limited and inconsistent. Here, we applied an animal model of encephalitis to assess how neuroinflammation affects the expression of A1Rs. Two groups of animals were studied: Infected rats (n=7) were intranasally inoculated with herpes simplex virus-1 (HSV-1, 1 × 10(7) plaque forming units), sham-infected rats (n=6) received only phosphate-buffered saline. Six or seven days later, microPET scans (60 min with arterial blood sampling) were made using the tracer 8-dicyclopropyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX). Tracer clearance from plasma and partition coefficient (K₁/k₂ estimated from a 2-tissue compartment model fit) were not significantly altered after virus infection. PET tracer distribution volume calculated from a Logan plot was significantly increased in the hippocampus (+37%) and medulla (+27%) of virus infected rats. Tracer binding potential (k₃/k₄ estimated from the model fit) was significantly increased in the cerebellum (+87%) and the medulla (+148%) which may indicate increased A1R expression. This was confirmed by immunohistochemical analysis showing a strong increase of A1R immunoreactivity in the cerebellum of HSV-1-infected rats. Both the quantitative PET data and immunohistochemical analysis indicate that A1Rs are upregulated in brain areas where active virus is present. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Exercise and chemotherapy-induced amenorrhea.

    Science.gov (United States)

    Mathis, Katlynn M; Sturgeon, Kathleen M; Winkels, Renate M; Wiskemann, Joachim; Williams, Nancy I; Schmitz, Kathryn

    2018-07-01

    Chemotherapy-induced amenorrhea (CIA) is the temporary or permanent loss of menses experienced by premenopausal women undergoing chemotherapy treatment for cancer. Two possible mechanisms through which chemotherapy induces CIA have been identified: systemic endothelial dysfunction, resulting in decreased blood flow to the ovaries, and increased oxidative stress within the ovaries, both of which are proposed to lead to apoptosis of follicles. Endothelial dysfunction in ovarian arteries in women undergoing or who have undergone chemotherapy treatment is characterized by prothrombotic changes and thickening of the vascular wall. These changes result in occlusion of the blood vessels. Oxidative stress is increased and antioxidants decreased in the ovaries secondary to chemotherapy drugs, specifically cyclophosphamide. It is hypothesized that low to moderate intensity aerobic exercise during chemotherapy may prevent these changes and lessen the risk for developing CIA in premenopausal women. Low to moderate intensity aerobic exercise has been shown to improve endothelial function and blood flow in patients with cardiovascular disease-a disease state characterized by endothelial dysfunction and for which patients who have undergone chemotherapy are at increased risk. In mice, moderate intensity aerobic exercise has been shown to decrease the amount of oxidative stress within the ovaries, and in humans, chronic aerobic exercise has been shown to increase antioxidant production systemically. This hypothesis should be tested in both a mouse model, using sedentary and exercising mice treated with chemotherapy drugs that commonly result in CIA, as well as a human model to determine the effects of low to moderate intensity aerobic exercise on ovarian function in premenopausal women undergoing chemotherapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Chemotherapy for head and neck cancer

    International Nuclear Information System (INIS)

    Pfister, David G.

    1997-01-01

    Purpose/Objective: The role of chemotherapy in the management of squamous cell carcinoma of the upper aerodigestive tract is undergoing rapid evolution. Historically, the use of chemotherapy was limited to patients with incurable disease who had exhausted all surgical and radiation therapy options. The results of recent randomized trials, however, suggest an increasing role for chemotherapy as part of primary management in patients with unresectable disease; advanced larynx or hypopharynx cancer with the intent of larynx preservation, or advanced nasopharynx cancer. This refresher course will provide a comprehensive overview of the current indications for chemotherapy in the management of these malignancies, and will highlight areas of controversy and future directions of investigation. More specifically, the following areas will be emphasized. 1. The identification of drugs commonly used in the management of head and neck cancer, their customary dosing and side effects. 2. The impact of induction and/or adjuvant chemotherapy combined with surgery and radiation therapy as defined by randomized trials, including a discussion of the Head and Neck Contracts program and the Intergroup adjuvant trial. 3. The development of larynx/function preservation treatment programs, including a review of the Veterans Administration and EORTC larynx preservation studies. 4. The evolving role of chemotherapy as part of innovative combined modality programs, especially in patients with unresectable disease. The rationale and utility of sequential versus concomitant/alternating chemotherapy-radiation strategies, and relevant randomized clinical trials comparing the different strategies will be discussed. 5. The appropriate application of chemotherapy in the palliative setting, including a discussion of the relative merits of single-agent versus combination chemotherapy

  13. Chemotherapy for head and neck cancer

    International Nuclear Information System (INIS)

    Pfister, David G.

    1995-01-01

    Purpose/Objective: The role of chemotherapy in the management of squamous cell carcinoma of the upper aerodigestive tract is undergoing rapid evolution. Historically, the use of chemotherapy was limited to patients with incurable disease who had exhausted all surgical and radiation therapy options. The results of recent randomized trials, however, suggest an increasing role for chemotherapy as part of primary management in patients seeking to avoid potentially morbid surgical procedures or with unresectable disease. This refresher course will provide a comprehensive overview of the current indications for chemotherapy in the management of these malignancies, and will highlight areas of controversy and future directions of investigation. More specifically, the following areas will be emphasized. 1. The identification of drugs commonly used in the management of head and neck cancer, their customary dosing and side effects. 2. The impact of induction and/or adjuvant chemotherapy combined with surgery and radiation therapy as defined by randomized trials, including a discussion of the Head and Neck Contracts program and the Intergroup adjuvant trial. 3. The development of larynx/function preservation treatment programs, including a review of the Memorial Hospital experience with larynx preservation and the Veterans Administration larynx preservation study. 4. The evolving role of chemotherapy as part of innovative combined modality programs, especially in patients with unresectable disease. The rationale and utility of sequential versus concomitant/alternating chemotherapy-radiation strategies, and relevant randomized clinical trials comparing the different strategies will be discussed. 5. The appropriate application of chemotherapy in the palliative setting, including a discussion of the relative merits of single-agent versus combination chemotherapy

  14. Neoadjuvant chemotherapy in locally advanced colon cancer

    DEFF Research Database (Denmark)

    Jakobsen, Anders; Andersen, Fahimeh; Fischer, Anders

    2015-01-01

    BACKGROUND: Neoadjuvant chemotherapy has proven valuable in several tumors, but it has not been elucidated in colon cancer. The present phase II trial addressed the issue in high-risk patients selected by computed tomography (CT) scan. MATERIAL AND METHODS: Patients with resectable colon cancer...... 32% (p = 0.005) translating into a three-year DFS of 94% versus 63% (p = 0.005). CONCLUSION: Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy. Validation in a randomized trial is warranted....

  15. Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

    Science.gov (United States)

    Gaudin, Alice; Yemisci, Müge; Eroglu, Hakan; Lepetre-Mouelhi, Sinda; Turkoglu, Omer Faruk; Dönmez-Demir, Buket; Caban, Seçil; Sargon, Mustafa Fevzi; Garcia-Argote, Sébastien; Pieters, Grégory; Loreau, Olivier; Rousseau, Bernard; Tagit, Oya; Hildebrandt, Niko; Le Dantec, Yannick; Mougin, Julie; Valetti, Sabrina; Chacun, Hélène; Nicolas, Valérie; Desmaële, Didier; Andrieux, Karine; Capan, Yilmaz; Dalkara, Turgay; Couvreur, Patrick

    2014-12-01

    There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

  16. Acute rejection after kidney transplantation promotes graft fibrosis with elevated adenosine level in rat.

    Directory of Open Access Journals (Sweden)

    Mingliang Li

    Full Text Available Chronic allograft nephropathy is a worldwide issue with the major feature of progressive allograft fibrosis, eventually ending with graft loss. Adenosine has been demonstrated to play an important role in process of fibrosis. Our study aimed to investigate the relationship between adenosine and fibrosis in renal allograft acute rejection in rat.Wistar rats and SD rats were selected as experimental animals. Our study designed two groups. In the allograft transplantation group, kidneys of Wistar rats were orthotopically transplanted into SD rat recipients, the same species but not genetically identical, to induce acute rejection. Kidney transplantations of SD rats to SD rats which were genetically identical were served as the control. We established rat models and detected a series of indicators. All data were analyzed statistically. P<0.05 was considered statistically significant.Compared with the control group, levels of adenosine increased significantly in the allograft transplantation group, in which acute rejection was induced (P<0.05. Progressive allograft fibrosis as well as collagen deposition were observed.These findings suggested that level of adenosine was upregulated in acute rejection after kidney allograft transplantation in rat. Acute rejection may promote renal allograft fibrosis via the adenosine signaling pathways.

  17. Adenosine Deaminase Inhibitor EHNA Exhibits a Potent Anticancer Effect Against Malignant Pleural Mesothelioma

    Directory of Open Access Journals (Sweden)

    Yasuhiro Nakajima

    2015-01-01

    Full Text Available Background/Aims: Malignant pleural mesothelioma (MPM is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA inhibitor EHNA as a target of MPM treatment. Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM- and treatment time (24-48 h-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

  18. Adenosine Receptor Stimulation Improves Glucocorticoid-Induced Osteoporosis in a Rat Model

    Directory of Open Access Journals (Sweden)

    Gabriele Pizzino

    2017-09-01

    Full Text Available Glucocorticoid-induced osteoporosis (GIO is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN, an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist, or vehicle (0.9% NaCl. Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist, or zoledronate (as control for gold standard treatment, or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

  19. Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression

    Directory of Open Access Journals (Sweden)

    Laura López-Cruz

    2018-06-01

    Full Text Available Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A1/A2A receptors, and has been demonstrated to modulate behavior in classical animal models of depression. Moreover, selective adenosine receptor antagonists are being assessed for their antidepressant effects in animal studies. This review focuses on how caffeine and selective adenosine antagonists can improve different aspects of depression in humans, as well as in animal models. The effects on motivational symptoms of depression such as anergia, fatigue, and psychomotor slowing receive particular attention. Thus, the ability of adenosine receptor antagonists to reverse the anergia induced by dopamine antagonism or depletion is of special interest. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression.

  20. Aberrant Bone Density in Aging Mice Lacking the Adenosine Transporter ENT1

    Science.gov (United States)

    Hinton, David J.; McGee-Lawrence, Meghan E.; Lee, Moonnoh R.; Kwong, Hoi K.; Westendorf, Jennifer J.; Choi, Doo-Sup

    2014-01-01

    Adenosine is known to regulate bone production and resorption in humans and mice. Type 1 equilibrative nucleoside transporter (ENT1) is responsible for the majority of adenosine transport across the plasma membrane and is ubiquitously expressed in both humans and mice. However, the contribution of ENT1-mediated adenosine levels has not been studied in bone remodeling. With the recent identification of the importance of adenosine signaling in bone homeostasis, it is essential to understand the role of ENT1 to develop novel therapeutic compounds for bone disorders. Here we examined the effect of ENT1 deletion on bone density using X-ray, dual energy X-ray absorptiometry and micro-computerized tomography analysis. Our results show that bone density and bone mineral density is reduced in the lower thoracic and lumbar spine as well as the femur of old ENT1 null mice (>7 months) compared to wild-type littermates. Furthermore, we found increased mRNA expression of tartrate-resistant acid phosphatase (TRAP), an osteoclast marker, in isolated long bones from 10 month old ENT1 null mice compared to wild-type mice. In addition, aged ENT1 null mice displayed severe deficit in motor coordination and locomotor activity, which might be attributed to dysregulated bone density. Overall, our study suggests that ENT1-regulated adenosine signaling plays an essential role in lumbar spine and femur bone density. PMID:24586402

  1. Aberrant bone density in aging mice lacking the adenosine transporter ENT1.

    Directory of Open Access Journals (Sweden)

    David J Hinton

    Full Text Available Adenosine is known to regulate bone production and resorption in humans and mice. Type 1 equilibrative nucleoside transporter (ENT1 is responsible for the majority of adenosine transport across the plasma membrane and is ubiquitously expressed in both humans and mice. However, the contribution of ENT1-mediated adenosine levels has not been studied in bone remodeling. With the recent identification of the importance of adenosine signaling in bone homeostasis, it is essential to understand the role of ENT1 to develop novel therapeutic compounds for bone disorders. Here we examined the effect of ENT1 deletion on bone density using X-ray, dual energy X-ray absorptiometry and micro-computerized tomography analysis. Our results show that bone density and bone mineral density is reduced in the lower thoracic and lumbar spine as well as the femur of old ENT1 null mice (>7 months compared to wild-type littermates. Furthermore, we found increased mRNA expression of tartrate-resistant acid phosphatase (TRAP, an osteoclast marker, in isolated long bones from 10 month old ENT1 null mice compared to wild-type mice. In addition, aged ENT1 null mice displayed severe deficit in motor coordination and locomotor activity, which might be attributed to dysregulated bone density. Overall, our study suggests that ENT1-regulated adenosine signaling plays an essential role in lumbar spine and femur bone density.

  2. Biochemistry of an olfactory purinergic system: dephosphorylation of excitatory nucleotides and uptake of adenosine

    Energy Technology Data Exchange (ETDEWEB)

    Trapido-Rosenthal, H G; Carr, W E; Gleeson, R A

    1987-10-01

    The olfactory organ of the spiny lobster, Panulirus argus, is composed of chemosensory sensilla containing the dendrites of primary chemosensory neurons. Receptors on these dendrites are activated by the nucleotides AMP, ADP, and ATP but not by the nucleoside adenosine. It is shown here that the lobster chemosensory sensilla contain enzymes that dephosphorylate excitatory nucleotides and an uptake system that internalizes the nonexcitatory dephosphorylated product adenosine. The uptake of (/sup 3/H)-adenosine is saturable with increasing concentration, linear with time for up to 3 h, sodium dependent, insensitive to moderate pH changes and has a Km of 7.1 microM and a Vmax of 5.2 fmol/sensillum/min (573 fmol/micrograms of protein/min). Double-label experiments show that sensilla dephosphorylate nucleotides extracellularly; /sup 3/H from adenine-labeled AMP or ATP is internalized, whereas 32P from phosphate-labeled nucleotides is not. The dephosphorylation of AMP is very rapid; /sup 3/H from AMP is internalized at the same rate as /sup 3/H from adenosine. Sensillar 5'-ectonucleotidase activity is inhibited by ADP and the ADP analog alpha, beta-methylene ADP. Collectively, these results indicate that the enzymes and the uptake system whereby chemosensory sensilla of the lobster inactivate excitatory nucleotides and clear adenosine from extracellular spaces are very similar to those present in the internal tissues of vertebrates, where nucleotides have many neuroactive effects.

  3. Investigations into the origin of the molecular recognition of several adenosine deaminase inhibitors.

    Science.gov (United States)

    Gillerman, Irina; Fischer, Bilha

    2011-01-13

    Inhibitors of adenosine deaminase (ADA, EC 3.5.4.4) are potential therapeutic agents for the treatment of various health disorders. Several highly potent inhibitors were previously identified, yet they exhibit unacceptable toxicities. We performed a SAR study involving a series of C2 or C8 substituted purine-riboside analogues with a view to discover less potent inhibitors with a lesser toxicity. We found that any substitution at C8 position of nebularine resulted in total loss of activity toward calf intestinal ADA. However, several 2-substituted-adenosine, 8-aza-adenosine, and nebularine analogues exhibited inhibitory activity. Specifically, 2-Cl-purine riboside, 8-aza-2-thiohexyl adenosine, 2-thiohexyl adenosine, and 2-MeS-purine riboside were found to be competitive inhibitors of ADA with K(i) values of 25, 22, 6, and 3 μM, respectively. We concluded that electronic parameters are not major recognition determinants of ADA but rather steric parameters. A C2 substituent which fits ADA hydrophobic pocket and improves H-bonding with the enzyme makes a good inhibitor. In addition, a gg rotamer about C4'-C5' bond is apparently an important recognition determinant.

  4. Astrocyte-derived adenosine is central to the hypnogenic effect of glucose

    Science.gov (United States)

    Scharbarg, Emeric; Daenens, Marion; Lemaître, Frédéric; Geoffroy, Hélène; Guille-Collignon, Manon; Gallopin, Thierry; Rancillac, Armelle

    2016-01-01

    Sleep has been hypothesised to maintain a close relationship with metabolism. Here we focus on the brain structure that triggers slow-wave sleep, the ventrolateral preoptic nucleus (VLPO), to explore the cellular and molecular signalling pathways recruited by an increase in glucose concentration. We used infrared videomicroscopy on ex vivo brain slices to establish that glucose induces vasodilations specifically in the VLPO via the astrocytic release of adenosine. Real-time detection by in situ purine biosensors further revealed that the adenosine level doubles in response to glucose, and triples during the wakefulness period. Finally, patch-clamp recordings uncovered the depolarizing effect of adenosine and its A2A receptor agonist, CGS-21680, on sleep-promoting VLPO neurons. Altogether, our results provide new insights into the metabolically driven release of adenosine. We hypothesise that adenosine adjusts the local energy supply to local neuronal activity in response to glucose. This pathway could contribute to sleep-wake transition and sleep intensity. PMID:26755200

  5. Extracellular adenosine-induced Rac1 activation in pulmonary endothelium: Molecular mechanisms and barrier-protective role.

    Science.gov (United States)

    Kovacs-Kasa, Anita; Kim, Kyung Mi; Cherian-Shaw, Mary; Black, Stephen M; Fulton, David J; Verin, Alexander D

    2018-08-01

    We have previously shown that Gs-coupled adenosine receptors (A2a) are primarily involved in adenosine-induced human pulmonary artery endothelial cell (HPAEC) barrier enhancement. However, the downstream events that mediate the strengthening of the endothelial cell (EC) barrier via adenosine signaling are largely unknown. In the current study, we tested the overall hypothesis that adenosine-induced Rac1 activation and EC barrier enhancement is mediated by Gs-dependent stimulation of cAMP-dependent Epac1-mediated signaling cascades. Adenoviral transduction of HPAEC with constitutively-active (C/A) Rac1 (V12Rac1) significantly increases transendothelial electrical resistance (TER) reflecting an enhancement of the EC barrier. Conversely, expression of an inactive Rac1 mutant (N17Rac1) decreases TER reflecting a compromised EC barrier. The adenosine-induced increase in TER was accompanied by activation of Rac1, decrease in contractility (MLC dephosphorylation), but not Rho inhibition. Conversely, inhibition of Rac1 activity attenuates adenosine-induced increase in TER. We next examined the role of cAMP-activated Epac1 and its putative downstream targets Rac1, Vav2, Rap1, and Tiam1. Depletion of Epac1 attenuated the adenosine-induced Rac1 activation and the increase in TER. Furthermore, silencing of Rac1 specific guanine nucleotide exchange factors (GEFs), Vav2 and Rap1a expression significantly attenuated adenosine-induced increases in TER and activation of Rac1. Depletion of Rap1b only modestly impacted adenosine-induced increases in TER and Tiam1 depletion had no effect on adenosine-induced Rac1 activation and TER. Together these data strongly suggest that Rac1 activity is required for adenosine-induced EC barrier enhancement and that the activation of Rac1 and ability to strengthen the EC barrier depends, at least in part, on cAMP-dependent Epac1/Vav2/Rap1-mediated signaling. © 2017 Wiley Periodicals, Inc.

  6. The effect of nucleotides and adenosine on stimulus-evoked glutamate release from rat brain cortical slices.

    Science.gov (United States)

    Bennett, G C; Boarder, M R

    2000-10-01

    Evidence has previously been presented that P1 receptors for adenosine, and P2 receptors for nucleotides such as ATP, regulate stimulus-evoked release of biogenic amines from nerve terminals in the brain. Here we investigated whether adenosine and nucleotides exert presynaptic control over depolarisation-elicited glutamate release. Slices of rat brain cortex were perfused and stimulated with pulses of 46 mM K(+) in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (0.2 mM). High K(+) substantially increased efflux of glutamate from the slices. Basal glutamate release was unchanged by the presence of nucleotides or adenosine at concentrations of 300 microM. Adenosine, ATP, ADP and adenosine 5'-O-(3-thiotriphoshate) at 300 microM attenuated depolarisation-evoked release of glutamate. However UTP, 2-methylthio ATP, 2-methylthio ADP, and alpha,beta-methylene ATP at 300 microM had no effect on stimulated glutamate efflux. Adenosine deaminase blocked the effect of adenosine, but left the response to ATP unchanged. The A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine antagonised the inhibitory effect of both adenosine and ATP. Cibacron blue 3GA inhibited stimulus-evoked glutamate release when applied alone. When cibacron blue 3GA was present with ATP, stimulus-evoked glutamate release was almost eliminated. However, this P2 antagonist had no effect on the inhibition by adenosine. These results show that the release of glutamate from depolarised nerve terminals of the rat cerebral cortex is inhibited by adenosine and ATP. ATP appears to act directly and not through conversion to adenosine.

  7. Modulation of short-term social memory in rats by adenosine A1 and A(2A) receptors.

    Science.gov (United States)

    Prediger, Rui D S; Takahashi, Reinaldo N

    2005-03-16

    The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. The present study was designed to examine the role of adenosine receptors in the short-term social memory of rats using the social recognition paradigm. Adenosine (5.0-10.0 mg/kg), the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.025-0.05 mg/kg) and the selective adenosine A(2A) receptor agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA, 1.0-5.0 mg/kg), given by i.p. route 30 min before the test, disrupted the juvenile recognition ability of adult rats. This negative effect of adenosine (5.0 mg/kg, i.p.) on social memory was prevented by pretreatment with the non-selective adenosine receptor antagonist caffeine (10.0 mg/kg, i.p.), the adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1.0 mg/kg, i.p.) and the adenosine A(2A) antagonist 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, 1.0 mg/kg, i.p.). Furthermore, acute administration of caffeine (10.0-30.0 mg/kg, i.p.), DPCPX (1.0-3.0 mg/kg, i.p.) or ZM241385 (0.5-1.0 mg/kg, i.p.) improved the short-term social memory in a specific manner. These results indicate that adenosine modulates the short-term social memory in rats by acting on both A1 and A(2A) receptors, with adenosine receptor agonists and antagonists, respectively, disrupting and enhancing the social memory.

  8. Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A2A antagonists MSX-3 and SCH58261, but not the adenosine A1 antagonist DPCPX.

    Science.gov (United States)

    Collins, Lyndsey E; Galtieri, Daniel J; Brennum, Lise T; Sager, Thomas N; Hockemeyer, Jörg; Müller, Christa E; Hinman, James R; Chrobak, James J; Salamone, John D

    2010-02-01

    Tremulous jaw movements in rats, which can be induced by dopamine (DA) antagonists, DA depletion, and cholinomimetics, have served as a useful model for studies of tremor. Although adenosine A(2A) antagonists can reduce the tremulous jaw movements induced by DA antagonists and DA depletion, there are conflicting reports about the interaction between adenosine antagonists and cholinomimetic drugs. The present studies investigated the ability of adenosine antagonists to reverse the tremorogenic effect of the muscarinic agonist pilocarpine. While the adenosine A(2A) antagonist MSX-3 was incapable of reversing the tremulous jaw movements induced by the 4.0mg/kg dose of pilocarpine, both MSX-3 and the adenosine A(2A) antagonist SCH58261 reversed the tremulous jaw movements elicited by 0.5mg/kg pilocarpine. Systemic administration of the adenosine A(1) antagonist DPCPX failed to reverse the tremulous jaw movements induced by either an acute 0.5mg/kg dose of the cholinomimetic pilocarpine or the DA D2 antagonist pimozide, indicating that the tremorolytic effects of adenosine antagonists may be receptor subtype specific. Behaviorally active doses of MSX-3 and SCH 58261 showed substantial in vivo occupancy of A(2A) receptors, but DPCPX did not. The results of these studies support the use of adenosine A(2A) antagonists for the treatment of tremor. Copyright 2009 Elsevier Inc. All rights reserved.

  9. Cancer chemotherapy and biotherapy: principles and practice

    National Research Council Canada - National Science Library

    Chabner, Bruce; Longo, Dan L

    2011-01-01

    "Updated to include the newest drugs and those currently in development, Cancer Chemotherapy and Biotherapy, Fifth Edition is a comprehensive reference on the preclinical and clinical pharmacology of anticancer agents...

  10. Managing Chemotherapy Side Effects: Hair Loss (Alopecia)

    Science.gov (United States)

    ... C ancer I nstitute Managing Chemotherapy Side Effects Hair Loss (Alopecia) “Losing my hair was hard at first. ... and anywhere on your body may fall out. Hair loss is called alopecia. When will my hair start ...

  11. Novel Combination Chemotherapy for Localized Ewing Sarcoma

    Science.gov (United States)

    In this clinical trial, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide to a standard chemotherapy regimen improves overall survival in patients with extracranial Ewing

  12. Managing Chemotherapy Side Effects: Nausea and Vomiting

    Science.gov (United States)

    N ational C ancer I nstitute Managing Chemotherapy Side Effects U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Nausea and Vomiting “I take medicine so I won’t feel sick ...

  13. Managing Chemotherapy Side Effects: Swelling (Fluid Retention)

    Science.gov (United States)

    N ational C ancer I nstitute Managing Chemotherapy Side Effects Swelling (Fluid retention) “My hands and feet were swollen and puffy. My nurse helped me understand why I had to stop eating salty ...

  14. Nanoscale drug delivery for targeted chemotherapy.

    Science.gov (United States)

    Xin, Yong; Huang, Qian; Tang, Jian-Qin; Hou, Xiao-Yang; Zhang, Pei; Zhang, Long Zhen; Jiang, Guan

    2016-08-28

    Despite significant improvements in diagnostic methods and innovations in therapies for specific cancers, effective treatments for neoplastic diseases still represent major challenges. Nanotechnology as an emerging technology has been widely used in many fields and also provides a new opportunity for the targeted delivery of cancer drugs. Nanoscale delivery of chemotherapy drugs to the tumor site is highly desirable. Recent studies have shown that nanoscale drug delivery systems not only have the ability to destroy cancer cells but may also be carriers for chemotherapy drugs. Some studies have demonstrated that delivery of chemotherapy via nanoscale carriers has greater therapeutic benefit than either treatment modality alone. In this review, novel approaches to nanoscale delivery of chemotherapy are described and recent progress in this field is discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Breast Cancer Chemotherapy and Your Heart

    Science.gov (United States)

    ... of the American Heart Association Cardiology Patient Page Breast Cancer Chemotherapy and Your Heart Christine Unitt , Kamaneh Montazeri , ... Disclosures Footnotes Figures & Tables Info & Metrics eLetters Introduction Breast cancer is the most commonly diagnosed cancer in women. ...

  16. The role of chemotherapy in brain metastases

    International Nuclear Information System (INIS)

    Ohori, Hisatsugu; Takahashi, Shin; Ishioka, Chikashi

    2007-01-01

    Brain metastases are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases have a very poor prognosis with a median survival of 1-2 months. Despite the use of surgery and radiotherapy including whole-brain radiation and stereotactic radiosurgery to locally control brain metastases, survival times for those patients has not improved. Although chemotherapy plays a limited role in the treatment of brain metastases, metastases from lung or breast cancer are often well-controlled by chemotherapy. Accumulating evidence suggest that brain metastases are equally sensitive to chemotherapy as are metastases elsewhere in the body in particular chemotherapy-naive cases. Finally, since nearly a half of patients with brain metastases die from progression of systemic disease, control of systemic disease as well as intracranial disease are both important. (author)

  17. Chemotherapy-induced sclerosing cholangitis

    Energy Technology Data Exchange (ETDEWEB)

    Sandrasegaran, K.; Alazmi, W.M.; Tann, M.; Fogel, E.L.; McHenry, L.; Lehman, G.A

    2006-08-15

    Aim: To review the computed tomography (CT), magnetic resonance imaging (MRI) and cholangiographic findings of chemotherapy-induced sclerosing cholangitis (CISC). Methods: Between January 1995 and December 2004, 11 patients in the endoscopic retrograde cholangiography database were identified with CISC. Twelve CT, four MRI, 69 endoscopic and nine antegrade cholangiographic studies in these patients were reviewed. Serial change in appearance and response to endoscopic treatment were recorded. Results: CISC showed segmental irregular biliary dilatation with strictures of proximal extrahepatic bile ducts. The distal 5 cm of common bile duct was not affected in any patient. CT and MRI findings included altered vascular perfusion of one or more liver segments, liver metastases or peritoneal carcinomatosis. Biliary strictures needed repeated stenting in 10 patients (mean: every 4.7 months). Cirrhosis (n = 1) or confluent fibrosis (n = 0) were uncommon findings. Conclusion: CISC shares similar cholangiographic appearances to primary sclerosing cholangitis (PSC). Unlike PSC, biliary disease primarily involved ducts at the hepatic porta rather than intrahepatic ducts. Multiphasic contrast-enhanced CT or MRI may show evidence of perfusion abnormalities, cavitary liver lesions, or metastatic disease.

  18. Combined chemotherapy including platinum derivatives for medulloblastoma. The usefulness as maintenance chemotherapy

    International Nuclear Information System (INIS)

    Sasaki, Hikaru; Otani, Mitsuhiro; Yoshida, Kazunari; Kagami, Hiroshi; Shimazaki, Kenji; Toya, Shigeo; Kawase, Takeshi

    1997-01-01

    The authors reviewed 24 cerebellar medulloblastoma patients treated at Keio University to determine usefulness of combined chemotherapy including platinum derivatives (cisplatin, carboplatin) as the induction and maintenance treatment. All patients underwent radical surgery and craniospinal irradiation. Ten received adjuvant chemotherapy other than platinum derivatives (mainly with nitrosourea compounds), five were treated by induction and maintenance chemotherapy including platinum derivatives, and nine patients did not undergo chemotherapy. The progression-free survival rate of patients treated with platinum derivatives was better than that of patients treated with other modes of chemotherapy and also that of patients who did not receive chemotherapy. The results were especially good in the case of four patients treated with maintenance chemotherapy consisting of carboplatin and etoposide, two of whom had been free from relapse beyond the risk period of Collins. The occurrences of toxicity in maintenance chemotherapy with carboplatin and etoposide were limited to transient leucopenia. The present study indicates combined chemotherapy including platinum derivatives benefits patients with medulloblastoma, and could be useful, especially as maintenance treatment. (author)

  19. Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyladenosine

    International Nuclear Information System (INIS)

    Goodman, R.R.; Synder, S.H.

    1982-01-01

    Adenosine (A1) receptor binding sites have been localized in rat brain by an in vitro light microscopic autoradiographic method. The binding of [ 3 H]N6-cyclohexyladenosine to slide-mounted rat brain tissue sections has the characteristics of A1 receptors. It is saturable with high affinity and has appropriate pharmacology and stereospecificity. The highest densities of adenosine receptors occur in the molecular layer of the cerebellum, the molecular and polymorphic layers of the hippocampus and dentate gyrus, the medial geniculate body, certain thalamic nuclei, and the lateral septum. High densities also are observed in certain layers of the cerebral cortex, the piriform cortex, the caudate-putamen, the nucleus accumbens, and the granule cell layer of the cerebellum. Most white matter areas, as well as certain gray matter areas, such as the hypothalamus, have negligible receptor concentrations. These localizations suggest possible central nervous system sites of action of adenosine

  20. Circadian rhythm in adenosine A1 receptor of mouse cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Florio, C.; Rosati, A.M.; Traversa, U.; Vertua, R. (Univ. of Trieste (Italy))

    1991-01-01

    In order to investigate diurnal variation in adenosine A1 receptors binding parameters, Bmax and Kd values of specifically bound N6-cyclohexyl-({sup 3}H)adenosine were determined in the cerebral cortex of mice that had been housed under controlled light-dark cycles for 4 weeks. Significant differences were found for Bmax values measured at 3-hr intervals across a 24-h period, with low Bmax values during the light period and high Bmax values during the dark period. The amplitude between 03.00 and 18.00 hr was 33%. No substantial rhythm was found in the Kd values. It is suggested that the changes in the density of A1 receptors could reflect a physiologically-relevant mechanism by which adenosine exerts its modulatory role in the central nervous system.

  1. Circadian rhythm in adenosine A1 receptor of mouse cerebral cortex

    International Nuclear Information System (INIS)

    Florio, C.; Rosati, A.M.; Traversa, U.; Vertua, R.

    1991-01-01

    In order to investigate diurnal variation in adenosine A1 receptors binding parameters, Bmax and Kd values of specifically bound N6-cyclohexyl-[ 3 H]adenosine were determined in the cerebral cortex of mice that had been housed under controlled light-dark cycles for 4 weeks. Significant differences were found for Bmax values measured at 3-hr intervals across a 24-h period, with low Bmax values during the light period and high Bmax values during the dark period. The amplitude between 03.00 and 18.00 hr was 33%. No substantial rhythm was found in the Kd values. It is suggested that the changes in the density of A1 receptors could reflect a physiologically-relevant mechanism by which adenosine exerts its modulatory role in the central nervous system

  2. Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Maclean, D.; Rådegran, G.

    1998-01-01

    BACKGROUND: Adenosine has been proposed to be a locally produced regulator of blood flow in skeletal muscle. However, the fundamental questions of to what extent adenosine is formed in skeletal muscle tissue of humans, whether it is present in the interstitium, and where it exerts its vasodilatory...... rest (0.13+/-0.03, 0.07+/-0.03, and 0.07+/-0.02 micromol/L, respectively) to exercise (10 W; 2.00+/-1.32, 2.08+/-1.23, and 1.65+/-0.50 micromol/L, respectively; Pskeletal muscle...... and demonstrates that adenosine and its precursors increase in the exercising muscle interstitium, at a rate associated with intensity of muscle contraction and the magnitude of muscle blood flow....

  3. Mechanisms of chemotherapy-induced behavioral toxicities

    Directory of Open Access Journals (Sweden)

    Elisabeth G Vichaya

    2015-04-01

    Full Text Available While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms of chemotherapy include (i cognitive deficiencies such as problems with attention, memory and executive functioning; (ii fatigue and motivational deficit; and (iii neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

  4. Chemotherapy for intracranial ependymoma in adults

    International Nuclear Information System (INIS)

    Gramatzki, Dorothee; Roth, Patrick; Felsberg, Jörg; Hofer, Silvia; Rushing, Elisabeth J.; Hentschel, Bettina; Westphal, Manfred; Krex, Dietmar; Simon, Matthias; Schnell, Oliver; Wick, Wolfgang; Reifenberger, Guido; Weller, Michael

    2016-01-01

    Ependymal tumors in adults are rare, accounting for less than 4 % of primary tumors of the central nervous system in this age group. The low prevalence of intracranial ependymoma in adults limits the ability to perform clinical trials. Therefore, treatment decisions are based on small, mostly retrospective studies and the role of chemotherapy has remained unclear. We performed a retrospective study on 17 adult patients diagnosed with intracranial World Health Organisation grade II or III ependymoma, who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Macdonald criteria. Progression-free (PFS) and overall survival (OS) were calculated from start of chemotherapy, using the Kaplan-Meier method. Eleven patients had supratentorial and 6 infratentorial tumors. Ten patients were treated with temozolomide (TMZ), 3 with procarbazine/lomustine/vincristine (PCV), 3 with platinum-based chemotherapy and 1 patient received epirubicin/ifosfamide. Response rates were as follows: TMZ 8/10 stable disease; PCV 3/3 stable disease; platinum-based chemotherapy 1/3 partial response; epirubicin/ifosfamide 1/1 complete response. PFS rates at 6, 12 and 24 months were 52.9, 35.3 and 23.5 %. OS rates at 6, 12 and 24 months were 82.4, 82.4 and 70.1 %. There was no indication for a favourable prognostic role of O 6 -methylguanyl-DNA-methyltransferase (MGMT) promoter methylation which was detected in 3/12 investigated tumors. Survival outcomes in response to chemotherapy in adult intracranial ependymoma patients vary substantially, but individual patients may respond to any kind of chemotherapy. There were too few patients to compare survival data between chemotherapeutic subgroups. The online version of this article (doi:10.1186/s12885-016-2323-0) contains supplementary material, which is available to authorized users

  5. Plasma concentrations of the cyclic nucleotides, adenosine 3',5'-monophosphate and guanosine 3'.5'-monophosphate, in healthy adults treated with theophylline

    DEFF Research Database (Denmark)

    Fenger, M; Eriksen, P B; Andersen, O

    1982-01-01

    Plasma concentrations of cyclic adenosine monophosphate and cyclic guanosine monophosphate were measured in 10 health adults before, during and after periods of theophylline administration. Cyclic adenosine monophosphate concentrations did not change significantly, but cyclic guanosine monophosph...

  6. Neoadjuvant Chemotherapy for Advanced Epithelial Ovarian Cancer

    International Nuclear Information System (INIS)

    Avendano Juan; Buitrago, Giancarlo; Ramos, Pedro; Suescun Oscar

    2010-01-01

    Objective: To describe the experience at the National Cancer Institute (NCI) on the use of neoadjuvant chemotherapy as primary treatment for epithelial ovarian cancer among patients in stages IIIC and IV. Methods: We conducted a descriptive retrospective study (case series type) of patients diagnosed with epithelial ovarian cancer in stages IIIC and IV, treated at the NCI from January 1, 2003 to December 31,2006, who underwent neoadjuvant chemotherapy as primary treatment. Demographic characteristics and clinical outcomes are described. Results: Seventeen patients who fulfilled the above mentioned criteria were selected. Once neoadjuvant chemotherapy ended, 5 patients (29.4%) achieved complete or partial clinical response; 4 (23.8%) remained in stable condition, and 8 (47.6%) showed signs of progressive illness. Interval debulking surgery was performed on objective response patients. Maximum cytoreduction was achieved in 5 patients (100%); first relapse was reported at month 18 of follow-up; 2 disease-free survivors were identified in December, 2007; 8 (49%) reported some degree of non-severe chemotherapy-related toxicity. No mortality was related to chemotherapy, no post surgical complications were observed and no patient required advanced support management. Conclusions: Neoadjuvant chemotherapy, followed by optimal interval debulking surgery among selected patients, can be an alternative treatment for advanced epithelial ovarian cancer among women with irresecability or the critically ill. Further studies with improved design are required to confirm these findings.

  7. Impact of adjuvant chemotherapy for gliomatosis cerebri

    International Nuclear Information System (INIS)

    Kong, Doo-Sik; Nam, Do-Hyun; Kim, Sung Tae; Lee, Jung-Il; Suh, Yeon-Lim; Lim, Do Hoon; Kim, Won Seog; Kwon, Ki-Hoon; Park, Kwan; Kim, Jong Hyun

    2010-01-01

    Gliomatosis cerebri (GC) is characterized by a diffuse infiltration of tumor cells throughout CNS, however, few details are available about the chemotherapeutic effect on GC. The aim of this study was to investigate its clinical course and to determine the efficacy of chemotherapy for GC. Between Jan. 1999 and Dec. 2004, 37 GC patients were diagnosed by biopsy and treated with radiotherapy in a single institution. To determine the efficacy of chemotherapy for GC, we retrospectively reviewed their clinical courses. The study cohort was divided into 2 groups, those with and without receiving post-radiotherapy adjuvant chemotherapy such as temozolomide or nitrosourea-based chemotherapy. Nineteen patients with adjuvant chemotherapy were assigned to the chemotreatment group and 18 with radiotherapy alone were assigned to the control group. Mean survival for chemotreatment group and control group were 24.2 and 13.1 months, respectively (p = 0.045). Time to progression for these groups were 16.0 and 6.0 months, respectively (p = 0.007). Overall review of the clinical course of patients with GC provided that early appearance of new contrast-enhancing lesions within 6 months from the initial diagnosis and higher histological grade were closely associated with poor survival (p < 0.001 and p = 0.008). Adjuvant chemotherapy following radiotherapy could prolong the survival in patients with GC. In addition, newly developed contrast-enhanced lesions on the follow-up MR images indicate the progression of GC

  8. Cancer occurring after radiotherapy and chemotherapy

    International Nuclear Information System (INIS)

    Holm, L.E.

    1990-01-01

    Radiotherapy and chemotherapy can effectively control cancer but can also cause new cancers to develop as long-term complications. Almost all types of cancer have been associated with radiotherapy. The breast, thyroid, and bone marrow are the organs most susceptible to radiation carcinogenesis. The bone marrow is also most frequently involved by chemotherapy and the leukemia risk is much higher than after radiotherapy. The combination of intensive radiotherapy and chemotherapy is particularly leukemogenic. The latent period between radiotherapy/chemotherapy and the appearance of a second primary cancer ranges from a few years to several decades. The risk for a second primary cancer following radiotherapy or chemotherapy emphasizes the need for life long follow-up of patients receiving such treatments. This is particularly the case in individuals with long life expectancy, for example, patients treated for childhood neoplasms. The benefits of radiotherapy and chemotherapy in oncology exceed the risks for second primary cancers. Efforts should be directed towards identifying those patients who will benefit from the treatments so that only they are exposed to the risk. 33 references

  9. Photon buildup factors of some chemotherapy drugs.

    Science.gov (United States)

    Kavaz, Esra; Ahmadishadbad, Nader; Özdemir, Yüksel

    2015-02-01

    Everyday more and more people are diagnosed with some form of cancer. Some are treatable with chemotherapy alone, while others need radiotherapy and occasionally surgery. Recently, concurrent administration of chemotherapy and radiotherapy has been increasingly used in cancer treatment, leading to improvements in survival as well as quality of life. Accordingly, interaction of chemotherapy drugs with radiation will be meaningful to examine. In the present study, gamma ray energy absorption and exposure of buildup factors were computed using the five-parameter geometric progression (G-P) fitting formula for some chemotherapy drugs in the energy range 0.015-15 MeV, and for penetration depths up to 40 mean free path (mfp). The generated energy absorption (EABF) and exposure buildup factors (EBF) of chemotherapy drugs have been studied as a function of penetration depth and incident photon energy. The significant variations in EABF and EBF for chemotherapy drugs have been observed at the moderate energy region. It has been concluded that the buildup of photons is less in azathioprine and is more in vinblastine compared with other drugs. Buildup factors investigated in the present work could be useful in radiation dosimetry and therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Analysis of larger than tetrameric poly(adenosine diphosphoribose) by a radioimmunoassay in nuclei separated in organic solvents

    International Nuclear Information System (INIS)

    Ferro, A.M.; Minaga, T.; Piper, W.N.; Kun, E.

    1978-01-01

    Antibodies were prepared against poly(adenosine diphosphoribose) of an average chain length of 40 adenosine diphosphoribose units by repeated injection of the polymer mixed with methylated albumin and adjuvants into rabbits. The antibody was present mainly in the 7 S fraction of the immunoglobulins. A membrane binding assay was developed, and its specificity determined for the detection of (adenosine diphosphoribose) (n>4) in organs. The method is suitable for the study of the variation of the polymer content of nuclei. The size recognition of the anti-poly(adenosine diphosphoribose) globulin fraction was the same for polymers composed of 4-40 adenosine diphosphoribose units, but smaller oligomers were not detectible. A quantitative extraction technique was developed and applied for radioimmunoassay of nuclear (adenosine diphosphoribose) n>4. Organs were freeze-clamped, freeze dried, broken into subcellular fragments in a colloid mill, and the nuclear fraction was subsequently separated in organic solvents in order to preserve the polymer. Nicotinamide and nicotinic acid, when administered in vivo, augmented the (adenosine diphosphoribose) (n>4) content of rat liver and heart. Tissues of infant pigeons contained larger quantities of (adenosine diphosphoribose) (n>4) than tissues of adult rates. (Auth.)

  11. A cell wall-bound adenosine nucleosidase is involved in the salvage of extracellular ATP in Solanum tuberosum.

    Science.gov (United States)

    Riewe, David; Grosman, Lukasz; Fernie, Alisdair R; Zauber, Henrik; Wucke, Cornelia; Geigenberger, Peter

    2008-10-01

    Extracellular ATP (eATP) has recently been demonstrated to play a crucial role in plant development and growth. To investigate the fate of eATP within the apoplast, we used intact potato (Solanum tuberosum) tuber slices as an experimental system enabling access to the apoplast without interference of cytosolic contamination. (i) Incubation of intact tuber slices with ATP led to the formation of ADP, AMP, adenosine, adenine and ribose, indicating operation of apyrase, 5'-nucleotidase and nucleosidase. (ii) Measurement of apyrase, 5'-nucleotidase and nucleosidase activities in fractionated tuber tissue confirmed the apoplastic localization for apyrase and phosphatase in potato and led to the identification of a novel cell wall-bound adenosine nucleosidase activity. (iii) When intact tuber slices were incubated with saturating concentrations of adenosine, the conversion of adenosine into adenine was much higher than adenosine import into the cell, suggesting a potential bypass of adenosine import. Consistent with this, import of radiolabeled adenine into tuber slices was inhibited when ATP, ADP or AMP were added to the slices. (iv) In wild-type plants, apyrase and adenosine nucleosidase activities were found to be co-regulated, indicating functional linkage of these enzymes in a shared pathway. (v) Moreover, adenosine nucleosidase activity was reduced in transgenic lines with strongly reduced apoplastic apyrase activity. When taken together, these results suggest that a complete ATP salvage pathway is present in the apoplast of plant cells.

  12. Adenosine inhibits neutrophil vascular endothelial growth factor release and transendothelial migration via A2B receptor activation.

    LENUS (Irish Health Repository)

    Wakai, A

    2012-02-03

    The effects of adenosine on neutrophil (polymorphonuclear neutrophils; PMN)-directed changes in vascular permeability are poorly characterized. This study investigated whether adenosine modulates activated PMN vascular endothelial growth factor (vascular permeability factor; VEGF) release and transendothelial migration. PMN activated with tumour necrosis factor-alpha (TNF-alpha, 10 ng\\/mL) were incubated with adenosine and its receptor-specific analogues. Culture supernatants were assayed for VEGF. PMN transendothelial migration across human umbilical vein endothelial cell (HUVEC) monolayers was assessed in vitro. Adhesion molecule receptor expression was assessed flow cytometrically. Adenosine and some of its receptor-specific analogues dose-dependently inhibited activated PMN VEGF release. The rank order of potency was consistent with the affinity profile of human A2B receptors. The inhibitory effect of adenosine was reversed by 3,7-dimethyl-1-propargylxanthine, an A2 receptor antagonist. Adenosine (100 microM) or the A2B receptor agonist 5\\'-N-ethylcarboxamidoadenosine (NECA, 100 microM) significantly reduced PMN transendothelial migration. However, expression of activated PMN beta2 integrins and HUVEC ICAM-1 were not significantly altered by adenosine or NECA. Adenosine attenuates human PMN VEGF release and transendothelial migration via the A2B receptor. This provides a novel target for the modulation of PMN-directed vascular hyperpermeability in conditions such as the capillary leak syndrome.

  13. Adenosine induces vasoconstriction through Gi-dependent activation of phospholipase C in isolated perfused afferent arterioles of mice

    DEFF Research Database (Denmark)

    Hansen, Pernille B; Castrop, Hayo; Briggs, Josie

    2003-01-01

    -induced vasoconstriction was stable for up to 30 min and was most pronounced in the most distal part of the afferent arterioles. Adenosine did not cause vasoconstriction in arterioles from A1AR-/- mice. Pretreatment with pertussis toxin (PTX) (400 ng/ml) for 2 h blocked the vasoconstricting action of adenosine or N(6...

  14. Extracellular 2′,3′-cAMP Is a Source of Adenosine*

    OpenAIRE

    Jackson, Edwin K.; Ren, Jin; Mi, Zaichuan

    2009-01-01

    We discovered that renal injury releases 2′,3′-cAMP (positional isomer of 3′,5′-cAMP) into the interstitium. This finding motivated a novel hypothesis: renal injury leads to activation of an extracellular 2′,3′-cAMP-adenosine pathway (i.e. metabolism of extracellular 2′,3′-cAMP to 3′-AMP and 2′-AMP, which are metabolized to adenosine, a retaliatory metabolite). In isolated rat kidneys, arterial infusions of 2′,3′-cAMP (30 μmol/liter) increased the mean venous secretion of 3′-AMP (3,400-fold),...

  15. Effects of adenosine on renin release from isolated rat glomeruli and kidney slices

    DEFF Research Database (Denmark)

    Skøtt, O; Baumbach, L

    1985-01-01

    was used. The specificity of the renin release process was validated by measuring adenylate kinase as a marker for cytoplasmatic leak. Adenosine (10 micrograms/ml) halved basal renin release from incubated KS as compared to controls (P less than 0.001, n = 8, 8). Renin release from LAG stimulated...... by calcium depletion was also inhibited (P less than 0.05, n = 8, 9) whereas basal release was not affected (n = 6, 12). No effect was detected neither on basal nor on calcium stimulated renin release from SAG. We conclude that adenosine inhibits renin release in vitro by a mechanism independent...

  16. Adenosine as a signaling molecule in the retina: biochemical and developmental aspects

    Directory of Open Access Journals (Sweden)

    ROBERTO PAES-DE-CARVALHO

    2002-09-01

    Full Text Available The nucleoside adenosine plays an important role as a neurotransmitter or neuromodulator in the central nervous system, including the retina. In the present paper we review compelling evidence showing that adenosine is a signaling molecule in the developing retina. In the chick retina, adenosine transporters are present since early stages of development before the appearance of adenosine A1 receptors modulating dopamine-dependent adenylate cyclase activity or A2 receptors that directly activate the enzyme. Experiments using retinal cell cultures revealed that adenosine is taken up by specific cell populations that when stimulated by depolarization or neurotransmitters such as dopamine or glutamate, release the nucleoside through calcium-dependent transporter-mediated mechanisms. The presence of adenosine in the extracellular medium and the long-term activation of adenosine receptors is able to regulate the survival of retinal neurons and blocks glutamate excitoxicity. Thus, adenosine besides working as a neurotransmitter or neuromodulator in the mature retina, is considered as an important signaling molecule during retinal development having important functions such as regulation of neuronal survival and differentiation.O nucleosídeo adenosina apresenta um importante papel como neurotransmissor ou neuromodulador no sistema nervoso central, inclusive na retina. Neste artigo apresentamos uma revisão das evidências que mostram que a adenosina é uma molécula sinalizadora na retina em desenvolvimento. Na retina de pinto, transportadores de adenosina estão presentes desde estágios precoces do desenvolvimento, antes do aparecimento dos receptores A1 que modulam a atividade adenilato ciclase dependente de dopamina ou dos receptores A2 que ativam diretamente a enzima. Experimentos usando culturas de células de retina revelaram que a adenosina é captada por populações celulares específicas que, quando estimuladas por despolarização ou por

  17. Quality of life of lung cancer patients receiving outpatient chemotherapy

    OpenAIRE

    MATSUDA, AYAKO; KOBAYASHI, MIKA; SAKAKIBARA, YUMI; TAMAOKA, MEIYO; FURUIYE, MASASHI; INASE, NAOHIKO; MATSUSHIMA, EISUKE

    2011-01-01

    An increasing number of cancer patients receive outpatient chemotherapy as an alternative to inpatient chemotherapy. The aim of this study was to investigate whether quality of life (QOL) during outpatient chemotherapy was better than QOL prior to hospital discharge, and to explore possible related factors prior to hospital discharge that affected the QOL of lung cancer patients who received outpatient chemotherapy. Lung cancer inpatients who were scheduled for outpatient chemotherapy were as...

  18. n-3 polyunsaturated fatty acid supplementation during cancer chemotherapy

    OpenAIRE

    Morland, Sarah Louise; Martins, Karen J.B.; Mazurak, Vera C.

    2016-01-01

    Evidence from several clinical trials suggests that n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation during cancer chemotherapy improves patient outcomes related to chemotherapy tolerability, regardless of the type of chemotherapy used. While the effects of n-3 PUFA supplementation during chemotherapy have been the subject of several reviews, the mechanisms by which n-3 PUFA improve patient responses through improved chemotherapy tolerability are unclear. There are several barriers c...

  19. Targeting chemotherapy-resistant leukemia by combining DNT cellular therapy with conventional chemotherapy.

    Science.gov (United States)

    Chen, Branson; Lee, Jong Bok; Kang, Hyeonjeong; Minden, Mark D; Zhang, Li

    2018-04-24

    While conventional chemotherapy is effective at eliminating the bulk of leukemic cells, chemotherapy resistance in acute myeloid leukemia (AML) is a prevalent problem that hinders conventional therapies and contributes to disease relapse, and ultimately patient death. We have recently shown that allogeneic double negative T cells (DNTs) are able to target the majority of primary AML blasts in vitro and in patient-derived xenograft models. However, some primary AML blast samples are resistant to DNT cell therapy. Given the differences in the modes of action of DNTs and chemotherapy, we hypothesize that DNT therapy can be used in combination with conventional chemotherapy to further improve their anti-leukemic effects and to target chemotherapy-resistant disease. Drug titration assays and flow-based cytotoxicity assays using ex vivo expanded allogeneic DNTs were performed on multiple AML cell lines to identify therapy-resistance. Primary AML samples were also tested to validate our in vitro findings. Further, a xenograft model was employed to demonstrate the feasibility of combining conventional chemotherapy and adoptive DNT therapy to target therapy-resistant AML. Lastly, blocking assays with neutralizing antibodies were employed to determine the mechanism by which chemotherapy increases the susceptibility of AML to DNT-mediated cytotoxicity. Here, we demonstrate that KG1a, a stem-like AML cell line that is resistant to DNTs and chemotherapy, and chemotherapy-resistant primary AML samples both became more susceptible to DNT-mediated cytotoxicity in vitro following pre-treatment with daunorubicin. Moreover, chemotherapy treatment followed by adoptive DNT cell therapy significantly decreased bone marrow engraftment of KG1a in a xenograft model. Mechanistically, daunorubicin increased the expression of NKG2D and DNAM-1 ligands on KG1a; blocking of these pathways attenuated DNT-mediated cytotoxicity. Our results demonstrate the feasibility and benefit of using DNTs as

  20. Intracellular ATP influences synaptic plasticity in area CA1 of rat hippocampus via metabolism to adenosine and activity-dependent activation of adenosine A1 receptors.

    Science.gov (United States)

    zur Nedden, Stephanie; Hawley, Simon; Pentland, Naomi; Hardie, D Grahame; Doney, Alexander S; Frenguelli, Bruno G

    2011-04-20

    The extent to which brain slices reflect the energetic status of the in vivo brain has been a subject of debate. We addressed this issue to investigate the recovery of energetic parameters and adenine nucleotides in rat hippocampal slices and the influence this has on synaptic transmission and plasticity. We show that, although adenine nucleotide levels recover appreciably within 10 min of incubation, it takes 3 h for a full recovery of the energy charge (to ≥ 0.93) and that incubation of brain slices at 34°C results in a significantly higher ATP/AMP ratio and a threefold lower activity of AMP-activated protein kinase compared with slices incubated at room temperature. Supplementation of artificial CSF with d-ribose and adenine (Rib/Ade) increased the total adenine nucleotide pool of brain slices, which, when corrected for the influence of the dead cut edges, closely approached in vivo values. Rib/Ade did not affect basal synaptic transmission or paired-pulse facilitation but did inhibit long-term potentiation (LTP) induced by tetanic or weak theta-burst stimulation. This decrease in LTP was reversed by strong theta-burst stimulation or antagonizing the inhibitory adenosine A(1) receptor suggesting that the elevated tissue ATP levels had resulted in greater activity-dependent adenosine release during LTP induction. This was confirmed by direct measurement of adenosine release with adenosine biosensors. These observations provide new insight into the recovery of adenine nucleotides after slice preparation, the sources of loss of such compounds in brain slices, the means by which to restore them, and the functional consequences of doing so.

  1. Adapting immunisation schedules for children undergoing chemotherapy.

    Science.gov (United States)

    Fernández-Prada, María; Rodríguez-Martínez, María; García-García, Rebeca; García-Corte, María Dolores; Martínez-Ortega, Carmen

    2018-02-01

    Children undergoing chemotherapy for cancer have special vaccination needs after completion of the treatment. The aim of this study was to evaluate the adaptation of post-chemotherapy vaccination schedules. An observational study was performed on a retrospective cohort that included all children aged from 0 to 14 years, who completed chemotherapy in a tertiary hospital between 2009 and 2015. Inclusion and exclusion criteria were applied. Immunisation was administered in accordance with the guidelines of the Vaccine Advisory Committee of the Spanish Association of Paediatrics. Primary Care immunisation and clinical records of the Preventive Medicine and Public Health Department were reviewed. Of the 99 children who had received chemotherapy, 51 (70.6% males) were included in the study. As regards the type of tumour, 54.9% had a solid organ tumour, and 45.1% had a haematological tumour. Post-chemotherapy immunisation was administered to 70.6%. The most common vaccines received were: diphtheria-tetanus-pertussis or diphtheria-tetanus (54.9%), meningococcus C (41.2%), and seasonal influenza (39.2%). The rate of adaptation of the immunisation schedule after chemotherapy was 9.8%. The pneumococcal conjugate vaccine against 7v or 13v was administered to 21.6% of study subjects. However, only 17.6% received polysaccharide 23v. None received vaccination against hepatitis A. No statistically significant differences were observed between adherence to immunisation schedules and type of tumour (P=.066), gender (P=.304), or age (P=.342). Post-chemotherapy immunisation of children with cancer is poor. The participation of health professionals in training programs and referral of paediatric cancer patients to Vaccine Units could improve the rate of schedule adaptation and proper immunisation of this population. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  2. Adjuvant chemotherapy for endometrial cancer after hysterectomy

    Science.gov (United States)

    Johnson, Nick; Bryant, Andrew; Miles, Tracie; Hogberg, Thomas; Cornes, Paul

    2014-01-01

    Background Endometrial adenocarcinoma (womb cancer) is a malignant growth of the lining (endometrium) of the womb (uterus). It is distinct from sarcomas (tumours of the uterine muscle). Survival depends the risk of microscopic metastases after surgery. Adjuvant (postoperative) chemotherapy improves survival from some other adenocarcinomas, and there is evidence that endometrial cancer is sensitive to cytotoxic therapy. This systematic review examines the effect of chemotherapy on survival after hysterectomy for endometrial cancer. Objectives To assess efficacy of adjuvant (postoperative) chemotherapy for endometrial cancer. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Selection criteria Randomised controlled trials (RCTs) comparing adjuvant chemotherapy with any other adjuvant treatment or no other treatment. Data collection and analysis We used a random-effects meta-analysis to assess hazard ratios (HR) for overall and progression-free survival and risk ratios (RR) to compare death rates and site of initial relapse. Main results Five RCTs compared no additional treatment with additional chemotherapy after hysterectomy and radiotherapy. Four trials compared platinum based combination chemotherapy directly with radiotherapy. Indiscriminate pooling of survival data from 2197 women shows a significant overall survival advantage from adjuvant chemotherapy (RR (95% CI) = 0.88 (0.79 to 0.99)). Sensitivity analysis focused on trials of modern platinum based chemotherapy regimens and found the relative risk of death to be 0.85 ((0.76 to 0.96); number needed to treat for an additional beneficial outcome (NNT) = 25; absolute risk reduction = 4% (1% to 8%)). The HR for overall survival is 0.74 (0.64 to 0.89), significantly

  3. Erythropoiesis- and Thrombopoiesis-Characterizing Parameters in Adenosine A(3) Receptor Knock-Out Mice

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Dušek, L.; Hoferová, Zuzana; Weiterová, Lenka

    2013-01-01

    Roč. 62, č. 3 (2013), s. 305-311 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GAP303/11/0128 Institutional support: RVO:68081707 Keywords : ELEVATING EXTRACELLULAR ADENOSINE * COLONY-STIMULATING FACTOR * HEMATOPOIETIC PROGENITOR CELLS Subject RIV: BO - Biophysics Impact factor: 1.487, year: 2013

  4. Role of adipokinetic hormone and adenosine in the anti-stress response in Drosophila melanogaster

    Czech Academy of Sciences Publication Activity Database

    Zemanová, Milada; Stašková, Tereza; Kodrík, Dalibor

    91-92, AUG 01 (2016), s. 39-47 ISSN 0022-1910 R&D Projects: GA ČR GA14-07172S Institutional support: RVO:60077344 Keywords : stress * AKH * adenosine Subject RIV: ED - Physiology Impact factor: 2.227, year: 2016 http://www.sciencedirect.com/science/article/pii/S0022191016301937

  5. Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds.

    Science.gov (United States)

    Marín-Aguilar, Fabiola; Pavillard, Luis E; Giampieri, Francesca; Bullón, Pedro; Cordero, Mario D

    2017-01-29

    Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor which is activated by increases in adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio and/or adenosine diphosphate (ADP)/ATP ratio, and increases different metabolic pathways such as fatty acid oxidation, glucose transport and mitochondrial biogenesis. In this sense, AMPK maintains cellular energy homeostasis by induction of catabolism and inhibition of ATP-consuming biosynthetic pathways to preserve ATP levels. Several studies indicate a reduction of AMPK sensitivity to cellular stress during aging and this could impair the downstream signaling and the maintenance of the cellular energy balance and the stress resistance. However, several diseases have been related with an AMPK dysfunction. Alterations in AMPK signaling decrease mitochondrial biogenesis, increase cellular stress and induce inflammation, which are typical events of the aging process and have been associated to several pathological processes. In this sense, in the last few years AMPK has been identified as a very interesting target and different nutraceutical compounds are being studied for an interesting potential effect on AMPK induction. In this review, we will evaluate the interaction of the different nutraceutical compounds to induce the AMPK phosphorylation and the applications in diseases such as cancer, type II diabetes, neurodegenerative diseases or cardiovascular diseases.

  6. Formation and breakdown of adenosine in the heart : investigations on myocardial purine metabolismen

    NARCIS (Netherlands)

    P.W. Achterberg (Peter)

    1986-01-01

    textabstractAdenosine, a strong coronary vasodilator, is a breakdown product of the myocardial high-energy phosphate ATP. ATP serves as the direct energy source for contraction of the heart. Chapter 1 of this thesis gives a general introduction on contractility dependent ATP-breakdown, the

  7. Targeting Adenosine Signaling in Parkinson's Disease: From Pharmacological to Non-pharmacological Approaches

    Directory of Open Access Journals (Sweden)

    Luiza R. Nazario

    2017-11-01

    Full Text Available Parkinson's disease (PD is one of the most prevalent neurodegenerative disease displaying negative impacts on both the health and social ability of patients and considerable economical costs. The classical anti-parkinsonian drugs based in dopaminergic replacement are the standard treatment, but several motor side effects emerge during long-term use. This mini-review presents the rationale to several efforts from pre-clinical and clinical studies using adenosine receptor antagonists as a non-dopaminergic therapy. As several studies have indicated that the monotherapy with adenosine receptor antagonists reaches limited efficacy, the usage as a co-adjuvant appeared to be a promising strategy. The formulation of multi-targeted drugs, using adenosine receptor antagonists and other neurotransmitter systems than the dopaminergic one as targets, have been receiving attention since Parkinson's disease presents a complex biological impact. While pharmacological approaches to cure or ameliorate the conditions of PD are the leading strategy in this area, emerging positive aspects have arisen from non-pharmacological approaches and adenosine function inhibition appears to improve both strategies.

  8. REDUCTION OF ADENOSINE-A1-RECEPTORS IN THE PERFORANT PATHWAY TERMINAL ZONE IN ALZHEIMER HIPPOCAMPUS

    NARCIS (Netherlands)

    JAARSMA, D; SEBENS, JB; KORF, J

    1991-01-01

    The cells of origin of the perforant pathway are destroyed in Alzheimer's disease (AD). In rat the adenosine A1-receptors are specifically localized on the perforant path terminals in the molecular layer of the dentate gyrus. In the present study the density of A1-receptors in the hippocampus of

  9. High fetal plasma adenosine concentration: a role for the fetus in preeclampsia?

    LENUS (Irish Health Repository)

    Espinoza, Jimmy

    2012-02-01

    OBJECTIVE: Clinical observations suggest a role for the fetus in the maternal manifestations of preeclampsia, but the possible signaling mechanisms remain unclear. This study compares the fetal plasma concentrations of adenosine from normal pregnancies with those from preeclampsia. STUDY DESIGN: This secondary data analysis included normal pregnancies (n = 27) and patients with preeclampsia (n = 39). Patients with preeclampsia were subclassified into patients with (n = 25) and without (n = 14) abnormal uterine artery Doppler velocimetry (UADV). RESULTS: Fetal plasma concentrations of adenosine were significantly higher in patients with preeclampsia (1.35 +\\/- 0.09 mumol\\/L) than in normal pregnancies (0.52 +\\/- 0.06 mumol\\/L; P < .0001). Fetal plasma concentrations of adenosine in patients with preeclampsia with abnormal UADV (1.78 +\\/- 0.15 mumol\\/L), but not with normal UADV (0.58 +\\/- 0.14 mumol\\/L), were significantly higher than in normal pregnancies (P < .0001). CONCLUSION: Patients with preeclampsia with sonographic evidence of chronic uteroplacental ischemia have high fetal plasma concentrations of adenosine.

  10. Monoolein-alginate beads as a platform to promote adenosine cutaneous localization and wound healing.

    Science.gov (United States)

    Ng, Wing Y; Migotto, Amanda; Ferreira, Thamyres Soares; Lopes, Luciana B

    2017-09-01

    Alginate beads containing the polar lipid monoolein were developed as a strategy to manage wet wounds by providing improved uptake of excess exudate while releasing adenosine locally for promotion of healing. To obtain monoolein-containing beads, the lipid was mixed with almond oil (2:1w/w), and emulsified within the alginate aqueous dispersion, followed by ionotropic gelation in CaCl 2 solution. Compared to alginate-only, monoolein-alginate systems were 1.44-fold larger, their swelling ability was 1.40-fold higher and adenosine cumulative release was approximately 1.30-fold lower (at 24h). Monoolein-alginate beads were considered safe for topical application as demonstrated by the absence of changes on the viability of reconstructed skin equivalents compared to PBS. Smaller amounts of adenosine were delivered by the beads into and across damaged porcine skin (created by an incisional wound) compared to the drug aqueous solution, and cutaneous localization was favored. More specifically, the beads increased the viable skin layer/receptor phase delivery ratio by approximately 4-fold at 12h post-application. Considering the wide range of adenosine physiological effects and the importance of skin localization for its use in wound healing, these results demonstrate the potential of monoolein-containing beads for localized drug delivery and management of wet wounds. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5 '-monophosphate in COPD

    NARCIS (Netherlands)

    Rutgers, [No Value; Koeter, GH; van der Mark, TW; Postma, DS

    The role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) is unclear. We investigated the effects of budesonide on airway hyperresponsiveness (AHR) to methacholine (MCh) and adenosine 5'-monophosphate (AMP), to which we hypothesized the existence of greater

  12. Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) against organophosphate intoxication

    NARCIS (Netherlands)

    Bueters, T.J.H.; Groen, B.; Danhof, M.; IJzerman, A.P.; Helden, H.P.M. van

    2002-01-01

    The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun (O-ethyl-N-dimethylphosphoramidocyanidate), sarin

  13. Synthetic adenosine receptor agonists modulate murine haematopoiesis: a study employing the cytotoxic action of 5-fluorouracil

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Vacek, Antonín; Znojil, V.; Pipalová, I.

    2004-01-01

    Roč. 5, Suppl. 2 (2004), s. S65 ISSN 1466-4860. [Congress of the European Hematology Association /9./. 10.06.2004-13.06.2004, Geneva] R&D Projects: GA ČR GA305/02/0423 Keywords : 5-fluorouracil * haematopoiesis * adenosine Subject RIV: BO - Biophysics

  14. Regulatory role of adenosine signalling in heamatopoiesis: mobilization and in vitro studies

    Czech Academy of Sciences Publication Activity Database

    Weiterová, Lenka; Hofer, Michal; Pospíšil, Milan; Znojil, V.

    2004-01-01

    Roč. 5, Suppl. 2 (2004), s. S65-S66 ISSN 1466-4860. [Congress of the European Hematology Association /9./. 10.06.2004-13.06.2004, Geneva] R&D Projects: GA ČR GP305/03/D050; GA ČR GA305/02/0423 Keywords : adenosine signalling * heamatopoiesis Subject RIV: BO - Biophysics

  15. Adenosine deaminase production by an endophytic bacterium (Lysinibacillus sp.) from Avicennia marina.

    Science.gov (United States)

    Kathiresan, Kandasamy; Saravanakumar, Kandasamy; Sahu, Sunil Kumar; Sivasankaran, Muthu

    2014-06-01

    The present study was carried out with the following objectives: (1) to isolate the endophytic bacilli strains from the leaves of mangrove plant Avicennia marina, (2) to screen the potential strains for the production of adenosine deaminase, (3) to statistically optimize the factors that influence the enzyme activity in the potent strain, and (4) to identify the potent strain using 16S rRNA sequence and construct its phylogenetic tree. The bacterial strains isolated from the fresh leaves of a mangrove A. marina were assessed for adenosine deaminase activity by plating method. Optimization of reaction process was carried out using response surface methodology of central composite design. The potent strain was identified based on 16S rRNA sequencing and phylogeny. Of five endophytic strains, EMLK1 showed a significant deaminase activity over other four strains. The conditions for maximum activity of the isolated adenosine deaminase are described. The potent strain EMLK1 was identified as Lysinibacillus sp. (JQ710723) being the first report as a mangrove endophyte. Mangrove-derived endophytic bacillus strain Lysinibacillus sp. EMLK1 is proved to be a promising source for the production of adenosine deaminase and this enzyme deserves further studies for purification and its application in disease diagnosis.

  16. Hydrolytic cleavage of N-6-substituted adenine derivatives by eukaryotic adenine and adenosine deaminases

    Czech Academy of Sciences Publication Activity Database

    Pospíšilová, H.; Šebela, M.; Novák, Ondřej; Frébort, I.

    2008-01-01

    Roč. 28, č. 6 (2008), s. 335-347 ISSN 0144-8463 R&D Projects: GA ČR(CZ) GA522/06/0022 Institutional research plan: CEZ:AV0Z50380511 Keywords : adenine deaminase * adenosine deaminase (ADA) * aminohydrolase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.525, year: 2008

  17. Molecular mimicry between Helicobacter pylori antigens and H+, K+ --adenosine triphosphatase in human gastric autoimmunity

    NARCIS (Netherlands)

    Amedei, Amedeo; Bergman, Mathijs P.; Appelmelk, Ben J.; Azzurri, Annalisa; Benagiano, Marisa; Tamburini, Carlo; van der Zee, Ruurd; Telford, John L.; Vandenbroucke-Grauls, Christina M. J. E.; D'Elios, Mario M.; del Prete, Gianfranco

    2003-01-01

    Autoimmune gastritis and Helicobacter pylori-associated gastric atrophy develop through similar mechanisms involving the proton pump H+,K+-adenosine triphosphatase as autoantigen. Here, we report that H. pylori-infected patients with gastric autoimmunity harbor in vivo-activated gastric CD4+ T cells

  18. Hematopoiesis in 5-Fluorouracil-Treated Adenosine A(3) Receptor Knock-Out Mice

    Czech Academy of Sciences Publication Activity Database

    Hofer, Michal; Pospíšil, Milan; Dušek, L.; Hoferová, Zuzana; Komůrková, Denisa

    2015-01-01

    Roč. 64, č. 2 (2015), s. 255-262 ISSN 0862-8408 Institutional support: RVO:68081707 Keywords : Adenosine A(3) receptor knock-out mice * Hematopoiesis * 5-fluorouracil-induced hematotoxicity Subject RIV: BO - Biophysics Impact factor: 1.643, year: 2015

  19. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

    Directory of Open Access Journals (Sweden)

    Felicita Pedata

    2014-01-01

    Full Text Available The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes. Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, that is, microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, which upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that in turn promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. A2A receptors present on central cells and on blood cells account for important effects depending on the time-related evolution of the pathological condition. Evidence suggests that A2A receptor antagonists provide early protection via centrally mediated control of excessive excitotoxicity, while A2A receptor agonists provide protracted protection by controlling massive blood cell infiltration in the hours and days after ischemia. Focus on inflammatory responses provides for adenosine A2A receptor agonists a wide therapeutic time-window of hours and even days after stroke.

  20. Structural basis of the substrate specificity of Bacillus cereus adenosine phosphorylase

    Energy Technology Data Exchange (ETDEWEB)

    Dessanti, Paola; Zhang, Yang; Allegrini, Simone; Tozzi, Maria Grazia; Sgarrella, Francesco; Ealick, Steven E. (Cornell); (Sassari); (Pisa)

    2012-10-08

    Purine nucleoside phosphorylases catalyze the phosphorolytic cleavage of the glycosidic bond of purine (2{prime}-deoxy)nucleosides, generating the corresponding free base and (2{prime}-deoxy)ribose 1-phosphate. Two classes of PNPs have been identified: homotrimers specific for 6-oxopurines and homohexamers that accept both 6-oxopurines and 6-aminopurines. Bacillus cereus adenosine phosphorylase (AdoP) is a hexameric PNP; however, it is highly specific for 6-aminopurines. To investigate the structural basis for the unique substrate specificity of AdoP, the active-site mutant D204N was prepared and kinetically characterized and the structures of the wild-type protein and the D204N mutant complexed with adenosine and sulfate or with inosine and sulfate were determined at high resolution (1.2-1.4 {angstrom}). AdoP interacts directly with the preferred substrate through a hydrogen-bond donation from the catalytically important residue Asp204 to N7 of the purine base. Comparison with Escherichia coli PNP revealed a more optimal orientation of Asp204 towards N7 of adenosine and a more closed active site. When inosine is bound, two water molecules are interposed between Asp204 and the N7 and O6 atoms of the nucleoside, thus allowing the enzyme to find alternative but less efficient ways to stabilize the transition state. The mutation of Asp204 to asparagine led to a significant decrease in catalytic efficiency for adenosine without affecting the efficiency of inosine cleavage.

  1. Progress towards novel adenosine receptor therapeutics gleaned from the recent patent literature.

    Science.gov (United States)

    Press, Neil J; Fozard, John R

    2010-08-01

    The principle of treating disease with selective adenosine receptor ligands has been demonstrated with drugs on the market, while the lesser understood receptor subtypes are still being probed with new and drug-like pharmaceutical tools. The field of adenosine receptor research is, therefore, highly important as an emerging and proven point of intervention in disease. From 2008 to 2009, > 120 primary patent applications have claimed adenosine receptor ligands, which we analyze by applicant and target. Particularly significant disclosures are described in detail, paying particular attention to the biological data marshalled to support the case. The first published disclosure of new compounds, compound uses or drug targets is often in the patent literature, which can be difficult to trawl, interpret and verify as it is not subject to peer review. We have critically reviewed this area and share our conclusions regarding progress, trends and identification of early tool compounds or compounds of potential clinical significance ahead of peer-reviewed publication. Adenosine receptor research is a thriving field with continuing claims of exciting new compounds with high specificity and intriguing examples of new uses for such ligands.

  2. A2BR Adenosine Receptor Modulates Sweet Taste in Circumvallate Taste Buds

    Science.gov (United States)

    Yang, Dan; Shultz, Nicole; Vandenbeuch, Aurelie; Ravid, Katya; Kinnamon, Sue C.; Finger, Thomas E.

    2012-01-01

    In response to taste stimulation, taste buds release ATP, which activates ionotropic ATP receptors (P2X2/P2X3) on taste nerves as well as metabotropic (P2Y) purinergic receptors on taste bud cells. The action of the extracellular ATP is terminated by ectonucleotidases, ultimately generating adenosine, which itself can activate one or more G-protein coupled adenosine receptors: A1, A2A, A2B, and A3. Here we investigated the expression of adenosine receptors in mouse taste buds at both the nucleotide and protein expression levels. Of the adenosine receptors, only A2B receptor (A2BR) is expressed specifically in taste epithelia. Further, A2BR is expressed abundantly only in a subset of taste bud cells of posterior (circumvallate, foliate), but not anterior (fungiform, palate) taste fields in mice. Analysis of double-labeled tissue indicates that A2BR occurs on Type II taste bud cells that also express Gα14, which is present only in sweet-sensitive taste cells of the foliate and circumvallate papillae. Glossopharyngeal nerve recordings from A2BR knockout mice show significantly reduced responses to both sucrose and synthetic sweeteners, but normal responses to tastants representing other qualities. Thus, our study identified a novel regulator of sweet taste, the A2BR, which functions to potentiate sweet responses in posterior lingual taste fields. PMID:22253866

  3. A2BR adenosine receptor modulates sweet taste in circumvallate taste buds.

    Directory of Open Access Journals (Sweden)

    Shinji Kataoka

    Full Text Available In response to taste stimulation, taste buds release ATP, which activates ionotropic ATP receptors (P2X2/P2X3 on taste nerves as well as metabotropic (P2Y purinergic receptors on taste bud cells. The action of the extracellular ATP is terminated by ectonucleotidases, ultimately generating adenosine, which itself can activate one or more G-protein coupled adenosine receptors: A1, A2A, A2B, and A3. Here we investigated the expression of adenosine receptors in mouse taste buds at both the nucleotide and protein expression levels. Of the adenosine receptors, only A2B receptor (A2BR is expressed specifically in taste epithelia. Further, A2BR is expressed abundantly only in a subset of taste bud cells of posterior (circumvallate, foliate, but not anterior (fungiform, palate taste fields in mice. Analysis of double-labeled tissue indicates that A2BR occurs on Type II taste bud cells that also express Gα14, which is present only in sweet-sensitive taste cells of the foliate and circumvallate papillae. Glossopharyngeal nerve recordings from A2BR knockout mice show significantly reduced responses to both sucrose and synthetic sweeteners, but normal responses to tastants representing other qualities. Thus, our study identified a novel regulator of sweet taste, the A2BR, which functions to potentiate sweet responses in posterior lingual taste fields.

  4. Effect of adenosine on the growth of human T-lymphocyte leukemia cell line MOLT-4

    Czech Academy of Sciences Publication Activity Database

    Štreitová, Denisa; Weiterová, Lenka; Hofer, Michal; Holá, Jiřina; Horváth, Viktor; Kozubík, Alois; Znojil, V.

    2007-01-01

    Roč. 25, č. 6 (2007), s. 419-426 ISSN 0735-7907 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : MOLT-4 leukemia cell s * cell growth * adenosine Subject RIV: BO - Biophysics Impact factor: 2.106, year: 2007

  5. Regulation of adenosine deaminase (ADA) on induced mouse experimental autoimmune uveitis (EAU) ‡

    Science.gov (United States)

    Liang, Dongchun; Zuo, Aijun; Zhao, Ronglan; Shao, Hui; Kaplan, Henry J.; Sun, Deming

    2016-01-01

    Adenosine is an important regulator of the immune response and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies have shown that adenosine receptor (AR) agonists can be either anti- or pro-inflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoimmune uveitis (EAU) induced by immunizing EAU-prone mice with a known uveitogenic peptide, IRBP1–20. Our results showed that the effective time to administer a single dose of ADA to suppress induction of EAU was 8–14 days post-immunization, shortly before EAU expression, but ADA treatment at other time points exacerbated disease. ADA preferentially inhibited Th17 responses and this effect was γδ T cell-dependent. Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help improve the design of ADA- and AR-targeted therapies. PMID:26856700

  6. A2BR adenosine receptor modulates sweet taste in circumvallate taste buds.

    Science.gov (United States)

    Kataoka, Shinji; Baquero, Arian; Yang, Dan; Shultz, Nicole; Vandenbeuch, Aurelie; Ravid, Katya; Kinnamon, Sue C; Finger, Thomas E

    2012-01-01

    In response to taste stimulation, taste buds release ATP, which activates ionotropic ATP receptors (P2X2/P2X3) on taste nerves as well as metabotropic (P2Y) purinergic receptors on taste bud cells. The action of the extracellular ATP is terminated by ectonucleotidases, ultimately generating adenosine, which itself can activate one or more G-protein coupled adenosine receptors: A1, A2A, A2B, and A3. Here we investigated the expression of adenosine receptors in mouse taste buds at both the nucleotide and protein expression levels. Of the adenosine receptors, only A2B receptor (A2BR) is expressed specifically in taste epithelia. Further, A2BR is expressed abundantly only in a subset of taste bud cells of posterior (circumvallate, foliate), but not anterior (fungiform, palate) taste fields in mice. Analysis of double-labeled tissue indicates that A2BR occurs on Type II taste bud cells that also express Gα14, which is present only in sweet-sensitive taste cells of the foliate and circumvallate papillae. Glossopharyngeal nerve recordings from A2BR knockout mice show significantly reduced responses to both sucrose and synthetic sweeteners, but normal responses to tastants representing other qualities. Thus, our study identified a novel regulator of sweet taste, the A2BR, which functions to potentiate sweet responses in posterior lingual taste fields.

  7. Pregnancy outcomes after chemotherapy for trophoblastic neoplasia.

    Science.gov (United States)

    Garcia, Mila Trementosa; Lin, Lawrence Hsu; Fushida, Koji; Francisco, Rossana Pulcineli Vieira; Zugaib, Marcelo

    2016-12-01

    The successful development of chemotherapy enabled a fertilitysparing treatment for patients with trophoblastic neoplasia. After disease remission, the outcome of a subsequent pregnancy becomes a great concern for these women. To analyze existing studies in the literature that describe the reproductive outcomes of patients with trophoblastic neoplasia treated with chemotherapy. Systematic review was performed searching for articles on Medline/ Pubmed, Lilacs and Cochrane Library databases, using the terms "gestational trophoblastic disease" and "pregnancy outcome". A total of 18 articles were included. No evidence of decreased fertility after chemotherapy for trophoblastic neoplasia was observed. The abortion rates in patients who conceived within 6 months after chemotherapy was higher compared to those who waited longer. Some studies showed increased rates of stillbirth and repeat hydatidiform moles. Only one work showed increased congenital abnormalities. The pregnancies conceived after chemotherapy for trophoblastic neoplasia should be followed with clinical surveillance due to higher rates of some pregnancy complications. However, studies in the literature provide reassuring data about reproductive outcomes of these patients.

  8. Pregnancy outcomes after chemotherapy for trophoblastic neoplasia

    Directory of Open Access Journals (Sweden)

    MILA TREMENTOSA GARCIA

    Full Text Available SUMMARY Introduction The successful development of chemotherapy enabled a fertilitysparing treatment for patients with trophoblastic neoplasia. After disease remission, the outcome of a subsequent pregnancy becomes a great concern for these women. Objective To analyze existing studies in the literature that describe the reproductive outcomes of patients with trophoblastic neoplasia treated with chemotherapy. Method Systematic review was performed searching for articles on Medline/ Pubmed, Lilacs and Cochrane Library databases, using the terms “gestational trophoblastic disease” and “pregnancy outcome”. Results A total of 18 articles were included. No evidence of decreased fertility after chemotherapy for trophoblastic neoplasia was observed. The abortion rates in patients who conceived within 6 months after chemotherapy was higher compared to those who waited longer. Some studies showed increased rates of stillbirth and repeat hydatidiform moles. Only one work showed increased congenital abnormalities. Conclusion The pregnancies conceived after chemotherapy for trophoblastic neoplasia should be followed with clinical surveillance due to higher rates of some pregnancy complications. However, studies in the literature provide reassuring data about reproductive outcomes of these patients.

  9. Modelling of tumour repopulation after chemotherapy

    International Nuclear Information System (INIS)

    Marcu, Loredana; Bezak, Eva

    2010-01-01

    Full text: While repopulation is a clinically observed phe nomenon after radiotherapy, repopulation of tumour cells between cycles of chemotherapy is usually a neglected factor in cancer treatment. As the effect of both radiotherapy and chemotherapy on tumour cells is the same (attack on cancer cells), the response of the tumour to injury and cell loss from the two treatment methods should be similar, including repopulation. Cell recruitment is known to be a possible mechanism responsible for tumour regrowth after radio therapy. The literature data regarding mechanisms of repopulation after chemotherapy is very limited. The current paper employs a Monte Carlo modelling approach to implement the pharmacokinetics of a widely used drug (cisplatin) into a previously developed vit1ual head and neck tumour and to study the effect of cisplatin on tumour regres sion and regrowth during treatment. The mechanism of cell recruitment was modelled by releasing various percentages (5-50%) of quiescent cells into the mitotic cycle after each chemotherapy cell kill. The onset of repopulation was also simulated, with both immediate onset and late onset of cell recruitment. Repopulation during chemotherapy, if occu ring, is a highly potent phenomenon, similar to drug resis tance, therefore it should not be neglected during treatment.

  10. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.

    Science.gov (United States)

    Alzahrani, Khalid J H; Ali, Juma A M; Eze, Anthonius A; Looi, Wan Limm; Tagoe, Daniel N A; Creek, Darren J; Barrett, Michael P; de Koning, Harry P

    2017-08-01

    Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU) and 5F,2'deoxyuridine (5F,2'dUrd), and was designated uridine-uracil transporter 1 (UUT1); the other transporter mediated uptake of adenosine, uridine, 5F,2'dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1). To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [ 3 H]-uridine but not of [ 3 H]-inosine. Conversely, the NT2-like genes mediated uptake of [ 3 H]-inosine but not [ 3 H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2'dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2'dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights

  11. Adenosine 5'-Monophosphate Aerosol Challenge Does Not Provoke Airflow Limitation in Healthy Cats

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    K. Vondráková

    2006-01-01

    Full Text Available The purpose of our study was to investigate the effects of nebulized adenosine 5'- monophosphate on airflow limitation in healthy cats determined by barometric whole body plethysmography (BWBP, in comparison to the effects of carbachol. Ten healthy 4- to 6-year-old domestic shorthair cats were included in the study. Each cat was placed in a BWBP plexiglass chamber (volume 38 l. Changes in box pressure were measured at baseline and after nebulization of vehicle and increasing concentrations of carbachol and adenosine 5'- monophosphate. Airway responsiveness was monitored as increases in enhanced pause (PENH, a unitless variable derived from dose-response curves estimating airflow limitation. The chosen endpoint was the agonist concentration which increased PENH to 300% of the value obtained after saline nebulization (PCPENH 300. Inter-day repeatability of measurements was assessed by repeated bronchoprovocations with both agonists 2-3 days apart. For carbachol, PCPENH300 was reached in all cats and correlated significantly between days (mean ± SD; 0.54 ± 0.42 mg/ml and 0.64 ± 0.45 mg/ml respectively; r = 0.58, p < 0.05 In contrast, we found no reaction to adenosine 5'- monophosphate even with the highest concentration nebulized during both measurements. At baseline, mean ± SD PENH was 0.47 ± 0.18 and 0.58 ± 0.24 (measurements 1 and 2, whereas PENH after 500 mg/ml adenosine 5'- monophosphate was 0.46 ± 0.20 and 0.71 ± 0.37. All bronchoprovocation tests were well tolerated by the cats. We conclude that healthy airways in cats do not demonstrate airway responsiveness to inhaled adenosine 5'- monophosphate. This is in agreement with observations in humans as well as our previous findings in dogs, where adenosine 5'- monophosphate had no effect on healthy canine airways, but caused significant airflow limitation after induction of acute bronchitis. To define the value of bronchoprovocation testing with adenosine 5'- monophosphate in the feline

  12. Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition.

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    Kutryb-Zajac, Barbara; Mateuszuk, Lukasz; Zukowska, Paulina; Jasztal, Agnieszka; Zabielska, Magdalena A; Toczek, Marta; Jablonska, Patrycja; Zakrzewska, Agnieszka; Sitek, Barbara; Rogowski, Jan; Lango, Romuald; Slominska, Ewa M; Chlopicki, Stefan; Smolenski, Ryszard T

    2016-11-01

    Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis. Vascular activities of ecto-nucleoside triphosphate diphosphohydrolase 1, ecto-5'-nucleotidase, and ecto-adenosine deaminase (eADA) were measured in aortas of apolipoprotein E-/- low density lipoprotein receptor (ApoE-/-LDLR-/-) and wild-type mice as well as in human aortas. Plaques were analysed in the entire aorta, aortic root, and brachiocephalic artery by Oil-Red O and Orcein Martius Scarlet Blue staining and vascular accumulation of macrophages. The cellular location of ecto-enzymes was analysed by immunofluorescence. The effect of eADA inhibition on atherosclerosis progression was studied by a 2-month deoxycoformycin treatment of ApoE-/-LDLR-/- mice. The vascular eADA activity prominently increased in ApoE-/-LDLR-/- mice when compared with wild type already at the age of 1 month and progressed along atherosclerosis development, reaching a 10-fold difference at 10 months. The activity of eADA correlated with atherosclerotic changes in human aortas. High abundance of eADA in atherosclerotic vessels originated from activated endothelial cells and macrophages. There were no changes in ecto-nucleoside triphosphate diphosphohydrolase 1 activity, whereas ecto-5'-nucleotidase was moderately decreased in ApoE-/-LDLR-/- mice. Deoxycoformycin treatment attenuated plaque development in aortic root and brachiocephalic artery of ApoE-/-LDLR-/- mice, suppressed vascular

  13. Value of adenosine infusion for infarct size determination using real-time myocardial contrast echocardiography

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    da Luz Protásio

    2006-02-01

    Full Text Available Abstract Background Myocardial contrast echocardiography has been used for determination of infarct size (IS in experimental models. However, with intermittent harmonic imaging, IS seems to be underestimated immediately after reperfusion due to areas with preserved, yet dysfunctional, microvasculature. The use of exogenous vasodilators showed to be useful to unmask these infarcted areas with depressed coronary flow reserve. This study was undertaken to assess the value of adenosine for IS determination in an open-chest canine model of coronary occlusion and reperfusion, using real-time myocardial contrast echocardiography (RTMCE. Methods Nine dogs underwent 180 minutes of coronary occlusion followed by reperfusion. PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin was used as contrast agent. IS was determined by RTMCE before and during adenosine infusion at a rate of 140 mcg·Kg-1·min-1. Post-mortem necrotic area was determined by triphenyl-tetrazolium chloride (TTC staining. Results IS determined by RTMCE was 1.98 ± 1.30 cm2 and increased to 2.58 ± 1.53 cm2 during adenosine infusion (p = 0.004, with good correlation between measurements (r = 0.91; p 2 and showed no significant difference with IS determined by RTMCE before or during hyperemia. A slight better correlation between RTMCE and TTC measurements was observed during adenosine (r = 0.99; p Conclusion RTMCE can accurately determine IS in immediate period after acute myocardial infarction. Adenosine infusion results in a slight better detection of actual size of myocardial damage.

  14. Identification of the A2 adenosine receptor binding subunit by photoaffinity crosslinking

    International Nuclear Information System (INIS)

    Barrington, W.W.; Jacobson, K.A.; Hutchison, A.J.; Williams, M.; Stiles, G.L.

    1989-01-01

    A high-affinity iodinated agonist radioligand for the A2 adenosine receptor has been synthesized to facilitate studies of the A2 adenosine receptor binding subunit. The radioligand 125I-labeled PAPA-APEC (125I-labeled 2-[4-(2-[2-[(4- aminophenyl)methylcarbonylamino]ethylaminocarbonyl]- ethyl)phenyl]ethylamino-5'-N-ethylcarboxamidoadenosine) was synthesized and found to bind to the A2 adenosine receptor in bovine striatal membranes with high affinity (Kd = 1.5 nM) and A2 receptor selectivity. Competitive binding studies reveal the appropriate A2 receptor pharmacologic potency order with 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)-N6-[(R)-1-methyl- 2-phenylethyl]adenosine (R-PIA) greater than (+)-N6-[(S)-1-methyl-2- phenylethyl]adenosine (S-PIA). Adenylate cyclase assays, in human platelet membranes, demonstrate a dose-dependent stimulation of cAMP production. PAPA-APEC (1 microM) produces a 43% increase in cAMP production, which is essentially the same degree of increase produced by 5'-N- ethylcarboxamidoadenosine (the prototypic A2 receptor agonist). These findings combined with the observed guanine nucleotide-mediated decrease in binding suggest that PAPA-APEC is a full A2 agonist. The A2 receptor binding subunit was identified by photoaffinity-crosslinking studies using 125I-labeled PAPA-APEC and the heterobifunctional crosslinking agent N-succinimidyl 6-(4'-azido-2'-nitrophenylamino)hexanoate (SANPAH). After covalent incorporation, a single specifically radiolabeled protein with an apparent molecular mass of 45 kDa was observed on NaDodSO4/PAGE/autoradiography. Incorporation of 125I-labeled PAPA-APEC into this polypeptide is blocked by agonists and antagonists with the expected potency for A2 receptors and is decreased in the presence of 10(-4) M guanosine 5'-[beta, gamma-imido]triphosphate

  15. Regulatory effects of adenosine A2A receptors on psychomotor ability and mood behavior of mice

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    Li JIANG

    2011-07-01

    Full Text Available Objective To explore the effects of gene knock-out,agonist or inhibitor of adenosine A2A receptor on the locomotor activity,and anxiety-or depression-like behavior of mice.Methods Male C57BL/6 mice,comprising those underwent gene knock-out of adenosine A2A receptor(A2AKO and their wild-type(WT littermates,were assigned into A2AKO group and WT group.Another batch of male C57BL/6,specific-pathogen-free(SPF mice,were assigned into SCH58261 group,CGS21680 group and control group.Mice of aforesaid 3 groups were transperitoneally administered with SCH58261,a specific inhibitor of adenosine A2A receptor at a dose of 2mg/kg,CGS21680,a specific agonist of adenosine A2A receptor at a dose of 0.5mg/kg,and vehicle(0.25ml,comprising DMSO and saline,respectively.Ten minutes after injection,mice of the 3 groups underwent open-field test,elevated plus-maze test and forced swimming test to detect their locomotor activity,anxiety-and depression-like behavior.Results a Compared with WT group,the total movement distance decreased(P 0.05.b Compared with control group,the total movement distance decreased and the stay time in the peripheral area increased significantly in the open field test(P 0.05.Conclusions The agonist of adenosine A2A receptor may depress the spontaneous motility and exploratory behavior,and exacerbate the anxiety and depression,and it simulates the effect induced by knock-out of A2A receptor gene,but it is opposite to the effect induced by A2A receptor inhibitor.

  16. The role of adjuvant platinum-based chemotherapy in esophagogastric cancer patients who received neoadjuvant chemotherapy prior to definitive surgery.

    Science.gov (United States)

    Saunders, John H; Bowman, Christopher R; Reece-Smith, Alex M; Pang, Vincent; Dorrington, Matthew S; Mumtaz, Errum; Soomro, Irshad; Kaye, Philip; Madhusudan, Srinivasan; Parsons, Simon L

    2017-06-01

    For patients with operable esophagogastric cancer, peri-operative chemotherapy confers a significant overall survival benefit compared to surgery alone, however only 30-40% of patients demonstrate histopathological response. It is unclear whether those with no neoadjuvant chemotherapy response should go onto receive adjuvant chemotherapy, as no further benefit may be conferred. Esophagogastric cancers were prospectively captured with associated histopathological tumor regression grades following neoadjuvant chemotherapy. This cohort was then interrogated for clinico-pathological and survival outcomes. Following neoadjuvant chemotherapy and surgery, patients with chemotherapy responsive cancers, who were administered adjuvant chemotherapy gained a significant overall survival benefit. Multivariate Cox analysis, demonstrated a final adjusted hazard ratio for adjuvant therapy of 0.509; (95%CI 0.28-0.93); P = 0.028. In contrast, patients with non-responsive tumors, who underwent adjuvant chemotherapy, did not show any survival benefit. Chemotherapy toxicity was prevalent and contributed to only half of patients receiving adjuvant chemotherapy. These results suggest the benefit of the adjuvant portion of chemotherapy is limited to those who demonstrate a histopathological response to neoadjuvant chemotherapy. The administration of the adjuvant portion of chemotherapy to patients without a response to neoadjuvant chemotherapy may not provide any survival benefit, while potentially causing increased morbidity. © 2017 Wiley Periodicals, Inc.

  17. Comparative study of adenosine and exercise 201Tl myocardial perfusion tomographic imaging for detection of coronary heart disease

    International Nuclear Information System (INIS)

    Wang Xiong

    1997-01-01

    To compare diagnostic accuracy of adenosine and exercise 201 Tl myocardial perfusion tomographic imaging for detection of coronary heart disease (CHD) in patients with a normal rest ECG and no history of myocardial infarction, 81 patients with CHD and 10 normal control subjects underwent adenosine myocardial perfusion imaging, exercise nuclide myocardial perfusion imaging was performed in 117 patients with CHD and 16 normal control subjects, two groups also had coronary arteriography. Both exercise and adenosine testing parameters were analysed. It is shown: 1) The sensitivity and specificity for detection of CHD were 79% vs 80% for adenosine group and 81% vs 81% for exercise myocardial perfusion imaging group respectively. There was no significant difference in comparison with two matched groups (χ 2 = 1.13, χ 2 = 0.18, χ 2 = 0.12, P>0.05). 2) Side effects induced by adenosine accounted for 89% of patients, all symptoms were mild and disappeared quickly after the termination of the study except in 2 cases withdrawal of infusion needed because of severe angina pectoris. Adenosine myocardial perfusion imaging is a safe and sensitive method for detection of CHD. The diagnostic value of adenosine test is similar to that of exercise myocardial perfusion imaging and particularly useful in evaluating patients unable to perform exercise test or achieve adequate level of exercise

  18. Antitumor effect of cordycepin (3'-deoxyadenosine) on mouse melanoma and lung carcinoma cells involves adenosine A3 receptor stimulation.

    Science.gov (United States)

    Nakamura, Kazuki; Yoshikawa, Noriko; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

    2006-01-01

    An attempt was made to elucidate the molecular targetfor the antitumor effects of cordycepin (3'-deoxyadenosine) using non-selective and selective adenosine A1, A2a, A2b and A3 receptor agonists and antagonists. Although adenosine and 2'-deoxyadenosine (up to 100 microM) had no effect, cordycepin showed remarkable inhibitory effects on the growth curves of B16-BL6 mouse melanoma (IC50= 39 microM) and mouse Lewis lung carcinoma (IC50 = 48 microM) cell lines in vitro. Among the adenosine receptor agonists and antagonists used (up to 100 microM), only 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), a selective adenosine A3 receptor agonist, notably inhibited the growth of both mouse tumor cell lines (B16-BL6; IC50 = 5 microM, LLC; 14 microM). In addition, the tumor growth inhibitory effect of cordycepin was antagonized by 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191), a selective adenosine A3 receptor antagonist. These results suggest that cordycepin exerts inhibitory effects on the growth of mouse melanoma and lung carcinoma cells by stimulating adenosine A3 receptors on tumor cells.

  19. Activation of adenosine receptors and inhibition of cyclooxygenases: two recent pharmacological approaches to modulation of radiation suppressed hematopoiesis

    International Nuclear Information System (INIS)

    Hofer, M.; Pospisil, M.; Vacek, A.; Hola, J.; Weiterova, L.; Streitova, D.; Znojil, V.

    2008-01-01

    Searching for drugs conforming to requirements for protection and/or treatment of radiation-induced damage belongs to the most important tasks of current radiobiology. In the Laboratory of Experimental Hematology, Institute of Biophysics, v.v.i., Academy of Sciences of the Czech Republic, Brno, Czech Republic, two original approaches for stimulation of radiation-suppressed hematopoiesis have been tested in recent years, namely activation of adenosine receptors and inhibition of cyclooxygenases. Non-selective activation of adenosine receptors, induced by combined administration of dipyridamole, a drug preventing adenosine uptake and supporting thus its extracellular receptor-mediated action, and adenosine monophosphate, an adenosine prodrug, has been found to stimulate hematopoiesis when the drugs were given either pre- or post-irradiation. When synthetic adenosine receptor agonists selective for individual adenosine receptor subtypes were tested, stimulatory effects in myelosuppressed mice have been found after administration of IB-MECA, a selective adenosine A3 receptor agonist. Non-selective cyclooxygenase inhibitors, inhibiting both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), indomethacin, diclofenac, or flurbiprofen, have been observed to act positively on radiation-perturbed hematopoiesis in sublethally irradiated mice. However, their undesirable gastrointestinal side effects have been found to negatively influence survival of lethally irradiated animals. Recently tested selective COX-2 inhibitor meloxicam, preserving protective action of COX-1-synthesized prostaglandins in the gastrointestinal tissues, has been observed to retain the hematopoiesis-stimulating effects of non-selective cyclooxygenase inhibitors and to improve the survival of animals exposed to lethal radiation doses. These findings bear evidence for the possibility to use selective adenosine A3 receptor agonists and selective COX-2 inhibitors in human practice for treatment of

  20. Inhibition of synaptically evoked cortical acetylcholine release by adenosine: an in vivo microdialysis study in the rat.

    Science.gov (United States)

    Materi, L M; Rasmusson, D D; Semba, K

    2000-01-01

    The release of cortical acetylcholine from the intracortical axonal terminals of cholinergic basal forebrain neurons is closely associated with electroencephalographic activity. One factor which may act to reduce cortical acetylcholine release and promote sleep is adenosine. Using in vivo microdialysis, we examined the effect of adenosine and selective adenosine receptor agonists and antagonists on cortical acetylcholine release evoked by electrical stimulation of the pedunculopontine tegmental nucleus in urethane anesthetized rats. All drugs were administered locally within the cortex by reverse dialysis. None of the drugs tested altered basal release of acetylcholine in the cortex. Adenosine significantly reduced evoked cortical acetylcholine efflux in a concentration-dependent manner. This was mimicked by the adenosine A(1) receptor selective agonist N(6)-cyclopentyladenosine and blocked by the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The A(2A) receptor agonist 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne hydrochloride (CGS 21680) did not alter evoked cortical acetylcholine release even in the presence of DPCPX. Administered alone, neither DPCPX nor the non-selective adenosine receptor antagonist caffeine affected evoked cortical acetylcholine efflux. Simultaneous delivery of the adenosine uptake inhibitors dipyridamole and S-(4-nitrobenzyl)-6-thioinosine significantly reduced evoked cortical acetylcholine release, and this effect was blocked by the simultaneous administration of caffeine. These data indicate that activation of the A(1) adenosine receptor inhibits acetylcholine release in the cortex in vivo while the A(2A) receptor does not influence acetylcholine efflux. Such inhibition of cortical acetylcholine release by adenosine may contribute to an increased propensity to sleep during prolonged wakefulness.

  1. Prospective Study of Adenosine on Atrioventricular Nodal Conduction in Pediatric and Young Adult Patients After Heart Transplantation.

    Science.gov (United States)

    Flyer, Jonathan N; Zuckerman, Warren A; Richmond, Marc E; Anderson, Brett R; Mendelsberg, Tamar G; McAllister, Jennie M; Liberman, Leonardo; Addonizio, Linda J; Silver, Eric S

    2017-06-20

    Supraventricular tachycardia is common after heart transplantation. Adenosine, the standard therapy for treating supraventricular tachycardia in children and adults without transplantation, is relatively contraindicated after transplantation because of a presumed risk of prolonged atrioventricular block in denervated hearts. This study tested whether adenosine caused prolonged asystole after transplantation and if it was effective in blocking atrioventricular nodal conduction in these patients. This was a single-center prospective clinical study including healthy heart transplant recipients 6 months to 25 years of age presenting for routine cardiac catheterization during 2015 to 2016. After catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose-escalation protocol until atrioventricular block was achieved. The incidence of clinically significant asystole (≥12 seconds after adenosine) was quantified. The effects of patient characteristics on adenosine dose required to produce atrioventricular block and duration of effect were also measured. Eighty patients completed adenosine testing. No patient (0%; 95% confidence interval, 0-3) required rescue ventricular pacing. Atrioventricular block was observed in 77 patients (96%; 95% confidence interval, 89-99). The median longest atrioventricular block was 1.9 seconds (interquartile range, 1.4-3.2 seconds), with a mean duration of adenosine effect of 4.3±2.0 seconds. No patient characteristic significantly predicted the adenosine dose to produce atrioventricular block or duration of effect. Results were similar across patient weight categories. Adenosine induces atrioventricular block in healthy pediatric and young adult heart transplant recipients with minimal risk when low initial doses are used (25 μg/kg; 1.5 mg if ≥60 kg) and therapy is gradually escalated. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02462941. © 2017 American Heart Association, Inc.

  2. Limitation of Infarct Size and No-Reflow by Intracoronary Adenosine Depends Critically on Dose and Duration.

    Science.gov (United States)

    Yetgin, Tuncay; Uitterdijk, André; Te Lintel Hekkert, Maaike; Merkus, Daphne; Krabbendam-Peters, Ilona; van Beusekom, Heleen M M; Falotico, Robert; Serruys, Patrick W; Manintveld, Olivier C; van Geuns, Robert-Jan M; Zijlstra, Felix; Duncker, Dirk J

    2015-12-28

    In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings. Swine (54 ± 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 μg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. In protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03). During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  3. Comparison of fractional flow reserve measurements using intracoronary adenosine versus intracoronary sodium nitroprusside infusions in moderately stenotic coronary artery lesions

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    Safi, Morteza; Namazi, Mohammad Hasan; Fooladi, Esfandiar; Vakili, Hossein; Parsa, Saeed Alipour; Khaheshi, Isa [Cardiovascular Research Center, Modarres hospital, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Abbasi, Mohammad Amin [Department of Internal Medicine, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Movahed, Mohammad Reza, E-mail: rmova@aol.com [CareMore, Arizona, Tucson, AZ (United States); University of Arizona, Sarver Heart Center, Tucson, AZ (United States)

    2016-10-15

    Introduction: The aim of this study was to investigate the efficacy and safety of intracoronary (IC) sodium nitroprusside infusion in comparison to IC adenosine for fractional flow reserve (FFR) measurement in moderately diseased coronary artery lesions for functional assessment. Methods: During a nine month period, a consecutive of 98 patients with suspected or known coronary artery disease with moderate stenosis found during angiography (40% to 70% stenosis), were enrolled in this study. Hyperemia was induced by bolus doses of IC adenosine followed by sodium nitroprusside for FFR measurement. Results: Both IC adenosine and IC sodium nitroprusside induced similar and significant reduction in FFR. There was no statistically difference in FFR values between adenosine vs sodium nitroprusside infusions (mean FFR 84.3 ± 6.3 vs 85.7 ± 6.2, p = 0.1) respectively. Furthermore, comparing different FFR cut-off points between the groups (FFR < 0.75, 0.75–0.8 and > 0.8) showed no significant differences (p value = 0.7). Conclusion: An IC bolus of sodium nitroprusside (0.6 μg/kg) infusion induces a similar degree of hyperemia to IC bolus of 100–300 μg of adenosine. Therefore, IC sodium nitroprusside could be considered as an alternative drug to adenosine for FFR measurement with lower side effect profile. - Highlights: • Intracoronary (IC) sodium nitroprusside was compared with IC adenosine for FFR test. • IC adenosine and IC sodium nitroprusside induced similar reduction in FFR. • Different FFR cut-off points between the groups showed no significant differences. • IC sodium nitroprusside could be considered as an alternative to adenosine for FFR.

  4. Chemotherapy or radio-chemotherapy for advanced adenocarcinoma of the oesophagus and cardiac orifice

    International Nuclear Information System (INIS)

    Seitz, J.F.; Duffaud, F.; Dahan, L.; Ries, P.; Ville, E.; Laugier, R.

    2001-01-01

    Adenocarcinomas of esophagus and cardia represent in France approximately 20 to 40% of the esophagus cancers. They have a high risk to develop lymph nodes metastases and liver metastases. Currently, only 50 to 70% of patients may benefit from surgical curative resection at diagnosis, but more than 50% of them will recur. The standard of treatment of these metastatic adenocarcinomas is chemotherapy. Three large randomized comparative studies, between chemotherapy and supportive care, showed that chemotherapy significantly extends the median of survival (from 3-4 months to 10-12 months) and improves the quality of life. Currently, the combination of epirubicin-cisplatin-continuous 5FU (ECF) is the most effective regimen but it is difficult to administer and tolerate because of the long continuous 5FU infusion. In France, the most commonly used combination regimen still associates 5FU and cisplatin. New drugs (such as docetaxel, CPT11, oxaliplatin) used alone or in combination, especially with 5U, are very promising. Radio-chemotherapy is the preferred treatment for locoregional recurrences, because it improves dysphagia and enables to obtain complete tumor responses. Current results from concomitant radio-chemotherapy studies for esophagus cancer, based on 5FU alone, 5FU-cisplatin or 5FU-mitomycin, given as preoperative treatment or as exclusive treatment, support to use radio-chemotherapy for the treatment of loco-regional recurrences after surgical resection. Nevertheless, the optimal radio-chemotherapy schedule still remain to be defined (dose, duration, splitting of radiotherapy, choice of anticancer drugs). (authors)

  5. Metaplastic carcinoma. Breast. Relapse. Chemotherapy and Radiotherapy

    International Nuclear Information System (INIS)

    Marquez, A.; Terrasa, J.; Garcia, J.M.; Rifa, J.

    1996-01-01

    Metaplastic carcinoma of the breast is a rare tumor. The appearance of unexpected mesenchymal elements within the epithelial tumors is the squamous metaplasia. These tumors have a different clinical behaviour that classical breast carcinoma. We present a case of metaplastic mammary carcinoma with multiple relapses treated with a combination of chemotherapy and radiotherapy. The use of chemotherapy after local treatment has enhanced the relapse-free survival. The combined treatment modality seems to produce some benefit in the management of the local relapses of this neoplasms

  6. Retinoblastoma: Achieving new standards with methods of chemotherapy

    Directory of Open Access Journals (Sweden)

    Swathi Kaliki

    2015-01-01

    Full Text Available The management of retinoblastoma (RB has dramatically changed over the past two decades from previous radiotherapy methods to current chemotherapy strategies. RB is a remarkably chemotherapy-sensitive tumor. Chemotherapy is currently used as a first-line approach for children with this malignancy and can be delivered by intravenous, intra-arterial, periocular, and intravitreal routes. The choice of route for chemotherapy administration depends upon the tumor laterality and tumor staging. Intravenous chemotherapy (IVC is used most often in bilateral cases, orbital RB, and as an adjuvant treatment in high-risk RB. Intra-arterial chemotherapy (IAC is used in cases with group C or D RB and selected cases of group E tumor. Periocular chemotherapy is used as an adjunct treatment in eyes with group D and E RB and those with persistent/recurrent vitreous seeds. Intravitreal chemotherapy is reserved for eyes with persistent/recurrent vitreous seeds. In this review, we describe the various forms of chemotherapy used in the management of RB. A database search was performed on PubMed, using the terms "RB," and "treatment," "chemotherapy," "systemic chemotherapy," "IVC," "IAC," "periocular chemotherapy," or "intravitreal chemotherapy." Relevant English language articles were extracted, reviewed, and referenced appropriately.

  7. Change of SPARC expression after chemotherapy in gastric cancer

    International Nuclear Information System (INIS)

    Gao, Yong-Yin; Han, Ru-Bing; Wang, Xia; Ge, Shao-Hua; Li, Hong-Li; Deng, Ting; Liu, Rui; Bai, Ming; Zhou, Li-Kun; Zhang, Xin-Yuan; Ba, Yi; Huang, Ding-Zhi

    2015-01-01

    The expression of tumor biomarkers may change after chemotherapy. However, whether secreted protein acidic and rich in cysteine (SPARC) expression changes after chemotherapy in gastric cancer (GC) is unclear. This study investigated the influence of chemotherapy on SPARC expression in GC. Immunohistochemistry was used to analyze SPARC expression in 132 GC cases (including 54 cases with preoperative chemotherapy and 78 cases without preoperative chemotherapy). SPARC expression of postoperative specimens with and without preoperative chemotherapy was assessed to analyze the influence of chemotherapy on SPARC expression. SPARC was highly expressed in GC compared with the desmoplastic stroma surrounding tumor cells and noncancerous tissues. High SPARC expression was correlated with invasion depth, lymph node, and TNM stage. After chemotherapy, a lower proportion of high SPARC expression was observed in patients with preoperative chemotherapy than in the controls. For 54 patients with preoperative chemotherapy, gross type, histology, depth of invasion, lymph node, TNM stage, and SPARC expression were related to overall survival. Further multivariate analysis showed that lymph node, histology, and SPARC expression after chemotherapy were independent prognostic factors. SPARC expression may change after chemotherapy in GC. SPARC expression should be reassessed for patients with GC after chemotherapy

  8. Chemotherapy and Hair Loss: What to Expect during Treatment

    Science.gov (United States)

    Chemotherapy and hair loss: What to expect during treatment Your doctor can tell you whether your particular chemotherapy treatment is likely to cause hair loss. This allows you to plan ahead for head ...

  9. Chemotherapy and Sex: Is Sexual Activity OK during Treatment?

    Science.gov (United States)

    ... OK during treatment? Is it safe to have sex with my husband while undergoing chemotherapy? Answers from ... best to discuss any concerns about chemotherapy and sex with your doctor, who's familiar with your individual ...

  10. Side Effects of Chemotherapy and Radiation (For Parents)

    Science.gov (United States)

    ... Safe Videos for Educators Search English Español Side Effects of Chemotherapy and Radiation KidsHealth / For Parents / Side Effects of Chemotherapy and Radiation What's in this article? What to ...

  11. Managing Chemotherapy Side Effects: Sexual and Fertility Changes in Women

    Science.gov (United States)

    N ational C ancer I nstitute Managing Chemotherapy Side Effects Sexual and Fertility Changes in Women “Talk with your doctor before you start treatment. Ask how chemotherapy could affect your ability to have ...

  12. Management of chemotherapy-induced nausea and vomiting.

    LENUS (Irish Health Repository)

    Zubairi, Ishtiaq H

    2006-08-01

    Chemotherapy-induced nausea and vomiting are symptoms that cause major concern to oncology patients. This article explores the types of nausea and vomiting in the context of chemotherapy, and discusses their pathogenesis and management.

  13. Chemotherapy Side Effects: A Cause of Heart Disease?

    Science.gov (United States)

    ... Can chemotherapy side effects increase the risk of heart disease? Answers from Timothy J. Moynihan, M.D. Chemotherapy side effects may increase the risk of heart disease, including weakening of the heart muscle (cardiomyopathy) and ...

  14. [Supportive care during chemotherapy for lung cancer in daily practice].

    Science.gov (United States)

    Müller, Veronika; Tamási, Lilla; Gálffy, Gabriella; Losonczy, György

    2012-09-01

    Active oncotherapy, combination chemotherapy of lung cancer is accompanied with many side effects which may impair patients' quality of life and compromise the effectiveness of chemotherapy. Most side effects of chemotherapy are preventable or treatable with optimal supportive care which enhances success in patient care and treatment. The aim of this review is to summarize the most important conditions that may be associated with combined chemotherapy of lung cancer from the practical point of view.

  15. Intravenous Lidocaine Infusion to Treat Chemotherapy-Induced Peripheral Neuropathy.

    Science.gov (United States)

    Papapetrou, Peter; Kumar, Aashish J; Muppuri, Rudram; Chakrabortty, Shushovan

    2015-11-01

    Chemotherapy-induced peripheral neuropathy is a debilitating side effect of chemotherapy, which manifests as paresthesias, dysesthesias, and numbness in the hands and feet. Numerous chemoprotective agents and treatments have been used with limited success to treat chemotherapy-induced peripheral neuropathy. We report a case in which a patient presenting with chemotherapy-induced peripheral neuropathy received an IV lidocaine infusion over the course of 60 minutes with complete symptomatic pain relief for a prolonged period of 2 weeks.

  16. Radiation recall supraglottitis. A hazard in head and neck chemotherapy

    International Nuclear Information System (INIS)

    Wallenborn, P.A.; Postma, D.S.

    1984-01-01

    The enhanced effects of chemotherapy on previously irradiated tissue have been well demonstrated. When chemotherapy is given some time after irradiation and elicits a tissue reaction in the radiation field, the reaction is termed radiation recall. We review known interactions between chemotherapy and radiotherapy and report, to our knowledge, the first case of a supraglottitis radiation recall reaction. Familiarity with this phenomenon and potential complications of chemotherapy following head and neck irradiation may expedite early diagnosis and appropriate lifesaving treatment

  17. Aspects of enteral nutrition in cancer chemotherapy

    NARCIS (Netherlands)

    Smit, Jitske Martha

    1985-01-01

    This thesis deals with several aspects of the influences of intensive cancer chemotherapy on the nutritional status, the metabolism, and the gastrointestinal tract of the host and describes whether these results can be influenced by enteral hyperalimentation, We studied these aspects in patients

  18. Comparison of chemotherapy and hematopoietic stem cell ...

    African Journals Online (AJOL)

    2013-02-19

    Feb 19, 2013 ... scores before and after hematopoietic stem cell transplantation (HSCT) and chemotherapy. Materials and Methods: Thirty-six patients undergoing HSCT were included in the study. A pre-HSCT dental treatment protocol was implemented that consisted of restoration of all active carious lesions, treatment of ...

  19. Pathological response for neoadjuvant chemotherapy in locally ...

    African Journals Online (AJOL)

    Background: Breast cancer is the leading cancer in Sudanese females. Objectives: This study was done to evaluate the clinical response to neoadjuvant chemotherapy for patients treated at National Cancer Institute (NCI) and to compare it with the published literature. Methods: This is a retrospective study conducted in ...

  20. Antimicrobial chemotherapy and Sustainable Development: The ...

    African Journals Online (AJOL)

    Antimicrobial chemotherapy and Sustainable Development: The past, The Current Trend, and the futu. ... Within the past half century, a wide variety of antimicrobial substances have been discovered, designed and synthesized; literally hundreds of drugs have been successfully used in some fashion over the years. Today ...

  1. Chemotherapy of gastric cancer - a radiological control

    International Nuclear Information System (INIS)

    Theobaldy, S.; Hofmann-Preiss, K.; Walter, M.

    1987-01-01

    In most cases of metastatic gastric cancer, treatment with cytostatic drugs seems to be justified. Responsiveness to chemotherapy, according to the MAF-schedule (Methotrexat, Adriamycin, 5-Fluorouracil) was reported to be successful in 50% of this cancer type. (orig.) [de

  2. Haemorheological changes in cancer patients on chemotherapy

    International Nuclear Information System (INIS)

    Omoti, C.E.; Osime, E.

    2007-01-01

    To assess the rheological changes in haematological and non-haematological cancer patients pre and post chemotherapy. It is a prospective study of 50 patients comprising 16(32%) haematological and 34(68%) non-haematological cancers of various types from March to December 2005 at University of Benin Teaching Hospital, Nigeria. Rheologic parameters estimated by the various specific diagnostic methods were determined in cancer patient's pre and post chemotherapy. The rheological tests estimated were relative plasma viscosity (RPV) measured by means of a capillary viscometer, whole blood viscosity (WBV), erythrocyte sedimentation rate (ESR) and plasma fibrinogen concentration (PFC) estimated by the Ingram's Clot weight method. The RPV in pre chemotherapy (p=0.006) and WBV in post chemotherapy (p=0.0231) patients measured revealed a significant difference when compared to controls. The fibrinogen concentration (P<0.0001) and ESR values (P<0.0001) were significantly increased in cancer patients when compared to controls. We conclude that total reduction of hyperviscosity and hyperfibrinogenaemia may contribute to effective treatment strategies in cancer patients. (author)

  3. Default from neoadjuvant chemotherapy in premenopausal female ...

    African Journals Online (AJOL)

    Seventeen (38.6%) patients dropped out of treatment, before, during or after completing NAC. Ten of these defaulted due to inadequate funds to procure chemotherapy, three patients because they insisted on immediate mastectomy, and four of these patients refused surgery when they achieved complete clinical response, ...

  4. Combined radiotherapy-chemotherapy in clinical practice

    International Nuclear Information System (INIS)

    Horwich, A.

    1989-01-01

    This paper investigates the combination of radiotherapy and chemotherapy performed over the last 15 years. The improvement of the therapeutic ratio of anti- cancer effect to normal tissue toxicity and its requirement of a thorough understanding of the biological effects of each modality and of how these effects may interact is presented. Early studies and conclusions are examined

  5. Patient expectancy and post-chemotherapy nausea

    DEFF Research Database (Denmark)

    Colagiuri, Ben; Zachariae, Robert

    2010-01-01

    to determine the strength of the relationship between expectancy and post-chemotherapy nausea. METHODS: The findings from 17 relevant studies (n = 2,400) identified through systematic searches of Medline, PsycInfo, and Cinhal were analyzed using a combination of meta-analytic techniques. RESULTS: Overall...

  6. Contralateral paradoxical response to chemotherapy in tuberculous ...

    African Journals Online (AJOL)

    Pleural effusions may occur as a complication of primary tuberculosis or an established pulmonary or extrapulmonary infection. New formation or expansion of a tuberculous lesion during chemotherapy is referred to as paradoxical response. Paradoxical response has been described to occur weeks or months after starting ...

  7. 2′-O Methylation of Internal Adenosine by Flavivirus NS5 Methyltransferase

    Science.gov (United States)

    Dong, Hongping; Chang, David C.; Hua, Maggie Ho Chia; Lim, Siew Pheng; Chionh, Yok Hian; Hia, Fabian; Lee, Yie Hou; Kukkaro, Petra; Lok, Shee-Mei; Dedon, Peter C.; Shi, Pei-Yong

    2012-01-01

    RNA modification plays an important role in modulating host-pathogen interaction. Flavivirus NS5 protein encodes N-7 and 2′-O methyltransferase activities that are required for the formation of 5′ type I cap (m7GpppAm) of viral RNA genome. Here we reported, for the first time, that flavivirus NS5 has a novel internal RNA methylation activity. Recombinant NS5 proteins of West Nile virus and Dengue virus (serotype 4; DENV-4) specifically methylates polyA, but not polyG, polyC, or polyU, indicating that the methylation occurs at adenosine residue. RNAs with internal adenosines substituted with 2′-O-methyladenosines are not active substrates for internal methylation, whereas RNAs with adenosines substituted with N6-methyladenosines can be efficiently methylated, suggesting that the internal methylation occurs at the 2′-OH position of adenosine. Mass spectroscopic analysis further demonstrated that the internal methylation product is 2′-O-methyladenosine. Importantly, genomic RNA purified from DENV virion contains 2′-O-methyladenosine. The 2′-O methylation of internal adenosine does not require specific RNA sequence since recombinant methyltransferase of DENV-4 can efficiently methylate RNAs spanning different regions of viral genome, host ribosomal RNAs, and polyA. Structure-based mutagenesis results indicate that K61-D146-K181-E217 tetrad of DENV-4 methyltransferase forms the active site of internal methylation activity; in addition, distinct residues within the methyl donor (S-adenosyl-L-methionine) pocket, GTP pocket, and RNA-binding site are critical for the internal methylation activity. Functional analysis using flavivirus replicon and genome-length RNAs showed that internal methylation attenuated viral RNA translation and replication. Polymerase assay revealed that internal 2′-O-methyladenosine reduces the efficiency of RNA elongation. Collectively, our results demonstrate that flavivirus NS5 performs 2′-O methylation of internal adenosine of

  8. Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma

    DEFF Research Database (Denmark)

    Herbst, Christine; Rehan, Fareed Ahmed; Skoetz, Nicole

    2011-01-01

    BACKGROUND: Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been...... chemotherapy regimen plus radiotherapy. SELECTION CRITERIA: Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also...... excluded. DATA COLLECTION AND ANALYSIS: Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none...

  9. The effect of chemotherapy on rat brain PET: preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Su; Kim, Il Han; Yu, A Ram; Park, Ji Ae; Woo, Sang Keun; Kim, Jong Guk; Cheon, Gi Jeong; Kim, Byeong Il; Choi, Chang Woon; Lim, Sang Moo; Kim, Hee Joung; Kim, Kyeong Min [Korea Institute Radiological and Medical Science, Seoul (Korea, Republic of)

    2010-10-15

    Chemotherapy was widely used for the therapy of cancer patients. When chemotherapy was performed, transient cognitive memory problem was occurred. This cognitive problem in brain was called as chemobrain. In this study, we have developed rat model for chemobrain. Cerebral glucose metabolism after chemotherapy was assessed using animal PET and voxel based statistical analysis method

  10. The effect of chemotherapy on rat brain PET: preliminary study

    International Nuclear Information System (INIS)

    Kim, Jin Su; Kim, Il Han; Yu, A Ram; Park, Ji Ae; Woo, Sang Keun; Kim, Jong Guk; Cheon, Gi Jeong; Kim, Byeong Il; Choi, Chang Woon; Lim, Sang Moo; Kim, Hee Joung; Kim, Kyeong Min

    2010-01-01

    Chemotherapy was widely used for the therapy of cancer patients. When chemotherapy was performed, transient cognitive memory problem was occurred. This cognitive problem in brain was called as chemobrain. In this study, we have developed rat model for chemobrain. Cerebral glucose metabolism after chemotherapy was assessed using animal PET and voxel based statistical analysis method

  11. Chemotherapy-induced peripheral neuropathy : Impact on quality of life

    NARCIS (Netherlands)

    Scheel, A.; Beijers, A.J.M.; Mols, F.; Faber, C.G.; Vreugdenhil, G.

    2014-01-01

    Peripheral neuropathy is a frequently occurring side-effect of chemotherapy as a cancer treatment. The incidence of chemotherapy-induced peripheral neuropathy (CIPN) is increasing as a consequence of better treatment of cancer becoming available and increasing use of chemotherapy, and because CIPN

  12. Chemotherapy Agents: A Primer for the Interventional Radiologist

    OpenAIRE

    Mihlon, Frank; Ray, Charles E.; Messersmith, Wells

    2010-01-01

    In this article, the authors review the basic principles of cancer chemotherapy and provide an overview of each of the general classes of chemotherapeutic agents with a target audience of interventional radiologists in mind. Special attention is paid to agents used in regional chemotherapy as well as agents commonly included in systemic chemotherapeutic regimens for patients who also require regional chemotherapy.

  13. Routine surgery in addition to chemotherapy for treating spinal tuberculosis

    NARCIS (Netherlands)

    Jutte, PC; Van Loenhout-Rooyackers, JH; Loenhout-Rooyackers, J.H.

    2006-01-01

    Background Tuberculosis is generally curable with chemotherapy, but there is controversy in the literature about the need for surgical intervention in the one to two per cent of people with tuberculosis of the spine. Objectives To compare chemotherapy plus surgery with chemotherapy alone for

  14. Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon

    Directory of Open Access Journals (Sweden)

    Patrícia Alessandra Dastoli

    2011-02-01

    Full Text Available OBJECTIVE: To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD: Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS: Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60% and the bigger reduction was 98.37%. Eleven patients had a reduction greater than 90%. Five patients had a tumor reduction between 75 and 90% and in three patients the tumors were reduced by less than 75%. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION: The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

  15. The adenosine-triphosphatase system responsible for cation transport in electric organ: exclusion of phospholipids as intermediates

    Science.gov (United States)

    Glynn, I. M.; Slayman, Carolyn W.; Eichberg, J.; Dawson, R. M. C.

    1965-01-01

    1. Subcellular fractions were prepared from the electric organs of Electrophorus and Torpedo and assayed for adenosine-triphosphatase activity. 2. Treatment of the `low-speed' fraction from Torpedo with m-urea gave an adenosine-triphosphatase preparation that was almost completely (98%) inhibited by ouabain (0·1mg./ml.) and dependent on the simultaneous presence of Na+ and K+. 3. The adenosine-triphosphatase preparations were exposed to [γ-32P]ATP for 30sec. in the presence of (i) Na+, (ii) K+, (iii) Na++K+ and (iv) Na++K++ouabain. No significant labelling of phosphatidic acid, triphosphoinositide or any other phospholipid was observed. 4. The results suggest that phospholipids do not act as phosphorylated intermediates in the `transport adenosine-triphosphatase' system of electric organ. PMID:14340060

  16. Cyclic adenosine monophosphate-dependent phosphorylation of mammalian mitochondrial proteins: enzyme and substrate characterization and functional role

    Czech Academy of Sciences Publication Activity Database

    Dobrová, Zuzana; Sardanelli, A. M.; Speranza, F.; Scacco, S.; Signorile, A.; Lorusso, V.; Papa, S.

    2001-01-01

    Roč. 40, - (2001), s. 13941-13947 ISSN 0006-2960 Institutional research plan: CEZ:AV0Z5020903 Keywords : cAMP * cyclic adenosine monophosphate Subject RIV: CE - Biochemistry Impact factor: 4.114, year: 2001

  17. Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise

    NARCIS (Netherlands)

    D.J.G.M. Duncker (Dirk); R. Stubenitsky (René); P.D. Verdouw (Pieter)

    1998-01-01

    textabstractA pivotal role for adenosine in the regulation of coronary blood flow is still controversial. Consequently, we investigated its role in the regulation of coronary vasomotor tone in swine at rest and during graded treadmill exercise. During exercise,

  18. Comparative analyses of the effect of radiotherapy and chemotherapy or chemotherapy alone on patients' electrocardiogram

    International Nuclear Information System (INIS)

    Liang Li; Zhang Shulan; Zhang Zhaohui; Wang Junjie; Jia Tingzhen

    2005-01-01

    Objective: To investigate the change of breast cancer patients' electrocardiogram during combined radiotherapy and chemotherapy or chemotherapy alone for the sake of predicting the cardiotoxicity of combined radiotherapy and chemotherapy. Methods: From January, 1998 to June, 2004, 47 postoperative breast cancer patients were enrolled. Among them 29 patients received chemotherapy combined with radiotherapy (combinative group), and 18 patients received chemotherapy alone (non combinative group). The changes of electrocardiogram were observed and correlation factors were analyzed. Results: Abnormal electrocardiograms were noted in 11 (37.9%) and 2 patients (11.1%) of the combinative group and the non-combinative group respectively(z=-1.977, P=0.048). In the combinative group, heart events were significantly increased in patients above 60 years old (z=- 2.094 P=0.036). The changes of electrocardiogram were not significantly correlative with hypertension history, tumor site, dose of radiotherapy or chemotherapeutic drugs. But the incidence of abnormal electrocardiogram was higher in patients with a hypertension history than in those without it (54.5% vs 27.8%). Conclusion: The abnormalities of electrocardiogram were are more frequent in patients treated with both radiotherapy combined with chemotherapy. Our results suggest that breast cancer patients should be regularly reexamined with electrocardiography during therapy, especially whose age was those have a hypertension history and above 60 years old. (authors)

  19. Feasibility and safety of adenosine cardiovascular magnetic resonance in patients with MR conditional pacemaker systems at 1.5 Tesla.

    Science.gov (United States)

    Klein-Wiele, Oliver; Garmer, Marietta; Urbien, Rhyan; Busch, Martin; Kara, Kaffer; Mateiescu, Serban; Grönemeyer, Dietrich; Schulte-Hermes, Michael; Garbrecht, Marc; Hailer, Birgit

    2015-12-22

    Cardiovascular Magnetic Resonance (CMR) with adenosine stress is a valuable diagnostic tool in coronary artery disease (CAD). However, despite the development of MR conditional pacemakers CMR is not yet established in clinical routine for pacemaker patients with known or suspected CAD. A possible reason is that adenosine stress perfusion for ischemia detection in CMR has not been studied in patients with cardiac conduction disease requiring pacemaker therapy. Other than under resting conditions it is unclear whether MR safe pacing modes (paused pacing or asynchronous mode) can be applied safely because the effect of adenosine on heart rate is not precisely known in this entity of patients. We investigate for the first time feasibility and safety of adenosine stress CMR in pacemaker patients in clinical routine and evaluate a pacing protocol that considers heart rate changes under adenosine. We retrospectively analyzed CMR scans of 24 consecutive patients with MR conditional pacemakers (mean age 72.1 ± 11.0 years) who underwent CMR in clinical routine for the evaluation of known or suspected CAD. MR protocol included cine imaging, adenosine stress perfusion and late gadolinium enhancement. Pacemaker indications were sinus node dysfunction (n = 18) and second or third degree AV block (n = 6). Under a pacing protocol intended to avoid competitive pacing on the one hand and bradycardia due to AV block on the other no arrhythmia occurred. Pacemaker stimulation was paused to prevent competitive pacing in sinus node dysfunction with resting heart rate >45 bpm. Sympatho-excitatory effect of adenosine led to a significant acceleration of heart rate by 12.3 ± 8.3 bpm (p pacemakers. Heart rate response to adenosine has to be considered for the choice of pacing modes during CMR.

  20. Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

    Science.gov (United States)

    Randall, Patrick A.; Nunes, Eric J.; Janniere, Simone L.; Stopper, Colin M.; Farrar, Andrew M.; Sager, Thomas N.; Baqi, Younis; Hockemeyer, Jörg; Müller, Christa E.

    2012-01-01

    Rationale Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression. PMID:21347642

  1. A smart magnetic resonance imaging contrast agent responsive to adenosine based on a DNA aptamer-conjugated gadolinium complex.

    Science.gov (United States)

    Xu, Weichen; Lu, Yi

    2011-05-07

    We report a general strategy for developing a smart MRI contrast agent for the sensing of small molecules such as adenosine based on a DNA aptamer that is conjugated to a Gd compound and a protein streptavidin. The binding of adenosine to its aptamer results in the dissociation of the Gd compound from the large protein, leading to decreases in the rotational correlation time and thus change of MRI contrast. © The Royal Society of Chemistry 2011

  2. The Regulation of Skeletal Muscle Active Hyperemia: The Differential Role of Adenosine in Muscles of Varied Fiber Types

    Science.gov (United States)

    1986-04-21

    cyclase mediates the coronary relaxation induced by adenosine. Adenosine-induced relaxation is accompanied by cyclic AMP accumulation in bovine ...and the reaction was started by adding 0.01 ml L-glutamic dehydrogenase ( bovine liver; 1200 U•ml-1 in SO% glycerol and vhosphate buffer; p~ 7.4...Physiol: London 68: 213-237, 1929. Dudley, G.A. and R.L. Terjung. Influence of acidosis on AMP deaTIIinase activity in contracting fast-twitch muscle

  3. The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Andersen, M B; Fuxe, K; Werge, T

    2002-01-01

    The adenosine A2A receptor agonist CGS 21680 has shown effects similar to dopamine antagonists in behavioural assays in rats predictive for antipsychotic activity, without induction of extrapyramidal side-effects (EPS). In the present study, we examined whether this functional dopamine antagonism...... showed a functional anti-dopaminergic effect in Cebus apella monkeys without production of EPS. This further substantiates that adenosine A2A receptor agonists may have potential as antipsychotics with atypical profiles....

  4. Comparison of adenosine and treadmill exercise thallium-201 stress tests for the detection of coronary artery disease

    International Nuclear Information System (INIS)

    Abe, Shinya; Takeishi, Yasuchika; Chiba, Junya; Ikeda, Kozue; Tomoike, Hitonobu

    1993-01-01

    To determine the clinical usefulness of adenosine Tl-201 imaging for the evaluation of coronary artery disease, 22 patients with suspected coronary artery disease who underwent adenosine and exercise Tl-201 single photon emission computed tomography (SPECT) were studied. The peak levels of heart rate (83 vs 123 bpm, p<0.001), systolic blood pressure (124 vs 164 mmHg, p<0.001), diastolic blood pressure (70 vs 86 mmHg, p<0.01) and rate pressure products (10220 vs 20410 bpm x mmHg, p<0.001) were markedly smaller during adenosine infusion than during exercise. Segmental agreements between adenosine and exercise tests were 90% (218 of 242 segments) regarding the presence of perfusion defects and 89% (215 of 242 segments) regarding the presence of redistribution. Regional Tl-201 uptake (r=0.85, p<0.001) and the extent (r=0.75, p<0.001) and intensity (r=0.83, p<0.001) of Tl-201 defects during adenosine testing were closely correlated with those of exercise testing. Adenosine and exercise tests showed similar sensitivities for the identification of individual coronary stenosis (85% vs 78%). However, in patients who were unable to perform adequate exercise (maximal heart rate<120 bpm), the sensitivity of adenosine imaging tended to be higher than that of exercise imaging (92% vs 69%, p=0.07). Adenosine Tl-201 imaging is an alternative to the exercise test for assessing the severity and loci of coronary artery disease, especially in patients who are unable to perform adequate physical exercise. (author)

  5. Low, but not high, dose caffeine is a readily available probe for adenosine actions.

    Science.gov (United States)

    Fredholm, Bertil B; Yang, Jiangning; Wang, Yingqing

    2017-06-01

    Caffeine is very widely used and knowledge of its mode of action can be used to gain an understanding of basal physiological regulation. This review makes the point that caffeine is - in low doses - an antagonist of adenosine acting at A 1 , A 2A and A 2B receptors. We use published and unpublished data to make the point that high dose effects of caffeine are not only qualitatively different but have a different underlying mechanism. Therefore one must be careful in only using epidemiological or experimental data where rather low doses of caffeine are used to draw conclusions about the physiology and pathophysiology of adenosine. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Partial purification and properties of adenosine triphosphatase (ATPase) from liver fluke Fasciola hepatica.

    Science.gov (United States)

    Hassan, Husain; Abeer, Ali

    2014-01-01

    The adenosine triphosphatase (ATP phosphohydrolase, EC 3.6.1.3.;ATPase) is a membrane -bound enzyme which transport protons across the plasma membrane using ATP as an energy source. The adenosine triphosphatase (ATPase ; EC: 3.6.1.3) was extracted from membrane preparations of adult Fasciola hepatica by chloroform treatment and purified by means of ammonium sulphate fractionation, gel filtration on sephadex G-200 and DEAE- Cellulose chromatography. The molecular weight was calculated to be 305.000 dalton by gel filtration. Kinetic experiments demonstrated a biphasic linear lineweaver - burk relationship (km=0.142 and 1.66 mM) thus revealing the existence of two substrate binding enzyme sites. In our study revealed that partial inhibition of Mg²⁺ dependent purified enzyme by oligomycin suggest the absence of mitochondrial ATPase in F. hepatica.

  7. Impaired cerebral microcirculation induced by ammonium chloride in rats is due to cortical adenosine release

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Bjerrum, Esben Jannik; Larsen, Fin Stolze

    2018-01-01

    BACKGROUND: Liver failure results in hyperammonaemia, impaired regulation of cerebral microcirculation, encephalopathy and death. However, the key mediator that alters cerebral microcirculation remains unidentified. In this study we show that topical ammonium significantly increases periarteriolar......: In patients with liver failure disturbances in the brain function is caused in part by ammonia toxicity. In our project we have studied how ammonia, through adenosine release, affects the blood flow in the brain of rats. In our experimental model we demonstrated that the detrimental effect of ammonia on blood...... flow regulation was counteracted by blocking the adenosine receptors in the brain. With this observation we have identified a novel potential treatment target. If we can confirm our findings in a future clinical study it might help patients suffering from liver failure and the severe condition called...

  8. Role of adenosine in regulating the heterogeneity of skeletal muscle blood flow during exercise in humans

    DEFF Research Database (Denmark)

    Heinonen, Ilkka; Nesterov, Sergey V; Kemppainen, Jukka

    2007-01-01

    receptor blockade. BF heterogeneity within muscles was calculated from 16-mm(3) voxels in BF images and heterogeneity among the muscles from the mean values of the four QF compartments. Mean BF in the whole QF and its four parts increased, and heterogeneity decreased with workload both without......Evidence from both animal and human studies suggests that adenosine plays a role in the regulation of exercise hyperemia in skeletal muscle. We tested whether adenosine also plays a role in the regulation of blood flow (BF) distribution and heterogeneity among and within quadriceps femoris (QF...... and with theophylline (P heterogeneity among the QF muscles, yet blockade increased within-muscle BF heterogeneity in all four QF muscles (P = 0.03). Taken together, these results show that BF becomes less heterogeneous with increasing...

  9. Adenosine deaminase complexing protein (ADCP): a transformation sensitive protein with potentials of a cancer marker.

    Science.gov (United States)

    Herbschleb-Voogt, E; Ten Kate, J; Meera Khan, P

    1983-01-01

    Several observations by independent investigators in the past have indicated that adenosine deaminase complexing protein (ADCP), present in considerable quantities in certain human tissues, was absent or decreased in the cancers originated from them. During the present study, electrophoretic analysis of adenosine deaminase (ADA) isozymes and radioimmunoassay for ADCP in the primary fibroblasts and the transformed as well as certain tumor derived cell lines have demonstrated that ADCP present in large quantities in the primary cells was absent or nearly absent in the transformed or tumor-derived cell lines. Though the mechanisms involved are not yet clear, the above observations indicate that ADCP has the potentials of a useful marker in the studies on transformed cells and cancer tissues.

  10. Conformational change of adenosine deaminase during ligand-exchange in a crystal.

    Science.gov (United States)

    Kinoshita, Takayoshi; Tada, Toshiji; Nakanishi, Isao

    2008-08-15

    Adenosine deaminase (ADA) perpetuates chronic inflammation by degrading extracellular adenosine which is toxic for lymphocytes. ADA has two distinct conformations: open form and closed form. From the crystal structures with various ligands, the non-nucleoside type inhibitors bind to the active site occupying the critical water-binding-position and sustain the open form of apo-ADA. In contrast, substrate mimics do not occupy the critical position, and induce the large conformational change to the closed form. However, it is difficult to predict the binding of (+)-erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), as it possesses characteristic parts of both the substrate and the non-nucleoside inhibitors. The crystal structure shows that EHNA binds to the open form through a novel recognition of the adenine base accompanying conformational change from the closed form of the PR-ADA complex in crystalline state.

  11. Adenosine A2B receptor: from cell biology to human diseases

    Science.gov (United States)

    Sun, Ying; Huang, Pingbo

    2016-08-01

    Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR’s functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases.

  12. An enzyme-free strategy for ultrasensitive detection of adenosine using a multipurpose aptamer probe and malachite green.

    Science.gov (United States)

    Zhao, Hui; Wang, Yong-Sheng; Tang, Xian; Zhou, Bin; Xue, Jin-Hua; Liu, Hui; Liu, Shan-Du; Cao, Jin-Xiu; Li, Ming-Hui; Chen, Si-Han

    2015-08-05

    We report on an enzyme-free and label-free strategy for the ultrasensitive determination of adenosine. A novel multipurpose adenosine aptamer (MAAP) is designed, which serves as an effective target recognition probe and a capture probe for malachite green. In the presence of adenosine, the conformation of the MAAP is converted from a hairpin structure to a G-quadruplex. Upon addition of malachite green into this solution, a noticeable enhancement of resonance light scattering was observed. The signal response is directly proportional to the concentration of adenosine ranging from 75 pM to 2.2 nM with a detection limit of 23 pM, which was 100-10,000 folds lower than those obtained by previous reported methods. Moreover, this strategy has been applied successfully for detecting adenosine in human urine and blood samples, further proving its reliability. The mechanism of adenosine inducing MAAP to form a G-quadruplex was demonstrated by a series of control experiments. Such a MAAP probe can also be used to other strategies such as fluorescence or spectrophotometric ones. We suppose that this strategy can be expanded to develop a universal analytical platform for various target molecules in the biomedical field and clinical diagnosis. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Crystal structures of T. b. rhodesiense adenosine kinase complexed with inhibitor and activator: implications for catalysis and hyperactivation.

    Directory of Open Access Journals (Sweden)

    Sabine Kuettel

    2011-05-01

    Full Text Available BACKGROUND: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP utilizing adenosine triphosphate (ATP as the preferred phosphoryl donor. METHODS AND FINDINGS: Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK: the structure of TbrAK in complex with the bisubstrate inhibitor P(1,P(5-di(adenosine-5'-pentaphosphate (AP5A at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl-2H-pyrazol-3-yl]morpholine (compound 1 at 2.8 Å resolution. CONCLUSIONS: The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK.

  14. A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Stefania Merighi

    2005-10-01

    Full Text Available Hypoxia-inducible factor-1 (HIF-1 is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% 02, adenosine upregulates HIF-1α protein expression in a dose-dependent and timedependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2 protein accumulation through the induction of HIF-1α. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1a and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells.

  15. Comparison of adenosine and exercise stress 201Tl myocardial perfusion imaging for diagnosing coronary heart disease in women

    International Nuclear Information System (INIS)

    Li Jiangjin; Ma Shuren; Meng Tao; Bao Zhi; Cui Jianhe

    2011-01-01

    Objective: To compare the diagnostic value of adenosine and exercise stress myocardial perfusion imaging (MPI) for detecting coronary heart disease (CHD) in women. Methods: One hundred and thirty-eight patients with CHD were randomly divided into two groups: adenosine stress group (n=69)and exercise stress group (n=69). All patients underwent myocardial SPECT evaluation. Coronary angiography (CAG), referred as 'gold standard' , was performed in each patient within 1 week before or after MPI. The diagnostic value of the two stress MPI was compared with χ 2 test or Fisher's exact test. Results: In adenosine stress group, the sensitivity, negative predictive value and accuracy were 88.2% (45/51), 72.7% (16/22), 88.4% (61/69), respectively, which were not significantly different from those of the exercise stress group (91.7% (44/48), 66.7% (8/12), 81.2% (52/64); χ 2 =0.571, 0.714, 0.249, P>0.05). However, the false positive rate of adenosine stress (11.1%, 2/18) was significantly lower than that of exercise stress (50.0%, 8/16), P=0.023. Conclusions: Adenosine and exercise stress MPI have similar value for CHD diagnosis in women, however, adenosine stress MPI may have an advantage of low false positive rate. (authors)

  16. Roles of the adenosine receptor and CD73 in the regulatory effect of γδ T cells.

    Directory of Open Access Journals (Sweden)

    Dongchun Liang

    Full Text Available The adenosine A2A receptor (A2AR, the main functional adenosine receptor on murine T cells, plays a unique role in the attenuation of inflammation and tissue damage in vivo. Here, we showed that, of the immune cell types tested, activated γδ T cells expressed the highest levels of A2AR mRNA and that A2AR ligation inhibited αβ T cell activation, but enhanced γδ T cell activation. We also showed that the inhibitory effect of an adenosine receptor agonist on autoreactive T cells was prevented by addition of a low percentage of activated γδ T cells. Furthermore, compared to resting cells, activated γδ T cells expressed significantly lower levels of CD73, an enzyme involved in the generation of extracellular adenosine. Exogenous AMP had a significant inhibitory effect on autoreactive T cell responses, but only in the presence of CD73+ γδ T cells, and this effect was abolished by a CD73 inhibitor. Our results show that expression of increased amounts of A2AR allows γδ T cells to bind adenosine and thereby attenuate its suppressive effect, while decreased expression of CD73 results in less generation of adenosine in the inflammatory site. Together, these events allow activated γδ T cells to acquire increased proinflammatory activity, leading to augmented autoimmune responses.

  17. Transgenic overexpression of adenosine kinase in brain leads to multiple learning impairments and altered sensitivity to psychomimetic drugs.

    Science.gov (United States)

    Yee, Benjamin K; Singer, Philipp; Chen, Jiang-Fan; Feldon, Joram; Boison, Detlev

    2007-12-01

    The neuromodulator adenosine fulfills a unique role in the brain affecting glutamatergic neurotransmission and dopaminergic signaling via activation of adenosine A1 and A2A receptors, respectively. The adenosine system is thus ideally positioned to integrate glutamatergic and dopaminergic neurotransmission, which in turn could affect behavior and cognition. In the adult brain, adenosine levels are largely regulated by its key metabolic enzyme adenosine kinase (ADK), which may assume the role of an 'upstream regulator' of these two neurotransmitter pathways. To test this hypothesis, transgenic mice with an overexpression of ADK in brain (Adk-tg), and therefore reduced brain adenosine levels, were evaluated in a panel of behavioral and psychopharmacological assays to assess possible glutamatergic and dopaminergic dysfunction. In comparison to non-transgenic control mice, Adk-tg mice are characterized by severe learning deficits in the Morris water maze task and in Pavlovian conditioning. The Adk-tg mice also exhibited reduced locomotor reaction to systemic amphetamine, whereas their reaction to the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 was enhanced. Our results confirmed that ADK overexpression could lead to functional concomitant alterations in dopaminergic and glutamatergic functions, which is in keeping with the hypothesized role of ADK in the balance and integration between glutamatergic and dopaminergic neurotransmission. The present findings are of relevance to current pathophysiological hypotheses of schizophrenia and its pharmacotherapy.

  18. Synthesis of high specific activity tritium labelled [2-3H]-adenosine-5'-triphosphate

    International Nuclear Information System (INIS)

    Jaiswal, D.K.; Morimoto, H.; Trump, E.L.; Williams, P.G.; Wemmer, D.E.

    1996-01-01

    A procedure for high level tritium labelling at the C2-H position of adenosine 5'-triphosphate ([2- 3 H]-ATP, 1), based on the tritiodehalogenation reaction of 2-bromoadenosine 5'-triphosphate (2) has been elaborated. This precursor was prepared in a six-step synthesis from guanosine. The tritiodehalogenation of (2) for three hours over palladium oxide in phosphate buffer yielded tritium labelled ATP with high specific activity, in good chemical yield. (author)

  19. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

    OpenAIRE

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R. Douglas

    2004-01-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility...

  20. Stimulatory effects of adenosine on prolactin secretion in the pituitary gland of the rat

    Directory of Open Access Journals (Sweden)

    D.L.W. Picanço-Diniz

    2002-07-01

    Full Text Available We investigated the effects of adenosine on prolactin (PRL secretion from rat anterior pituitaries incubated in vitro. The administration of 5-N-methylcarboxamidoadenosine (MECA, an analog agonist that preferentially activates A2 receptors, induced a dose-dependent (1 nM to 1 µM increase in the levels of PRL released, an effect abolished by 1,3-dipropyl-7-methylxanthine, an antagonist of A2 adenosine receptors. In addition, the basal levels of PRL secretion were decreased by the blockade of cyclooxygenase or lipoxygenase pathways, with indomethacin and nordihydroguaiaretic acid (NDGA, respectively. The stimulatory effects of MECA on PRL secretion persisted even after the addition of indomethacin, but not of NDGA, to the medium. MECA was unable to stimulate PRL secretion in the presence of dopamine, the strongest inhibitor of PRL release that works by inducing a decrease in adenylyl cyclase activity. Furthermore, the addition of adenosine (10 nM mimicked the effects of MECA on PRL secretion, an effect that persisted regardless of the presence of LiCl (5 mM. The basal secretion of PRL was significatively reduced by LiCl, and restored by the concomitant addition of both LiCl and myo-inositol. These results indicate that PRL secretion is under a multifactorial regulatory mechanism, with the participation of different enzymes, including adenylyl cyclase, inositol-1-phosphatase, cyclooxygenase, and lipoxygenase. However, the increase in PRL secretion observed in the lactotroph in response to A2 adenosine receptor activation probably was mediated by mechanisms involving regulation of adenylyl cyclase, independent of membrane phosphoinositide synthesis or cyclooxygenase activity and partially dependent on lipoxygenase arachidonic acid-derived substances.

  1. The Effects of Diabetes Mellitus on the Relationship Between Myocardial Adenosine Production and Coronary Vascular Resistance

    Science.gov (United States)

    1987-03-13

    10) and diabetic (n 6) groups. The dogs were vaccinated for rabies and distemper and were free of heartworms and other parasites. Induction of...diabetic dogs suggests that diabetes mellitus attenuates the stimulated release of adenosine. Since insulin administration in this study increased...should be mimicked by exogenous administration of the substance. 7) Agents that potentiate or attenuate the action of administered mediator should

  2.   Adenosine-diphosphate (ADP) reduces infarct size and improves porcine heart function after myocardial infarction

    DEFF Research Database (Denmark)

    Bune, Laurids Touborg; Larsen, Jens Kjærgaard Rolighed; Thaning, Pia

    2013-01-01

    Acute myocardial infarction continues to be a major cause of morbidity and mortality. Timely reperfusion can substantially improve outcomes and the administration of cardioprotective substances during reperfusion is therefore highly attractive. Adenosine diphosphate (ADP) and uridine-5-triphoshat...... infusion during reperfusion reduces IS by ~20% independently from systemic release of t-PA. ADP-induced reduction in both preload and afterload could account for the beneficial myocardial effect....

  3. Protective effect of preconditioning and adenosine pretreatment in experimental skeletal muscle reperfusion injury.

    Science.gov (United States)

    Papanastasiou, S; Estdale, S E; Homer-Vanniasinkam, S; Mathie, R T

    1999-07-01

    Prolonged ischaemia followed by reperfusion (I/R) of skeletal muscle results in significant tissue injury. Ischaemic preconditioning (IPC), achieved by repeated brief periods of I/R before prolonged ischaemia or adenosine pretreatment, can prevent I/R injury in cardiac muscle. The aim of this study was to ascertain in a rodent model if damage to skeletal muscle due to global hindlimb tourniquet-induced I/R could be similarly attenuated. Anaesthetized rats were randomized (n = 6-10 per group) to five groups: sham-operated controls; I/R (4 h of ischaemia, 2 h of reperfusion); IPC (three cycles of 10 min of ischaemia/10 min of reperfusion) alone; IPC immediately preceding I/R; or adenosine 1000 microg/kg immediately before I/R. At the end of reperfusion, biopsies were taken from the left gastrocnemius muscle for measurement of myeloperoxidase (MPO) and reduced glutathione (GSH). Before ischaemia and at the end of reperfusion, blood samples were taken for measurement of nitric oxide metabolites, tumour necrosis factor (TNF) alpha and macrophage inflammatory protein (MIP) 2. IPC before I/R resulted in lower levels of MPO (P < 0.001) and TNF-alpha (P = 0.004), and higher levels of GSH (P < 0.001) and nitric oxide metabolites (P = 0.002) than I/R alone. Adenosine had effects comparable to IPC pretreatment (P < 0.001 for MPO, P = 0.002 for GSH, P = 0.02 for nitric oxide metabolites and P = 0.001 for TNF-alpha). There was no difference in the blood pressure or the MIP-2 concentration among the groups. IPC or pretreatment with adenosine ameliorates the I/R injury of skeletal muscle.

  4. Stability of 2 mg/mL Adenosine Solution in Polyvinyl Chloride and Polyolefin Infusion Bags.

    Science.gov (United States)

    DeAngelis, Michael; Ferrara, Alexander; Gregory, Kaleigh; Zammit, Kimberly; Zhao, Fang

    2018-04-01

    Adenosine is a potent endogenous mediator of vasodilation. Compounded sterile solutions of adenosine are used in cardiac catheterization lab to perform stress tests on the heart. These tests are used to determine the fractional flow reserve (FFR) and are commonly used in the management and diagnosis of cardiovascular conditions. The purpose of this study was to assess the physical and chemical stability of 2 mg/mL adenosine in 0.9% Sodium Chloride Injection, USP in polyvinyl chloride [PVC]) and polyolefin infusion bags stored at room temperature (20°C-25°C) and under refrigeration (2°C-8°C). The compounding and analytical methods used in this study were very similar to those described in the prior publications from the authors' laboratory. To ensure a uniform starting concentration of all stability samples, a batch of 2 mg/mL adenosine solution was prepared and then packaged into empty PVC and polyolefin infusion bags. These stability samples were prepared in triplicate for each bag type and storage temperature (a total of 12 samples). The infusion bag samples were assessed for stability immediately after preparation and after 1 day, 3 days, 7 days, and 14 days. At each time point, the infusion bags were first visually inspected against a light background for color change, clarity, and particulates. Aliquots were drawn from each sample at each time point for pH analysis and high-performance liquid chromatography (HPLC) analysis. Over 14 days of storage at room temperature or refrigeration, no considerable change in visual appearance or pH was observed in any bags. All samples retained 90% to 110% of the initial drug concentration. No significant degradation peaks were observed in the HPLC chromatograms.

  5. Anticonvulsant activity of B2, an adenosine analog, on chemical convulsant-induced seizures.

    Directory of Open Access Journals (Sweden)

    Min Li

    Full Text Available Epilepsy is a chronic neurological disorder characterized by recurrent seizures. However, approximately one-third of epilepsy patients still suffer from uncontrolled seizures. Effective treatments for epilepsy are yet to be developed. N (6-(3-methoxyl-4-hydroxybenzyl adenine riboside (B2 is a N(6-substitued adenosine analog. Here we describe an investigation of the effects and mechanisms of B2 on chemical convulsant-induced seizures. Seizures were induced in mice by administration of 4-aminopyridine (4-AP, pentylenetetrazol (PTZ, picrotoxin, kainite acid (KA, or strychnine. B2 has a dose-related anticonvulsant effect in these chemical-induced seizure models. The protective effects of B2 include increased latency of seizure onset, decreased seizure occurrence, shorter seizure duration and reduced mortality rate. Radioligand binding and cAMP accumulation assays indicated that B2 might be a functional ligand for both adenosine A1 and A2A receptors. Furthermore, DPCPX, a selective A1 receptor antagonist, but not SCH58261, a selective A2A receptor antagonist, blocked the anticonvulsant effect of B2 on PTZ-induced seizure. c-Fos is a cellular marker for neuronal activity. Immunohistochemical and western blot analyses indicated that B2 significantly reversed PTZ-induced c-Fos expression in the hippocampus. Together, these results indicate that B2 has significant anticonvulsant effects. The anticonvulsant effects of B2 may be attributed to adenosine A1 receptor activation and reduced neuronal excitability in the hippocampus. These observations also support that the use of adenosine receptor agonist may be a promising approach for the treatment of epilepsy.

  6. Molecular Pathways of Disturbed Sleep and Depression: Studies on Adenosine and Gene Expression Patterns

    OpenAIRE

    Gass, Natalia

    2010-01-01

    Background: Adenosine is a potent sleep-promoting substance, and one of its targets is the basal forebrain. Fairly little is known about its mechanism of action in the basal forebrain and about the receptor subtype mediating its regulating effects on sleep homeostasis. Homeostatic deficiency might be one of the causes of the profoundly disturbed sleep pattern in major depressive disorder, which could explain the reduced amounts of delta-activity-rich stages 3 and 4. Since major depression has...

  7. Outcome of Patients With Adenosine-Induced ST Segment Depression and Normal Myocardial Perfusion

    International Nuclear Information System (INIS)

    El-Refaei, S.; Selim, M.

    2011-01-01

    The aim of the present study was to determine the outcome of patients with normal MPS and adenosine-induced ST segment depression. A total of 1867 patients underwent adenosine Tc99m-tetrofosmin MPS in nuclear medicine unit in Saudi German Hospital, Saudi Arabia, between January 2004 and May 2008. Their ECGs were checked for ST segment depression during adenosine infusion. All patients with ≥ 1 mm horizontal or down-sloping ST segment depression or≥ 1.5 mm up-sloping ST segment depression were included in the study. Fifty-six patients met our inclusion criteria, of which 45 (80%) were females. During the follow-up period, a total of 15 of patients ended up doing coronary angiography, either for high clinical suspicion or following a second positive MPS performed 6-18 months after the first study. Seven of them were positive for coronary artery disease and were subsequently treated with revascularization procedure, and 8 returned either normal angiography or non-obstructive coronary artery disease. Male diabetic smoking patients were more prevalent and underwent revascularization. The patients were followed up for a mean of 22.8 ±7.8 months. No cardiac deaths or myocardial infarctions were reported. It could be concluded that adenosine-induced ST segment depression in patients with normal myocardial perfusion was a benign finding and did not increase the very low risk of cardiac events in those patients. However, male smokers and/or diabetics might need further investigation. This suggestion needs further evaluation

  8. AB089. Impaired adenosine signaling influences erectile function in aging rats

    OpenAIRE

    Yang, Xingliang; Yuan, Jiuhong

    2017-01-01

    Background As one of the most common disorders in old adult, erectile dysfunction (ED) remains attracting andrological physicians? attention. The aim of this study is to investigate the alterations of adenosine signaling in the penis of aging rats, and the influence to erectile function. Methods According to apomorphine test, the aging rats (18 months) with ED were selected as age-related erectile dysfunction (A-ED) group, and the young rats (2 months) were selected as normal control (NC) gro...

  9. Cytokinin metabolism of pathogenic fungus Leptosphaeria maculans involves isopentenyltransferase, adenosine kinase and cytokinin oxidase/dehydrogenase

    Czech Academy of Sciences Publication Activity Database

    Trdá, Lucie; Barešová, Monika; Šašek, Vladimír; Nováková, Miroslava; Zahajská, Lenka; Dobrev, Petre; Motyka, Václav; Burketová, Lenka

    2017-01-01

    Roč. 8, JUL 21 (2017), č. článku 1374. ISSN 1664-302X R&D Projects: GA ČR GA13-26798S; GA ČR(CZ) GA16-14649S Institutional support: RVO:61389030 Keywords : Adenosine kinase * Cytokinin * Cytokinin oxidase/dehydrogenase * Isopentenyltransferase * Leptosphaeria maculans * Zeatin cis/trans isomerase Subject RIV: GF - Plant Pathology, Vermin, Weed, Plant Protection OBOR OECD: Microbiology Impact factor: 4.076, year: 2016

  10. Activation of adenosine A(1) receptors alters behavioral and biochemical parameters in hyperthyroid rats.

    Science.gov (United States)

    Bruno, Alessandra Nejar; Fontella, Fernanda Urruth; Bonan, Carla Denise; Barreto-Chaves, Maria Luiza M; Dalmaz, Carla; Sarkis, João José Freitas

    2006-02-28

    Adenosine acting on A(1) receptors has been related with neuroprotective and neuromodulatory actions, protection against oxidative stress and decrease of anxiety and nociceptive signaling. Previous studies demonstrated an inhibition of the enzymes that hydrolyze ATP to adenosine in the rat central nervous system after hyperthyroidism induction. Manifestations of hyperthyroidism include increased anxiety, nervousness, high O(2) consumption and physical hyperactivity. Here, we investigated the effects of administration of a specific agonist of adenosine A(1) receptor (N(6)-cyclopentyladenosine; CPA) on nociception, anxiety, exploratory response, locomotion and brain oxidative stress of hyperthyroid rats. Hyperthyroidism was induced by daily intraperitoneal injections of l-thyroxine (T4) for 14 days. Nociception was assessed with a tail-flick apparatus and exploratory behavior, locomotion and anxiety were analyzed by open-field and plus-maze tests. We verified the total antioxidant reactivity (TAR), lipid peroxide levels by the thiobarbituric acid reactive species (TBARS) reaction and the free radicals content by the DCF test. Our results demonstrated that CPA reverted the hyperalgesia induced by hyperthyroidism and decreased the exploratory behavior, locomotion and anxiety in hyperthyroid rats. Furthermore, CPA decreased lipid peroxidation in hippocampus and cerebral cortex of control rats and in cerebral cortex of hyperthyroid rats. CPA also increased the total antioxidant reactivity in hippocampus and cerebral cortex of control and hyperthyroid rats, but the production of free radicals verified by the DCF test was changed only in cerebral cortex. These results suggest that some of the hyperthyroidism effects are subjected to regulation by adenosine A(1) receptor, demonstrating the involvement of the adenosinergic system in this pathology.

  11. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function

    Science.gov (United States)

    Kara, Firas M.; Chitu, Violeta; Sloane, Jennifer; Axelrod, Matthew; Fredholm, Bertil B.; Stanley, E. Richard; Cronstein, Bruce N.

    2010-01-01

    Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A1R, A2AR, A2BR, and A3R). Because A1R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A1R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A1R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-κB ligand in the presence or absence of the A1R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A1R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A1R antagonist DPCPX inhibits osteoclast formation (IC50=1 nM), with altered morphology and reduced ability to resorb bone. A1R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A1R and further suggest that A1R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.—Kara, F. M., Chitu, V., Sloane, J., Axelrod, M., Fredholm, B. B., Stanley, R., Cronstein, B. N. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. PMID:20181934

  12. Effects of an induced adenosine deaminase deficiency on T-cell differentiation in the rat

    International Nuclear Information System (INIS)

    Barton, R.W.

    1985-01-01

    Inherited deficiency of the enzyme adenosine deaminase (ADA) has been found in a significant proportion of patients with severe combined immunodeficiency disease and inherited defect generally characterized by a deficiency of both B and T cells. Two questions are central to understanding the pathophysiology of this disease: (1) at what stage or stages in lymphocyte development are the effects of the enzyme deficiency manifested; (2) what are the biochemical mechanisms responsible for the selective pathogenicity of the lymphoid system. We have examined the stage or stages of rat T-cell development in vivo which are affected by an induced adenosine deaminase deficiency using the ADA inhibitors, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 2'-deoxycoformycin (DCF). In normal rats given daily administration of an ADA inhibitor, cortical thymocytes were markedly depleted; peripheral lymphocytes and pluripotent hemopoietic stem cells (CFU-S) all were relatively unaffected. Since a deficiency of ADA affects lymphocyte development, the regeneration of cortical and medullary thymocytes and their precursors after sublethal irradiation was used as a model of lymphoid development. By Day 5 after irradiation the thymus was reduced to 0.10-0.5% of its normal size; whereas at Days 9 and 14 the thymus was 20-40% and 60-80% regenerated, respectively. When irradiated rats were given daily parenteral injections of the ADA inhibitor plus adenosine or deoxyadenosine, thymus regeneration at Days 9 and 14 was markedly inhibited, whereas the regeneration of thymocyte precursors was essentially unaffected. Thymus regeneration was at least 40-fold lower than in rats given adenosine or deoxyadenosine alone. Virtually identical results were obtained with both ADA inhibitors, EHNA and DCF

  13. Identification of the heart as the critical site of adenosine mediated embryo protection

    Directory of Open Access Journals (Sweden)

    Greene Robert W

    2010-05-01

    Full Text Available Abstract Background Our understanding of the mechanisms that protect the developing embryo from intrauterine stress is limited. Recently, adenosine has been demonstrated to play a critical role in protecting the embryo against hypoxia via adenosine A1 receptors (A1ARs, which are expressed in the heart, nervous system, and other sites during development. However, the sites of A1AR action that mediate embryo protection are not known. To determine if the heart is a key site of adenosine-mediated embryo protection, A1ARs were selectively deleted in the embryonic heart using a Cre-LoxP system in which the alpha-myosin heavy chain promoter drives Cre-recombinase expression and excision of the A1AR gene from cardiomyocytes. Results With increasing exposure of maternal hypoxia (10% O2 from 48-96 hours beginning at embryonic day (E 8.5, embryo viability decreased in the cardiac-A1AR deleted embryos. 48 hours of hypoxia reduced embryonic viability by 49% in embryos exposed from E10.5-12.5 but no effect on viability was observed in younger embryos exposed to hypoxia from E8.5-10.5. After 72 hours of hypoxia, 57.8% of the cardiac-A1AR deleted embryos were either dead or re-absorbed compared to 13.7% of control littermates and after 96 hours 81.6% of cardiac-A1AR deleted embryos were dead or re-absorbed. After 72 hours of hypoxia, cardiac size was reduced significantly more in the cardiac-A1AR deleted hearts compared to controls. Gene expression analysis revealed clusters of genes that are regulated by both hypoxia and A1AR expression. Conclusions These data identify the embryonic heart as the critical site where adenosine acts to protect the embryo against hypoxia. As such these studies identify a previously unrecognized mechanism of embryo protection.

  14. Microcontroller-assisted compensation of adenosine triphosphate levels: instrument and method development.

    Science.gov (United States)

    Hu, Jie-Bi; Chen, Ting-Ru; Chen, Yu-Chie; Urban, Pawel L

    2015-01-30

    In order to ascertain optimum conditions for biocatalytic processes carried out in vitro, we have designed a bio-opto-electronic system which ensures real-time compensation for depletion of adenosine triphosphate (ATP) in reactions involving transfer of phosphate groups. The system covers ATP concentration range of 2-48 μM. The report demonstrates feasibility of the device operation using apyrase as the ATP-depleting enzyme.

  15. Evaluation of response to neoadjuvant chemotherapy in breast cancer

    International Nuclear Information System (INIS)

    Jia Li; Deng Zhiyong

    2013-01-01

    Preoperative neoadjuvant chemotherapy has become the standardized treatment for patients with locally advanced breast cancer. With the wide application of neoadjuvant chemotherapy in clinic, evaluation of response to neoadjuvant chemotherapy seems increasingly important. How to evaluate the curative effect of chemotherapy timely, accurately, effectively and noninvasively has become the focus of clinical research. At present, clinical palpation,radiographic measurement and pathological examination are usually used in clinic, and the study of breast cancer biology factor is also rapidly spread. The application status of different evaluation methods of neoadjuvant chemotherapy were reviewed in this article. (authors)

  16. Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine

    Science.gov (United States)

    Zylka, Mark J.; Sowa, Nathaniel A.; Taylor-Blake, Bonnie; Twomey, Margaret A.; Herrala, Annakaisa; Voikar, Vootele; Vihko, Pirkko

    2008-01-01

    SUMMARY Thiamine monophosphatase (TMPase, also known as Fluoride-Resistant Acid Phosphatase) is a classic histochemical marker of small-diameter dorsal root ganglia neurons. The molecular identity of TMPase is currently unknown. We found that TMPase is identical to the transmembrane isoform of Prostatic Acid Phosphatase (PAP), an enzyme with unknown molecular and physiological functions. We then found that PAP knockout mice have normal acute pain sensitivity but enhanced sensitivity in chronic inflammatory and neuropathic pain models. In gain-of-function studies, intraspinal injection of PAP protein has potent anti-nociceptive, anti-hyperalgesic and anti-allodynic effects that last longer than the opioid analgesic morphine. PAP suppresses pain by functioning as an ecto-5’-nucleotidase. Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. Our studies reveal molecular and physiological functions for PAP in purine nucleotide metabolism and nociception and suggest a novel use for PAP in the treatment of chronic pain. PMID:18940592

  17. A Phenotypic Screen for Functional Mutants of Human Adenosine Deaminase Acting on RNA 1.

    Science.gov (United States)

    Wang, Yuru; Havel, Jocelyn; Beal, Peter A

    2015-11-20

    Adenosine deaminases acting on RNA (ADARs) are RNA-editing enzymes responsible for the conversion of adenosine to inosine at specific locations in cellular RNAs. ADAR1 and ADAR2 are two members of the family that have been shown to be catalytically active. Earlier, we reported a phenotypic screen for the study of human ADAR2 using budding yeast S. cerevisiae as the host system. While this screen has been successfully applied to the study of ADAR2, it failed with ADAR1. Here, we report a new reporter that uses a novel editing substrate and is suitable for the study of ADAR1. We screened plasmid libraries with randomized codons for two important residues in human ADAR1 (G1007 and E1008). The screening results combined with in vitro deamination assays led to the identification of mutants that are more active than the wild type protein. Furthermore, a screen of the ADAR1 E1008X library with a reporter construct bearing an A•G mismatch at the editing site suggests one role for the residue at position 1008 is to sense the identity of the base pairing partner for the editing site adenosine. This work has provided a starting point for future in vitro evolution studies of ADAR1 and led to new insight into ADAR's editing site selectivity.

  18. Cordycepin Increases Nonrapid Eye Movement Sleep via Adenosine Receptors in Rats.

    Science.gov (United States)

    Hu, Zhenzhen; Lee, Chung-Il; Shah, Vikash Kumar; Oh, Eun-Hye; Han, Jin-Yi; Bae, Jae-Ryong; Lee, Kinam; Chong, Myong-Soo; Hong, Jin Tae; Oh, Ki-Wan

    2013-01-01

    Cordycepin (3'-deoxyadenosine) is a naturally occurring adenosine analogue and one of the bioactive constituents isolated from Cordyceps militaris/Cordyceps sinensis, species of the fungal genus Cordyceps. It has traditionally been a prized Chinese folk medicine for the human well-being. Because of similarity of chemical structure of adenosine, cordycepin has been focused on the diverse effects of the central nervous systems (CNSs), like sleep regulation. Therefore, this study was undertaken to know whether cordycepin increases the natural sleep in rats, and its effect is mediated by adenosine receptors (ARs). Sleep was recorded using electroencephalogram (EEG) for 4 hours after oral administration of cordycepin in rats. Sleep architecture and EEG power spectra were analyzed. Cordycepin reduced sleep-wake cycles and increased nonrapid eye movement (NREM) sleep. Interestingly, cordycepin increased θ (theta) waves power density during NREM sleep. In addition, the protein levels of AR subtypes (A1, A2A, and A2B) were increased after the administration of cordycepin, especially in the rat hypothalamus which plays an important role in sleep regulation. Therefore, we suggest that cordycepin increases theta waves power density during NREM sleep via nonspecific AR in rats. In addition, this experiment can provide basic evidence that cordycepin may be helpful for sleep-disturbed subjects.

  19. Carbohydrate management, anaerobic metabolism, and adenosine levels in the armoured catfish, Liposarcus pardalis (castelnau), during hypoxia.

    Science.gov (United States)

    Maccormack, Tyson James; Lewis, Johanne Mari; Almeida-Val, Vera Maria Fonseca; Val, Adalberto Luis; Driedzic, William Robert

    2006-04-01

    The armoured catfish, Liposarcus pardalis, tolerates severe hypoxia at high temperatures. Although this species can breathe air, it also has a strong anaerobic metabolism. We assessed tissue to plasma glucose ratios and glycogen and lactate in a number of tissues under "natural" pond hypoxia, and severe aquarium hypoxia without aerial respiration. Armour lactate content and adenosine in brain and heart were also investigated. During normoxia, tissue to plasma glucose ratios in gill, brain, and heart were close to one. Hypoxia increased plasma glucose and decreased tissue to plasma ratios to less than one, suggesting glucose phosphorylation is activated more than uptake. High normoxic white muscle glucose relative to plasma suggests gluconeogenesis or active glucose uptake. Excess muscle glucose may serve as a metabolic reserve since hypoxia decreased muscle to plasma glucose ratios. Mild pond hypoxia changed glucose management in the absence of lactate accumulation. Lactate was elevated in all tissues except armour following aquarium hypoxia; however, confinement in aquaria increased armour lactate, even under normoxia. A stress-associated acidosis may contribute to armour lactate sequestration. High plasma lactate levels were associated with brain adenosine accumulation. An increase in heart adenosine was triggered by confinement in aquaria, although not by hypoxia alone.

  20. Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney

    Directory of Open Access Journals (Sweden)

    Ayodele Jacob Akinyemi

    2017-04-01

    Full Text Available In this study, the effect of enzymes involved in degradation of renal adenosine and l-arginine was investigated in rats exposed to cadmium (Cd and treated with curcumin, the principal active phytochemical in turmeric rhizome. Animals were divided into six groups (n = 6: saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. The results of this study revealed that the activities of renal adenosine deaminase and arginase were significantly increased in Cd-treated rats when compared with the control (p < 0.05. However, co-treatment with curcumin inhibits the activities of these enzymes compared with Cd-treated rats. Furthermore, Cd intoxication increased the levels of some renal biomarkers (serum urea, creatinine, and electrolytes and malondialdehyde level with a concomitant decrease in functional sulfhydryl group and nitric oxide (NO. However, co-treatment with curcumin at 12.5 mg/kg and 25 mg/kg, respectively, increases the nonenzymatic antioxidant status and NO in the kidney, with a concomitant decrease in the levels of malondialdehyde and renal biomarkers. Therefore, our results reinforce the importance of adenosine deaminase and arginase activities in Cd poisoning conditions and suggest some possible mechanisms of action by which curcumin prevent Cd-induced renal toxicity in rats.

  1. Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis

    International Nuclear Information System (INIS)

    Boy, Christian; Meyer, Philipp T.; Kircheis, Gerald; Haussinger, Dieter; Holschbach, Marcus H.; Coenen, Heinz H.; Herzog, Hans; Elmenhorst, David; Kaiser, Hans J.; Zilles, Karl; Bauer, Andreas

    2008-01-01

    The cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A 1 adenosine receptors (A 1 AR), is likely to be involved. The present study investigates changes of cerebral A 1 AR binding in cirrhotic patients by means of positron emission tomography (PET) and [ 18 F]CPFPX, a novel selective A 1 AR antagonist. PET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan's non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to B max /K D ). Cortical and subcortical regions showed lower A 1 AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p 1 AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A 1 AR density or affinity, as well as blockade of the A 1 AR by endogenous adenosine or exogenous xanthines. (orig.)

  2. A2A Adenosine Receptor Antagonists as Therapeutic Candidates: are they still an interesting challenge?

    Science.gov (United States)

    Cacciari, Barbara; Federico, Stephanie; Spalluto, Giampiero

    2018-04-22

    In the past decades, many efforts were done to develope ligands for the adenosine receptors, with the purpose to individuate agonists and antagonists affine and selective for each subtypes , named A1, A2A, A2B, and A3. These intense studies allowed a deeper and deeper knowledge of the nature and, moreover, of the pathophysiological roles of all the adenosine receptor subtypes. In particular, the involvment of the A2A adenosine receptor subtype in some physiological mechanisms in the brain, that could be related to important diseases such as the Parkinson's disease, encouraged the research in this field. Particular attention was given to the antagonists endowed with high affinity and selectivity since they could have a real employment in the treatment of Parkinson's disease, and some compounds, such as istradefylline, preladenant and tozadenant, are already studied in clinical trials. Actually, the role of A2A antagonists in Parkinson's disease is becoming contradictory due to contrasting results in the last studies, but, at the same time, new possible employments are emerging for this class of antagonists in cancer pathologies as much interesting to legitimate further efforts in the research of A2A ligands. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Secondary deuterium isotope effects for acid-catalyzed hydrolysis of inosine and adenosine

    International Nuclear Information System (INIS)

    Romero, R.; Stein, R.; Bull, H.G.; Cordes, E.H.

    1978-01-01

    Kinetic α deuterium isotope effects have been measured for acid-catalyzed hydrolysis of inosine and adenosine. For inosine hydrolysis, values of k/sub H/k/sub D/ follow: in 1.0 M HCl, 1.21 and 1.20 at 25 and 50 0 C, respectively; in 0.1 M HCl, 1.19 and 1.18 at 25 and 50 0 C, respectively. For adenosine hydrolysis, k/sub H/k/sub D/ is 1.23 in 0.1 M HCl at 25 0 C. The values require that the transition states for hydrolysis of both the monocation and dication of inosine and the dication of adenosine have marked oxocarbonium ion character. Detailed mechanisms which accord with this and other experimental observations include (1) a classical Al mechanism in which the C--N bond is largely cleaved in the transition state; (2) a mechanism involving some form of nucleophilic participation by solvent in which bond cleavage is advanced relative to bond formation in the transition state; or (3) complete C--N bond cleavage with rate-determining diffusion apart of oxocarbonium ion and purine base. 53 references, 1 figure, 2 tables

  4. Effects of adenosine and defibrotide adjunct to a standard crystalloid cardioplegic solution.

    Science.gov (United States)

    Mantovani, V; Mariscalco, G; Borsani, P; Tenconi, S; Bruno, V D; Leva, C; Ferrarese, S; Sala, A

    2005-06-01

    Adenosine has many actions potentially useful as adjunct to a cardioplegia. Defibrotide was recently shown to have protective effects during cardiac arrest. The aim of this study was to compare these 2 substances to delineate their profile of action in the setting of cardioplegic arrest. A Langendorff model for isolated rat hearts was employed: 3 groups of 8 hearts each were used, respectively with plain St. Thomas cardioplegia as control (group C), and the same solution added with adenosine (group A) or defibrotide (group D). The hearts had a baseline perfusion for 30 minutes with Krebs-Henseleit solution at 37 degrees C, cardioplegia administration for 3 minutes, then 30 minutes of ischemia without any perfusion and finally 30 minutes of reperfusion with Krebs-Henseleit solution at 37 degrees C. The time to attain heart arrest was 20% shorter in group A, but this difference did not reach statistical significance (A: 13.6+/-1.5; D: 16.8+/-2.7; C: 17.3+/-2.2 s). The heart rate during reperfusion in group A was almost identical to baseline, while in both group C and D it was significantly lower (A: 101%, D: 93.4%, C: 82.4%, pdefibrotide have protective effects in an isolated model of cardioplegic arrest. Adenosine is significantly more active on heart rate while defibrotide is more active on contractily. Further studies are justified in order to test the combination of these 2 drugs.

  5. Radiochromatographic determination of activity of adenosine deaminase and purine nucleoside phosphorylase in blood cells

    International Nuclear Information System (INIS)

    Pechan, I.; Rendekova, V.; Pechanova, E.; Krizko, J.

    1982-01-01

    Expeditious and sensitive methods are described for determining the activities of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) in human lymphocytes and erythrocytes. ADA and PNP activity is determined on the basis of the reaction of (U- 14 C)adenosine or (8- 14 C)inosine with the lysate of human blood cells. Reaction products are separated using paper chromatography. Following the measurement of the radioactivity of spots of adenosine, inosine and hypoxanthine, a calculation is made of ADA and PNP activity from the results of the said measurements. On a sample of 52 clinically healthy people average ADA and PNP activity in isolated lymphocytes was found to be (51.6+-18.8) and (185.6+-94.7) pcat/10 6 cells and in erythrocytes (9.8+-2.98) and (17.1+-3.19) pcat/mg of proteins, respectively. The advantage of the method is the small amount of sample needed (1 to 2 ml) which allows its application in pediatrics. (Ha)

  6. Pharmacokinetic Properties of Adenosine Amine Congener in Cochlear Perilymph after Systemic Administration

    Directory of Open Access Journals (Sweden)

    Hao Chang

    2017-01-01

    Full Text Available Noise-induced hearing loss (NIHL is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated by administration of drugs acting on adenosine receptors in the inner ear, and a selective A1 adenosine receptor agonist adenosine amine congener (ADAC has emerged as a potentially effective treatment for cochlear injury and resulting hearing loss. This study investigated pharmacokinetic properties of ADAC in rat perilymph after systemic (intravenous administration using a newly developed liquid chromatography-tandem mass spectrometry detection method. The method was developed and validated in accordance with the USA FDA guidelines including accuracy, precision, specificity, and linearity. Perilymph was sampled from the apical turn of the cochlea to prevent contamination with the cerebrospinal fluid. ADAC was detected in cochlear perilymph within two minutes following intravenous administration and remained in perilymph above its minimal effective concentration for at least two hours. The pharmacokinetic pattern of ADAC was significantly altered by exposure to noise, suggesting transient changes in permeability of the blood-labyrinth barrier and/or cochlear blood flow. This study supports ADAC development as a potential clinical otological treatment for acute sensorineural hearing loss caused by exposure to traumatic noise.

  7. Cordycepin Increases Nonrapid Eye Movement Sleep via Adenosine Receptors in Rats

    Directory of Open Access Journals (Sweden)

    Zhenzhen Hu

    2013-01-01

    Full Text Available Cordycepin (3′-deoxyadenosine is a naturally occurring adenosine analogue and one of the bioactive constituents isolated from Cordyceps militaris/Cordyceps sinensis, species of the fungal genus Cordyceps. It has traditionally been a prized Chinese folk medicine for the human well-being. Because of similarity of chemical structure of adenosine, cordycepin has been focused on the diverse effects of the central nervous systems (CNSs, like sleep regulation. Therefore, this study was undertaken to know whether cordycepin increases the natural sleep in rats, and its effect is mediated by adenosine receptors (ARs. Sleep was recorded using electroencephalogram (EEG for 4 hours after oral administration of cordycepin in rats. Sleep architecture and EEG power spectra were analyzed. Cordycepin reduced sleep-wake cycles and increased nonrapid eye movement (NREM sleep. Interestingly, cordycepin increased θ (theta waves power density during NREM sleep. In addition, the protein levels of AR subtypes (A1, A2A, and A2B were increased after the administration of cordycepin, especially in the rat hypothalamus which plays an important role in sleep regulation. Therefore, we suggest that cordycepin increases theta waves power density during NREM sleep via nonspecific AR in rats. In addition, this experiment can provide basic evidence that cordycepin may be helpful for sleep-disturbed subjects.

  8. Progress in Personalizing Chemotherapy for Bladder Cancer

    Directory of Open Access Journals (Sweden)

    James S. Chang

    2012-01-01

    Full Text Available Platinum-based chemotherapy is commonly used for the treatment of locally advanced and metastatic bladder cancer. However, there are currently no methods to predict chemotherapy response in this disease setting. A better understanding of the biology of bladder cancer has led to developments of molecular biomarkers that may help guide clinical decision making. These biomarkers, while promising, have not yet been validated in prospective trials and are not ready for clinical applications. As alkylating agents, platinum drugs kill cancer cells mainly through induction of DNA damage. A microdosing approach is currently being tested to determine if chemoresistance can be identified by measuring platinum-induced DNA damage using highly sensitive accelerator mass spectrometry technology. The hope is that these emerging strategies will help pave the road towards personalized therapy in advanced bladder cancer.

  9. Teratoid Wilms tumour with chemotherapy resistance

    Directory of Open Access Journals (Sweden)

    Renuka Gahine

    2015-01-01

    Full Text Available We present a case of Teratoid Wilms tumour (a rare histologic variant in a 4 year old male who presented with an abdominal lump. Wilms Tumour with paracaval lymphadenopathy and tumour thrombi in right renal vein and inferior vena cava was made radiologically. FNAC report was suggestive of Wilms tumour and patient was subjected to 6 cycles of chemotherapy with not much reduction in size. Post nephrectomy histological diagnosis of Teratoid Wilms tumour was established. Resistance to chemotherapy and radiotherapy is thought to be due to presence of well differentiated histologic appearance. Teratoid Wilms tumour is usually not an aggressive neoplasm and prognosis is comparatively neoplasm and prognosis is comparatively good if the tumour is excised completely thus surgery being the best treatment.

  10. [Effectiveness of scalp cooling in chemotherapy].

    Science.gov (United States)

    Poder, Thomas G; He, Jie; Lemieux, Renald

    2011-10-01

    The main objectives of this literature review are to determine if scalp cooling is efficient and safe, if there are side effects and if the patients' quality of life improves. In terms of effectiveness, scalp cooling seems to get good performance in its aim to prevent hair loss in patients receiving chemotherapy. The weighted average results of all identified studies indicate that this technology allows for 63.5% of patients to have a good preservation of their hair. In studies with a group of control, the weighted rates of good preservation of the hair are 50.6% with scalp cooling and 16.3% without. From the standpoint of safety technology, the main risk is that of scalp metastases. However, no study has successfully demonstrated a statistically significant difference between groups of patients receiving chemotherapy with or without scalp cooling.

  11. Chemotherapy in patients with hepatic failure

    International Nuclear Information System (INIS)

    Roldán, G.; Sosa, A.

    2004-01-01

    The toxicity of chemotherapy in the liver may manifest as hepatocyte dysfunction with chemical hepatitis, veno-occlusive disease or chronic fibrosis. The hepatocyte dysfunction is caused by direct effect of the drug or its metabolites evidencing by increased bilirubin and liver enzymes (Sgot, SGPT). Prolonged effect leads to cholestasis and fatty infiltration. This dysfunction is concomitant enhanced by viral infection, liver metastases and other drugs as antiemetics. The vast majority of the indicated drugs in a cancer patient, cytostatics, antiemetics, analgésios, anticonvulsants, etc, are metabolized in the liver. The evidence of abnormal hepatocyte function in a patient in which involves chemotherapy raises the need for dose modification indicated and / or discontinuation. The aim of this paper is to review existing information on the use of cytostatics in cancer patients with hepatic impairment, classifying drugs according to their potential hepato toxicity and recommended dose modification in patients with hepatic dysfunction

  12. Enzalutamide in metastatic prostate cancer before chemotherapy

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana E

    2014-01-01

    BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have...... the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas...... skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P

  13. Head and neck cancer: metronomic chemotherapy

    International Nuclear Information System (INIS)

    De Felice, Francesca; Musio, Daniela; Tombolini, Vincenzo

    2015-01-01

    In the era of personalized medicine, head and neck squamous cell carcinoma (HNSCC) represents a critical oncologic topic. Conventional chemotherapy regimens consist of drugs administration in cycles near or at the maximum tolerated dose (MDT), followed by a long drug-free period to permit the patient to recover from acute toxicities. Despite this strategy is successful in controlling the cancer process at the beginning, a significant number of HNSCC patients tend to recurred or progress, especially those patients with locally advanced or metastatic disease. The repertoire of drugs directed against tumor cells has greatly increased and metronomic chemotherapy (MC) could be an effective treatment option. It is the purpose of this article to review the concept of MC and describe its potential use in HNSCC. We provide an update of ongoing progress and current challenges related to this issue

  14. Intestinal response to myeloablative chemotherapy in piglets

    DEFF Research Database (Denmark)

    Pontoppidan, Peter Erik Lotko; Shen, René Liang; Petersen, Bodil L

    2014-01-01

    Chemotherapy-induced myeloablation prior to allogeneic hematopoietic stem cell transplantation (HSCT) may be associated with severe toxicity. The current understanding of the pathophysiology of oral and gastrointestinal (GI) toxicity is largely derived from studies in rodents and very little...... is known from humans, especially children. We hypothesized that milk-fed piglets can be used as a clinically relevant model of GI-toxicity related to a standard conditioning chemotherapy (intravenous busulfan, Bu plus cyclophosphamide, Cy) used prior to HSCT. In study 1, dose-response relationships were....../kg) and bone marrow was collected on day 11. Histology of bone marrow samples showed total aplasia after treatment A. Using this treatment in study 2, Bu-Cy pigs showed lowered spleen and intestinal weights and variable clinical signs of dehydration, sepsis, and pneumonia at tissue collection. Oral mucositis...

  15. Chronic Pain and Neuropathy Following Adjuvant Chemotherapy

    DEFF Research Database (Denmark)

    Ventzel, Lise; Madsen, Caspar S; Karlsson, Páll

    2017-01-01

    Objective: To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning. Design: A retrospective cross-sectional study. Setting: A chro...... mechanisms useful for future studies in the tailored treatment of prevention of chemotherapy-induced peripheral neuropathy and pain.......Objective: To determine symptoms and characteristics of chronic sensory neuropathy in patients treated with oxaliplatin and docetaxel, including patterns of somatosensory abnormalities, pain descriptors, and psychological functioning. Design: A retrospective cross-sectional study. Setting......: A chronic pain research center. Subjects: Thirty-eight patients with chronic peripheral pain and/or dysesthesia following chemotherapy. Methods:  Sensory profiles, psychological functioning, and quality of life were assessed using standardized questionnaires. In addition, standardized quantitative sensory...

  16. Using Epigenetic Therapy to Overcome Chemotherapy Resistance.

    Science.gov (United States)

    Strauss, Julius; Figg, William D

    2016-01-01

    It has been known for decades that as cancer progresses, tumors develop genetic alterations, making them highly prone to developing resistance to therapies. Classically, it has been thought that these acquired genetic changes are fixed. This has led to the paradigm of moving from one cancer therapy to the next while avoiding past therapies. However, emerging data on epigenetic changes during tumor progression and use of epigenetic therapies have shown that epigenetic modifications leading to chemotherapy resistance have the potential to be reversible with epigenetic therapy. In fact, promising clinical data exist that treatment with epigenetic agents can diminish chemotherapy resistance in a number of tumor types including chronic myelogenous leukemia, colorectal, ovarian, lung and breast cancer. The potential for epigenetic-modifying drugs to allow for treatment of resistant disease is exciting and clinical trials have just begun to evaluate this area. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  17. Pharmacological prevention of reperfusion injury in acute myocardial infarction. A potential role for adenosine as a therapeutic agent.

    Science.gov (United States)

    Quintana, Miguel; Kahan, Thomas; Hjemdahl, Paul

    2004-01-01

    The concept of reperfusion injury, although first recognized from animal studies, is now recognized as a clinical phenomenon that may result in microvascular damage, no-reflow phenomenon, myocardial stunning, myocardial hibernation and ischemic preconditioning. The final consequence of this event is left ventricular (LV) systolic dysfunction leading to increased morbidity and mortality. The typical clinical case of reperfusion injury occurs in acute myocardial infarction (MI) with ST segment elevation in which an occlusion of a major epicardial coronary artery is followed by recanalization of the artery. This may occur either spontaneously or by means of thrombolysis and/or by primary percutaneous coronary intervention (PCI) with efficient platelet inhibition by aspirin (acetylsalicylic acid), clopidogrel and glycoprotein IIb/IIIa inhibitors. Although the pathophysiology of reperfusion injury is complex, the major role that neutrophils play in this process is well known. Neutrophils generate free radicals, degranulation products, arachidonic acid metabolites and platelet-activating factors that interact with endothelial cells, inducing endothelial injury and neutralization of nitrous oxide vasodilator capacity. Adenosine, through its multi-targeted pharmacological actions, is able to inhibit some of the above-mentioned detrimental effects. The net protective of adenosine in in vivo models of reperfusion injury is the reduction of the infarct size, the improvement of the regional myocardial blood flow and of the regional function of the ischemic area. Additionally, adenosine preserves the post-ischemic coronary flow reserve, coronary blood flow and the post-ischemic regional contractility. In small-scale studies in patients with acute MI, treatment with adenosine has been associated with smaller infarcts, less no-reflow phenomenon and improved LV function. During elective PCI adenosine reduced ST segment shifts, lactate production and ischemic symptoms. During the

  18. Role of adipokinetic hormone and adenosine in the anti-stress response in Drosophila melanogaster.

    Science.gov (United States)

    Zemanová, Milada; Stašková, Tereza; Kodrík, Dalibor

    2016-01-01

    The role of adipokinetic hormone (AKH) and adenosine in the anti-stress response was studied in Drosophila melanogaster larvae and adults carrying a mutation in the Akh gene (Akh(1)), the adenosine receptor gene (AdoR(1)), or in both of these genes (Akh(1) AdoR(1) double mutant). Stress was induced by starvation or by the addition of an oxidative stressor paraquat (PQ) to food. Mortality tests revealed that the Akh(1) mutant was the most resistant to starvation, while the AdoR(1) mutant was the most sensitive. Conversely, the Akh(1) AdoR(1) double mutant was more sensitive to PQ toxicity than either of the single mutants. Administration of PQ significantly increased the Drome-AKH level in w(1118) and AdoR(1) larvae; however, this was not accompanied by a simultaneous increase in Akh gene expression. In contrast, PQ significantly increased the expression of the glutathione S-transferase D1 (GstD1) gene. The presence of both a functional adenosine receptor and AKH seem to be important for the proper control of GstD1 gene expression under oxidative stress, however, the latter appears to play more dominant role. On the other hand, differences in glutathione S-transferase (GST) activity among the strains, and between untreated and PQ-treated groups were minimal. In addition, the glutathione level was significantly lower in all untreated AKH- or AdoR-deficient mutant flies as compared with the untreated control w(1118) flies and further declined following treatment with PQ. All oxidative stress characteristics modified by mutations in Akh gene were restored or even improved by 'rescue' mutation in flies which ectopically express Akh. Thus, the results of the present study demonstrate the important roles of AKH and adenosine in the anti-stress response elicited by PQ in a D. melanogaster model, and provide the first evidence for the involvement of adenosine in the anti-oxidative stress response in insects. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Endocrine consequences of irradiation and cancer chemotherapy

    International Nuclear Information System (INIS)

    Shalet, S.M.; Beardwell, C.

    1981-01-01

    A brief review is presented of endocrine dysfunction as a long-term effect of radiotherapy and cancer chemotherapy, with particular reference to children, and to Hodgkin's disease. The hypothalamus and pituitary, growth hormone and thyroid stimulating hormone, thyroid and parathyroid, and gonads are discussed. Suggestions are made for long-term measures to be taken, such as measuring growth rates, L-thyroxine replacement, sperm storage, etc. (U.K.)

  20. Success of Chemotherapy in Soft Matter

    OpenAIRE

    Trifonova, I.; Kurteva, G.; Stefanov, S. Z.

    2014-01-01

    The success of chemotharapy in soft matter as a survival is found in the paper. Therefore, it is found the analogous tumor stretching force in soft matter; ultrasonography is performed for this tumor; restoration in soft matter with such a tumor is found; Bayes estimate of the probability of chemotherapy success is derived from the transferred chemical energy and from soft matter entropy; survival probability is juxtaposed to this probability of success.

  1. Radio chemotherapy for uterine cervix carcinoma

    International Nuclear Information System (INIS)

    Resbeut, M.; Alzieu, C.; Gonzague-Casabianca, L.; Haie-Meder, C.

    2000-01-01

    Low-stage uterine cervix carcinoma can be treated by either surgery, radiation therapy or combined treatments with high cure rates ranging from 90 to 95 % for stage IB1 tumors. However, the standard treatment, combining external beam plus intracavitary radiation, fails to control the progression of the disease in 35 to 90 % of patients with locally advanced cervical cancer. No substantial improvements have been made in the treatment of these tumors in the past two decades. The addition of concurrent 5-FU in a phase III study failed to improve the results in the overall patient population, but the five-year DFS was significantly better in a subset of patients (tumor > 5 cm and IB/IIA or medial parametrial IIB disease). Concurrent chemo-radiation and adjuvant chemotherapy with epirubicin showed, in a phase III study, a significant longer DFS in patients treated with chemotherapy despite the same long-term local tumor control. After many phase II studies, five phase III studies have recently demonstrated a 40 to 60 % reduction in the relative risk of recurrence with cisplatin containing chemo-radiation. Across these studies, the risk of death was reduced by 30 to 50 %. The benefit was less clear in patients with stages III-IV tumors than in patients with lower stages associated with poor prognostic factors. Hematologic and gastrointestinal toxicity of chemo-radiation was greater than that of radiotherapy alone. However, late side effects were similar in the different treatment groups. These results must be confirmed with a longer follow-up. The importance of concurrent chemotherapy during the brachytherapy procedure should be analyzed. It has yet to be determined which chemotherapy regimen achieves the most favorable therapeutic ratio. (authors)

  2. Intrathecal chemotherapy for refractory disseminated medulloblastoma.

    Science.gov (United States)

    Yoshimura, Junichi; Nishiyama, Kenichi; Mori, Hiroshi; Takahashi, Hideaki; Fujii, Yukihiko

    2008-05-01

    To analyze the effect of intrathecal (IT) chemotherapy for disseminated medulloblastoma. Twenty-one patients received IT chemotherapy using the chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, MCNU) including nine patients for residual leptomeningeal lesions after initial surgery and radiation, and 12 for a recurrence with leptomeningeal dissemination. Of these 21 patients, 12 received a lumbar and/or ventricular bolus injection of the chemotherapeutic agents, one received the ventriculolumbar perfusion of the agents, and eight received both the perfusion and bolus injection. The doses ranged from 6-7 mg/m(2) of ACNU for perfusion and 3-3.5 mg/m(2) of ACNU, MCNU, or MTX for the bolus injection, and the cycles were administered from 3 to 12 times for perfusion and from 5 to 54 times for the bolus injection. The effects of chemotherapy were assessed by both radiological and cytological examinations, and the clinical symptoms were also assessed. Radiological and/or cytological responses were observed in 10 of 21 patients (47.6%), including seven cases demonstrating a complete remission. The 5-year overall survival rate and 5-year survival rate after dissemination were 61.5 and 46.4%, respectively. Five patients who received a lumbar bolus injection of nitrosoureas experienced paraplegia and double incontinence. One patient who received a ventricular injection of nitrosoureas experienced truncal ataxia. IT chemotherapy was found to be effective in some cases with refractory disseminated medulloblastoma and it seems to be an appropriate treatment choice for leptomeningeal recurrence. However, the frequent bolus injections of nitrosoureas should be avoided to prevent the side effects.

  3. Essential drugs for cancer chemotherapy. WHO consultation.

    OpenAIRE

    1994-01-01

    The WHO recommendation on essential drugs for cancer chemotherapy has been updated. General principles on the proper role of cancer chemotherapeutic agents in relation to efficacy and on the classification of tumours with respect to their curative potential are discussed. Curable cancers and those cancers where the cost-benefit ratio clearly favours drug treatment can be managed appropriately based on only 24 drugs. Fourteen of them should ideally be available for the treatment of the ten mos...

  4. COPBLAM: infusion chemotherapy for large cell lymphoma

    International Nuclear Information System (INIS)

    Coleman, M.; Bernhardt, B.; Boyd, D.B.; Gerstein, G.

    1986-01-01

    This chapter describes a new combination chemotherapy program that was initiated at the New York Hospital-Cornell Medical Center for large cell lymphoma (LCL). The program, known as COPBLAM (Cyclophosphamide, Oncovin, Prednisone, Bleomycin, Adriamycin, Matulane) was an intensive multidrug regimen designed to maximize tumor cell kill. Some of the novel concepts and features are described. The treatment was fully successful in 60% of the 48 patients studied that were undergoing radiation therapy

  5. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial.

    Science.gov (United States)

    Mahaffey, K W; Puma, J A; Barbagelata, N A; DiCarli, M F; Leesar, M A; Browne, K F; Eisenberg, P R; Bolli, R; Casas, A C; Molina-Viamonte, V; Orlandi, C; Blevins, R; Gibbons, R J; Califf, R M; Granger, C B

    1999-11-15

    The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size. Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects. The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke). In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89). Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.

  6. Management of chemotherapy induced diarrhea (abstract)

    International Nuclear Information System (INIS)

    Qureshi, A.M.

    1998-01-01

    Diarrhoea is seen with many tumors and following several chemotherapy regimen esp. those containing 5-fluorouracil and high dose folinic acid it causes debility even death, delays cancer treatment, reduces compliance increases cost. It causes dehydration, renal failure volume depletion. Quality of life is worsened and hospitalization may be needed in multifactorial, with secretion; absorption imbalance due to mucosal damage, necrosis or inflammation. Local infection is set up by opportunistic organism and cell necrosis. The large volume of fluid and electrolytes overwhelms colonic absorptive capacity. Agent usually used for treatment is opioids (such as Diphenoxylate / Loperamide]. Bismuth (for inflammatory diarrhea). NSAIDs or alpha 2-agonists. For optimal management, the cause and severity should be assessed and treatment planned. Advice is given about certain dietary restraints and avoidance of some drugs. Fever, infection, dehydration and electrolyte losses are treated, pain relieved. Diphenoxylate / Loperamide (later is more effective; 4 mg, STAT, then 2mg every 4 hours or even 2 hourly) may be used. It is moderately effective in CID. Octreotide is useful in carcinoid. VIPoma, AIDS idiopathic secretary diarrhea, ileostomy, dumping syndrome. It acts directly on epithelial cells to reduce secretin, motilin pancreatic polypeptide. It slows transit time, reduces fluid and electrolyte secretin, increases absorption of electrolytes. It is effective in 5 FU and high dose chemotherapy with a 90% response rates seen after 3 days treatment. High Dose Chemotherapy and total body irradiation - induced diarrhea usually resolves within 72 hours. (author)

  7. Chemotherapy resistance mechanisms in advanced skin cancer

    Directory of Open Access Journals (Sweden)

    Bhuvanesh Sukhlal Kalal

    2017-03-01

    Full Text Available Melanoma is a most dangerous and deadly type of skin cancer, and considered intrinsically resistant to both radiotherapy and chemotherapy. It has become a major public health concern as the incidence of melanoma has been rising steadily over recent decades with a 5-year survival remaining less than 5%. Detection of the disease in early stage may be curable, but late stage metastatic disease that has spread to other organs has an extremely poor prognosis with a median survival of less than 10 months. Since metastatic melanoma is unresponsive to therapy that is currently available, research is now focused on different treatment strategies such as combinations of surgery, chemotherapy and radiotherapy. The molecular basis of resistance to chemotherapy seen in melanoma is multifactorial; defective drug transport system, altered apoptotic pathway, deregulation of apoptosis and/or changes in enzymatic systems that mediate cellular metabolic machinery. Understanding of alterations in molecular processes involved in drug resistance may help in developing new therapeutic approaches to treatment of malignant melanoma.

  8. Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer.

    Science.gov (United States)

    Marin, Jose J G; Sanchez de Medina, Fermin; Castaño, Beatriz; Bujanda, Luis; Romero, Marta R; Martinez-Augustin, Olga; Moral-Avila, Rosario Del; Briz, Oscar

    2012-05-01

    Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in industrialized countries. Chemoprevention is a promising approach, but studies demonstrating their usefulness in large populations are still needed. Among several compounds with chemopreventive ability, cyclooxygenase inhibitors have received particular attention. However, these agents are not without side effects, which must be weighed against their beneficial actions. Early diagnosis is critical in the management of CRC patients, because, in early stages, surgery is curative in >90% of cases. If diagnosis occurs at stages II and III, which is often the case, neoadjuvant chemotherapy and radiotherapy before surgery are, in a few cases, recommended. Because of the high risk of recurrence in advanced cancers, chemotherapy is maintained after tumor resection. Chemotherapy is also indicated when the patient has metastases and in advanced cancer located in the rectum. In the last decade, the use of anticancer drugs in monotherapy or in combined regimens has markedly increased the survival of patients with CRC at stages III and IV. Although the rate of success is higher than in other gastrointestinal tumors, adverse effects and development of chemoresistance are important limitations to pharmacological therapy. Genetic profiling regarding mechanisms of chemoresistance are needed to carry out individualized prediction of the lack of effectiveness of pharmacological regimens. This would minimize side effects and prevent the selection of aggressive, cross-resistant clones, as well as avoiding undesirable delays in the use of the most efficient therapeutic approaches to treat these patients.

  9. Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

    Directory of Open Access Journals (Sweden)

    Hana Starobova

    2017-05-01

    Full Text Available Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

  10. Nail toxicity induced by cancer chemotherapy.

    Science.gov (United States)

    Gilbar, Peter; Hain, Alice; Peereboom, Veta-Marie

    2009-09-01

    To provide a comprehensive literature review of chemotherapy-induced nail toxicity, including clinical presentation, implicated drugs and approaches for prevention and management. A search of MEDLINE and EMBASE (1966-2008) databases was conducted using the terms (and variations of the terms) antineoplastic agents, nails, nail toxicity, onycholysis, and paronychia. Bibliographies from selected articles were reviewed for appropriate references. The retrieved literature was reviewed to include all articles relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of chemotherapy-induced nail toxicity. Nail toxicity is a relatively uncommon adverse effect linked to a number of chemotherapeutic agents. Clinical presentation varies, depending on which nail structure is affected and the severity of the insult. Nail changes may involve all or some nails. Toxicity may be asymptomatic and limited to cosmetic concerns, however, more severe effects, involving pain and discomfort can occur. Taxanes and anthracyclines are the antineoplastic drug groups most commonly implicated. It is suggested that the administration schedule may influence the incidence of nail abnormalities, for example reported cases linked to the weekly administration of paclitaxel.Before instituting chemotherapy, patients should be educated regarding potential nail toxicities and strategies for prevention implemented. Management includes appropriate nail cutting, avoiding potential irritants, topical, or oral antimicrobials, and possibly cessation or dose reduction of the offending agent. Cryotherapy, through the application of frozen gloves or socks, has been beneficial in reducing docetaxel-induced nail toxicity and may be effective for other drugs.

  11. [Buccal manifestations in patients submitted to chemotherapy].

    Science.gov (United States)

    Hespanhol, Fernando Luiz; Tinoco, Eduardo Muniz Barretto; Teixeira, Henrique Guilherme de Castro; Falabella, Márcio Eduardo Vieira; Assis, Neuza Maria de Souza Picorelli

    2010-06-01

    Several changes in the oral cavity due to chemotherapy can be observed and can lead to important systemic complications, increasing the time of the patient in hospital and the costs of the treatment as well as affect the quality of life of the patients. The aim of this study was to assess the oral manifestation in patients treated with chemotherapy according to sex, age and tumor type. Data was collected in an oncology hospital in Juiz de Fora, Minas Gerais State, from patients' records that were submitted to oncologic treatment. It was possible to verify that mucositis, associated or not to other type of lesions, was the most common lesion in both sex of all ages (15.5%). Xerostomia and other lesions, such as Candida infection and aphthous lesions, were also present. It is possible to improve the quality of life of the patient during and after anti-neoplastic therapies through a protocol of odontological assistance that includes changes of the oral environment previous to chemotherapy such as profilaxis, caries removal, treatment of periodontal and periapical lesions, oral hygiene instructions, diet orientation and laser therapy. It is very important the insertion of the dentist in the oncologic medical team for the early diagnosis of the oral manifestation and follow-up during treatment time.

  12. Stress test with adenosine in cerebral perfusion imaging for the diagnosis of ischemic cerebrovascular disease

    International Nuclear Information System (INIS)

    Yuan Gengbiao; Kuang Anren; Chen Xuehong; Li Xihuan; Feng Jianzhong

    2004-01-01

    Objective: This study purpose is to evaluate cerebrovascular response and reserve capacity (CVR, CVRC) by stress test with adenosine in cerebral perfusion imaging for the diagnosis of ischemic cerebrovascular diseases. Methods There were 25 patients suffered from transient ischemia attack and 16 patients suffered from occlusive cerebral artery in this study. The rest cerebral perfusion imaging was obtained 30 minutes post-injection of 99mTC-ethylene cysteinate dimmer. After 2-5 days, adenosine stress tests were performed. Adenosine (0.14 mg/kg min) was administered intravenously 3 minutes pre-injection of 99mTC-ECD.Under same condition, the rest and stress tests of cerebral perfusion imaging were performed. By visual and semiquantitative analysis, the results of the rest/stress imaging were divided into the following four patterns: A: The stress imaging showed an expand areas of hypoperfusion, asymmetry index (AI) was decreased; B: Rest imaging was normal but new hypoperfused areas appeared with AI index declining in stress test; C: The hypoperfused areas were decreased or disappeared in size with AI index increasing in stress test; D: No changes showed in cerebral perfusion imaging patterns and Al index between rest and stress tests. AI index was ratio of radio account of interest regions than average radio account of cerebella. Results It was found that A, B, C and D type were 24%,12%,56% and 8% respectively in the group of transient ischemia attack patients, and 31%,44%, 19% and 6% respectively in the group of occlusive cerebrovascular patients. In rest test, of 41 patients of cerebrovascular disease, there were 28 cases decreased of radio uptake, moreover in stress test, there were 38 case decreased of radio uptake, positive rate were 68.29% and 92.68% respectively. Compared to X±SD of AI index of rest/stress test, it is found to increasing and being significant statistics (p<0.01, Spass 8.0 statistics software). Conclusion: Adenosinal-induced vasodilatation

  13. Utility of Exercise Testing and Adenosine Response for Risk Assessment in Children with Wolff-Parkinson-White Syndrome.

    Science.gov (United States)

    Ergul, Yakup; Ozturk, Erkut; Ozyilmaz, Isa; Unsal, Serkan; Carus, Hayat; Tola, Hasan Tahsin; Tanidir, Ibrahim Cansaran; Guzeltas, Alper

    2015-01-01

    We aimed to determine the correlation between noninvasive testing (exercise stress testing [EST] and adenosine responsiveness of accessory pathway [AP] ) and invasive electrophysiology study (EPS) for assessment antegrade conduction of the AP in Wolff-Parkinson-White syndrome. This prospective, observational study enrolled 40 children (58% male children, median age of 13 years, and median weight of 47.5 kg) with Wolff-Parkinson-White syndrome. Conduction through the AP to a cycle length of ≤250 ms was considered rapid or high-risk; otherwise, patients were nonrapid or low-risk. The sudden disappearance of the delta-wave was seen in 10 cases (25%) during EST. Accessory pathway was found to be high-risk in 13 cases (13/40, 32.5%) while the accessory path was identified as low-risk in 27 cases; however, six patients (15%) had blocked AP conduction with adenosine during EPS. Low-risk classification by EST alone to identify patients with nonrapid conduction in baseline EPS had a specificity of 93% and a positive predictive value of 90% (accuracy 54%). Blocked AP conduction with adenosine as a marker of nonrapid baseline AP conduction had a specificity of 93% and a positive predictive value of 84%. Finally, AP was adenosine nonresponsive in the majority of patients (28/30, 93%) with persistent delta-waves, 40% of those who had a sudden disappearance of delta-waves had an adenosine-responsive AP (P value: .028). Abrupt loss of preexcitation during EST and blocked AP conduction with adenosine had high specificity and positive predictive value for nonrapid and low-risk antegrade conduction during baseline invasive EPS. Successful risk stratification of pediatric patients with Wolff-Parkinson-White is possible through the use of EST and the adenosine responsiveness of AP. © 2015 Wiley Periodicals, Inc.

  14. Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia

    Directory of Open Access Journals (Sweden)

    Selena Marini

    2017-08-01

    Full Text Available Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE, accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

  15. Pooled comparison of regadenoson versus adenosine for measuring fractional flow reserve and coronary flow in the catheterization laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Stolker, Joshua M., E-mail: jstolker@yahoo.com [Mercy Heart and Vascular, 901 Patients First Drive, Washington, MO 63090 (United States); Saint Louis University, 3635 Vista Ave, St. Louis, MO 63110 (United States); Lim, Michael J., E-mail: limmj@slu.edu [Saint Louis University, 3635 Vista Ave, St. Louis, MO 63110 (United States); Shavelle, David M., E-mail: david.shavelle@med.usc.edu [University of Southern California, 1510 San Pablo St, Suite 322, Los Angeles, CA 90033 (United States); Morris, D. Lynn, E-mail: morrisdl@einstein.edu [Albert Einstein Medical Center, 5501 Old York Rd, Philadelphia, PA 19141 (United States); Angiolillo, Dominick J., E-mail: dominick.angiolillo@jax.ufl.edu [University of Florida Health-Jacksonville, 655 West 8th St, Jacksonville, FL 32209 (United States); Guzman, Luis A., E-mail: luis.guzman@jax.ufl.edu [University of Florida Health-Jacksonville, 655 West 8th St, Jacksonville, FL 32209 (United States); Kennedy, Kevin F., E-mail: kfkennedy@saint-lukes.org [Saint Luke' s Mid America Heart Institute, 4401 Wornall Road, Kansas City, MO 64111 (United States); Weber, Elizabeth, E-mail: eweber1@slu.edu [Saint Louis University, 3635 Vista Ave, St. Louis, MO 63110 (United States); Zareh, Meena, E-mail: meena.zareh@med.usc.edu [University of Southern California, 1510 San Pablo St, Suite 322, Los Angeles, CA 90033 (United States); Neumayr, Robert H., E-mail: robneumayr@gmail.com [Mercy Heart and Vascular, 901 Patients First Drive, Washington, MO 63090 (United States); Saint Louis University, 3635 Vista Ave, St. Louis, MO 63110 (United States); Zenni, Martin M., E-mail: martin.zenni@jax.ufl.edu [University of Florida Health-Jacksonville, 655 West 8th St, Jacksonville, FL 32209 (United States)

    2015-07-15

    Background: Adenosine is the gold standard for augmenting coronary flow during fractional flow reserve (FFR) testing of intermediate coronary stenoses. However, intravenous infusion is time-consuming and intracoronary injection is subject to variability. Regadenoson is a newer adenosine alternative administered as a single intravenous bolus during nuclear stress testing, but its efficacy and safety during FFR testing have been evaluated only in small, single-center studies. Methods: We pooled data from 5 academic hospitals, in which patients undergoing clinically-indicated FFR prospectively underwent comparison of intravenous adenosine infusion (140–175 mcg/kg/min) versus regadenoson bolus (400 mcg). Hemodynamics and symptoms with adenosine were recorded until maximal hyperemia occurred, and after returning to baseline hemodynamics, regadenoson was administered and monitoring was repeated. In a subset of patients with coronary flow data, average peak velocity (APV) at the distal flow sensor was recorded. Results: Of 149 patients enrolled, mean age was 59 ± 9 years, 76% were male, and 54% underwent testing of the left anterior descending artery. Mean adenosine-FFR and regadenoson-FFR were identical (0.82 ± 0.10) with excellent correlation of individual values (r = 0.96, p < 0.001) and no difference in patient-reported symptoms. Four patients (2.6%) had discrepancies between the 2 drugs for the clinical decision-making cutoff of FFR ≤ 0.80. Coronary flow responses to adenosine and regadenoson were similar (APV at maximal hyperemia 36 cm/s for both, p = 0.81). Conclusions: Regadenoson single-bolus administration has comparable FFR, symptoms, and coronary flow augmentation when compared with standard intravenous adenosine infusion. With its greater ease of administration, regadenoson may be a more “user-friendly” option for invasive ischemic testing.

  16. Adenosine derived from Staphylococcus aureus-engulfed macrophages functions as a potent stimulant for the induction of inflammatory cytokines in mast cells

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Kim, Chan-Hee; Ryu, Kyoung-Hwa

    2011-01-01

    In this study, we attempted to isolate novel mast cell-stimulating molecules from Staphylococcus aureus. Water-soluble extract of S. aureus cell lysate strongly induced human interleukin- 8 in human mast cell line-1 and mouse interleukin-6 in mouse bone marrow-derived mast cells. The active...... adenosine receptor blocker, verified that purified adenosine can induce interleukin-8 production via adenosine receptors on mast cells. Moreover, adenosine was purified from S. aureusengulfed RAW264.7 cells, a murine macrophage cell line, used to induce phagocytosis of S. aureus. These results show a novel...

  17. Is neoadjuvant chemotherapy prior to radio-chemotherapy beneficial in T4 anal carcinoma?

    Science.gov (United States)

    Moureau-Zabotto, L; Viret, F; Giovaninni, M; Lelong, B; Bories, E; Delpero, J R; Pesenti, C; Caillol, F; de Chaisemartin, C; Minsat, M; Monges, G; Sarran, A; Resbeut, M

    2011-07-01

    This study retrospectively describes the outcome of a series of 38 patients (pts) with T4 anal carcinoma exclusively treated by radio and chemotherapy. From 1992 to 2007, 38 pts with UST4-N0-2-M0 anal carcinoma were treated with exclusive radiotherapy and chemotherapy. All patients received external beam radiotherapy (EBRT) (median dose 45 Gy) with a concomitant chemotherapy (5-fluorouracil-cisplatin). Eleven patients received neo-adjuvant chemotherapy (5-fluorouracil-cisplatin). After 2-8 weeks, a 15-20 Gy boost was delivered either with EBRT (20 pts) or interstitial (192)Ir brachytherapy (18 pts). Mean follow-up was 66 months. After chemoradiation therapy (CRT), 13 pts (34%) had a complete response, 23 pts (60%) a response >50% (2 pts were not evaluated). The 5-year-disease-free survival was 79.2 ± 6.5%, and the 5-year overall survival was 83.9 ± 6%. Eight patients developed tumor progression (mean delay 8.8 months), six of them requiring a salvage surgery with definitive colostomy for local relapse. Late severe complication requiring colostomy was observed in 2 pts. The 5-year-colostomy-free survival was 78 ± 6.9%. Patients who received primary chemotherapy had a statistically significant better 5-year colostomy-free survival (100% vs. 38 ± 16.4%, P = 0.0006). T4 anal carcinoma can be treated with a curative intent using a sphincter-sparing approach of CRT, and neo-adjuvant chemotherapy should be considered prior to radiotherapy. Copyright © 2011 Wiley-Liss, Inc.

  18. Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

    Science.gov (United States)

    Peyre, Matthieu; Cartalat-Carel, Stéphanie; Meyronet, David; Ricard, Damien; Jouvet, Anne; Pallud, Johan; Mokhtari, Karima; Guyotat, Jacques; Jouanneau, Emmanuel; Sunyach, Marie-Pierre; Frappaz, Didier; Honnorat, Jérôme; Ducray, François

    2010-01-01

    Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8–7.7) after PCV onset and 2.7 years (range, 0–7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonald's criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated. PMID:20488959

  19. Olanzapine is effective for refractory chemotherapy-induced nausea and vomiting irrespective of chemotherapy emetogenicity.

    Science.gov (United States)

    Vig, Sierra; Seibert, Laurel; Green, Myke R

    2014-01-01

    The role of olanzapine added to a dopamine antagonist and benzodiazepine for the treatment of refractory chemotherapy-induced nausea and vomiting (CINV) is incompletely characterized in all levels of chemotherapy emetogenicity. This retrospective study evaluated the efficacy of the addition of olanzapine in adults experiencing refractory CINV stratified by chemotherapy emetogenicity. Thirty-three adults who experienced CINV refractory to guideline-recommended prophylaxis and breakthrough antiemetics (dopamine antagonists and benzodiazepines) and received at least one dose of olanzapine 5-10 mg per os were evaluated. Failure was defined as >5 emesis events in 24 h or more than 10 cumulative doses of rescue antiemetics following first olanzapine dose per treatment cycle. Post hoc analyses investigated variables impacting olanzapine efficacy. The addition of olanzapine demonstrated an overall success rate of 70 %. This success rate did not differ between chemotherapy regimens of high versus low-to-moderate emetogenicity (p = 0.79), prophylaxis with serotonin antagonist plus corticosteroid and aprepitant versus serotonin antagonist alone (p = 0.77), or age over 50 versus ≤50 years (p > 0.99). A trend toward greater benefit was seen in women (p = 0.08). The addition of olanzapine to a dopamine antagonist and benzodiazepine demonstrated high efficacy rates for refractory CINV irrespective of chemotherapy emetogenicity. The high success rates among all groups suggests that incomplete resolution of CINV with prophylactic serotonin antagonists and breakthrough dopamine antagonists plus benzodiazepine may benefit from the addition of olanzapine regardless of gender, degree of chemotherapy emetogenicity, number of prophylactic antiemetics, or age. The trend toward greater control of emesis in women merits further investigation.

  20. Granulocyte colony stimulating factor priming chemotherapy is more effective than standard chemotherapy as salvage therapy in relapsed acute myeloid leukemia.

    Science.gov (United States)

    Shen, Ying; He, Aili; Wang, Fangxia; Bai, Ju; Wang, Jianli; Zhao, Wanhong; Zhang, Wanggang; Cao, Xingmei; Chen, Yinxia; Liu, Jie; Ma, Xiaorong; Chen, Hongli; Feng, Yuandong; Yang, Yun

    2017-12-29

    To improve the complete remission (CR) rate of newly diagnosed acute myeloid leukemia (AML) patients and alleviate the severe side effects of double induction chemotherapy, we combined a standard regimen with granulocyte colony-stimulating factor (G-CSF) priming chemotherapy to compose a new double induction regimen for AML patients who failed to achieve CR after the first course. Ninety-seven patients with AML who did not achieve CR after the first course of standard chemotherapy were enrolled. Among them, 45 patients received G-CSF priming combined with low-dose chemotherapy during days 20-22 of the first course of chemotherapy, serving as priming group, 52 patients were administered standard chemotherapy again, serving as control group. Between the two groups there were no differences in the French-American-British (FAB) classification, risk status, the first course of chemotherapy, blood cell count or blasts percentage of bone marrow before the second course. But the CR rate was significantly higher and the adverse effect was much lower in the priming group than the control group. Cox multivariate regression analysis showed that WBC level before the second course and the selection of the second chemotherapy regimen were two independent factors for long survival of patients. These results elucidate that standard chemotherapy followed by G-CSF priming new double induction chemotherapy is an effective method for AML patients to improve CR rate and reduce adverse effects. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  1. Adjuvant chemotherapy for rectal cancer: Is it needed?

    Science.gov (United States)

    Milinis, Kristijonas; Thornton, Michael; Montazeri, Amir; Rooney, Paul S

    2015-01-01

    Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies. PMID:26677436

  2. The interplay of immunotherapy and chemotherapy: harnessing potential synergies.

    Science.gov (United States)

    Emens, Leisha A; Middleton, Gary

    2015-05-01

    Although cancer chemotherapy has historically been considered immune suppressive, it is now accepted that certain chemotherapies can augment tumor immunity. The recent success of immune checkpoint inhibitors has renewed interest in immunotherapies, and in combining them with chemotherapy to achieve additive or synergistic clinical activity. Two major ways that chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect and by disrupting strategies that tumors use to evade immune recognition. This second strategy, in particular, is dependent on the drug, its dose, and the schedule of chemotherapy administration in relation to antigen exposure or release. In this Cancer Immunology at the Crossroads article, we focus on cancer vaccines and immune checkpoint blockade as a forum for reviewing preclinical and clinical data demonstrating the interplay between immunotherapy and chemotherapy. ©2015 American Association for Cancer Research.

  3. Ovarian carcinoma: Role of radiation therapy versus chemotherapy

    International Nuclear Information System (INIS)

    Shehata, W.M.; Meyer, R.L.; Cormier, W.J.; Jazy, F.K.

    1986-01-01

    The authors evaluated 83 patients with ovarian cancer who were irradiated or treated by a combination of cytoxan, adriamycin, and cisplatin. According to FIGO stage, eight patients had stage I disease, 12 had stage II disease, 61 had stage II disease and two has stage IV disease. Fifty patients had bulky disease and 33 had minimal disease of 2 cm or less. Sixty patients were irradiated to an open abdominopelvic field (30 Gy delivered over 4 weeks), with or without a pelvic boost. Fifty-five patients received combination chemotherapy and 30 received a single agent as initial therapy. The patients were divided into three groups. The 26 patients in group I received primary radiation therapy with or with out adjuvant single-agent chemotherapy, then combination chemotherapy to salvage. The 34 patients in group II were irradiated after chemotherapy, mainly combination chemotherapy, failed. The 23 patients in group III received, mainly combination chemotherapy with second-line drugs for salvage

  4. Poly(adenosine 5'-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness.

    Science.gov (United States)

    Liaudet, Lucas

    2002-03-01

    Poly(adenosine 5'-diphosphate) ribose polymerase is a nuclear enzyme activated in response to genotoxic stress induced by a variety of DNA damaging agents. Several oxygen and nitrogen-centered free radicals, notably peroxynitrite, are strong inducers of DNA damage and poly(adenosine 5'-diphosphate) ribose polymerase activation in vitro and in vivo. Activation of this nuclear enzyme depletes the intracellular stores of its substrate nicotinamide adenine dinucleotide, slowing the rate of glycolysis, mitochondrial electron transport and adenosine triphosphate formation. This process triggers a severe energetic crisis within the cell, leading to acute cell dysfunction and cell necrosis. Poly(adenosine 5'-diphosphate) ribose polymerase also plays an important role in the regulation of inflammatory cascades, through a functional association with various transcription factors and transcription co-activators. Recent works identified this enzyme as a critical mediator of cellular metabolic dysfunction, inflammatory injury, and organ damage in conditions associated with overwhelming oxidative stress, including systemic inflammation, circulatory shock, and ischemia-reperfusion. Accordingly, pharmacological inhibitors of poly(adenosine 5'-diphosphate) ribose polymerase protect against cell death and tissue injury in such conditions, and may therefore represent novel therapeutic tools to limit multiple organ damage and dysfunction in critically ill patients.

  5. Comparison of effects of ATP-MgCl2 and adenosine-MgCl2 on renal function following ischemia

    International Nuclear Information System (INIS)

    Sumpio, B.E.; Hull, M.J.; Baue, A.E.; Chaudry, I.H.

    1987-01-01

    ATO-MgCl 2 administration had been shown to accelerate the recovery of renal function following warm ischemia. However, since the major breakdown product of ATP is adenosine, the relative contribution of ATP vs. adenosine in improving renal function following ischemia remains to be determined. To study this, kidneys were subjected to 45 min of normothermic ischemia and then perfused at 100 mmHg with oxygenated Krebs-HCO 3 buffer containing albumin, [ 3 H]inulin, substrates, and either 0.3 mM ATP-MgCl 2 or adenosine-MgCl 2 for 110 min. Perfusate and timed urine samples were collected and analyzed for radioactivity and [Na + ]. The functional parameters indicated that although adenosine-MgCl 2 treatment provided a transient improvement, it failed to provided a sustained improvement in renal function or attain control valued compared with ATP-MgCl 2 treatment. Thus, the salutary effects of ATP-MgCl 2 following warm ischemia in the kidney are not mediated by adenosine

  6. Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients

    International Nuclear Information System (INIS)

    Diamond, I.; Wrubel, B.; Estrin, W.; Gordon, A.

    1987-01-01

    Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine receptors, and their activation causes increases in cAMP levels. To test the hypothesis that basal and adenosine receptor-stimulated cAMP levels in lymphocytes might be abnormal in alcoholism, the authors studied lymphocytes from 10 alcoholic subjects, 10 age- and sex-matched normal individuals, and 10 patients with nonalcoholic liver disease. Basal and adenosine receptor-stimulated cAMP levels were reduced 75% in lymphocytes from alcoholic subjects. Also, there was a 76% reduction in ethanol stimulation of cAMP accumulation in lymphocytes from alcoholics. Similar results were demonstrable in isolated T cells. Unlike other laboratory tests examined, these measurements appeared to distinguish alcoholics from normal subjects and from patients with nonalcoholic liver disease. Reduced basal and adenosine receptor-stimulated levels of cAMP in lymphocytes from alcoholics may reflect a change in cell membranes due either to chronic alcohol abuse or to a genetic predisposition unique to alcoholic subjects

  7. Extracellular adenosine production by ecto-5′-nucleotidase (CD73) enhances radiation-induced lung fibrosis

    Science.gov (United States)

    Wirsdörfer, Florian; de Leve, Simone; Cappuccini, Federica; Eldh, Therese; Meyer, Alina V.; Gau, Eva; Thompson, Linda F.; Chen, Ning-Yuan; Karmouty-Quintana, Harry; Fischer, Ute; Kasper, Michael; Klein, Diana; Ritchey, Jerry W.; Blackburn, Michael R.; Westendorf, Astrid M.; Stuschke, Martin; Jendrossek, Verena

    2016-01-01

    Radiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5'-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks post-irradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately three-fold. Histological evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P<0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase (PEG-ADA) or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacological strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies. PMID:26921334

  8. Cold induced changes of adenosine levels in common eelpout (Zoarces viviparus): a role in modulating cytochrome c oxidase expression.

    Science.gov (United States)

    Eckerle, L G; Lucassen, M; Hirse, T; Pörtner, H O

    2008-04-01

    Exposure of ectothermic organisms to variations in temperatures causes a transient mismatch between energy supply and demand, which needs to be compensated for during acclimation. Adenosine accumulation from ATP breakdown indicates such an imbalance and its reversal reflects a restoration of energy status. We monitored adenosine levels in blood serum and liver of common eelpout (Zoarces viviparus) during cold exposure in vivo. Furthermore, we tested its effect on the pattern of thermal acclimation in hepatocytes isolated from cold- (4 degrees C) versus warm- (11 degrees C) exposed fish. Adenosine levels increased during cold exposure in vivo and reached a transient maximum after 24 h in serum, but remained permanently elevated in liver. Whole animal cold acclimation induced a rise of liver citrate synthase activity by 44+/-15%, but left cytochrome c oxidase activity (COX) and RNA expression of the respective genes unchanged. Cold incubation of hepatocytes from warm-acclimated fish failed to cause an increase of mitochondrial enzyme activities despite increased COX4 mRNA levels. Conversely, warm acclimation of hepatocytes from cold-acclimated fish reduced both enzyme activities and COX2 and COX4 mRNA levels by 26-37%. Adenosine treatment of both warm- and cold-acclimated hepatocytes suppressed COX activities but activated COX mRNA expression. These effects were not receptor mediated. The present findings indicate that adenosine has the potential to regulate mitochondrial functioning in vivo, albeit the pathways resulting in the contrasting effects on expression and activity need to be identified.

  9. Thallium-201 myocardial perfusion imaging during adenosine-induced coronary vasodilation in patients with ischemic heart disease

    International Nuclear Information System (INIS)

    Takeishi, Yasuchika; Chiba, Junya; Abe, Shinya

    1992-01-01

    Thallium-201 ( 201 Tl) myocardial perfusion imaging during adenosine infusion was performed in consecutive 55 patients with suspected coronary artery disease. Adenosine was infused intravenously at a rate of 0.14 mg/kg/min for 6 minutes and a dose of 111 MBq of 201 Tl was administered in a separate vein at the end of third minutes of infusion. Myocardial SPECT imaging was begun 5 minutes and 3 hours after the end of adenosine infusion. For evaluating the presence of perfusion defects, 2 short axis images at the basal and spical levels and a vertical long axis image at the mid left ventricle were used. The regions with decreased 201 Tl uptake were assessed semi-quantitatively. Adenosine infusion caused a slight reduction in systolic blood pressure and an increase in heart rate. The rate pressure products increased slightly (9314±2377 vs. 10360±2148, p 201 Tl myocardial imaging during adenosine infusion was considered to be safe and useful for evaluating the patients with ischemic heart disease. (author)

  10. Practical aspects of the use of intrathecal chemotherapy

    OpenAIRE

    Olmos-Jiménez, Raquel; Espuny-Miró, Alberto; Cárceles-Rodríguez, Carlos; Díaz-Carrasco, María Sacramento

    2017-01-01

    Abstract Introduction: Intrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. Objective: To conduct a literature review about practical aspects of the use of intrathecal chemotherapy. Materials: Search in PubMed/ Medline using the terms “chemotherapy AND intrat...

  11. Experimental study on combination of chemotherapy and radiotherapy

    International Nuclear Information System (INIS)

    Tanaka, Juichi

    1986-01-01

    Recently, by applying multidrug therapy using cisplatin and bleomycin to the treatment of head and neck cancer, the response rate of chemotherapy has been markedly increased and thus, chemotherapy has taken an important part in the treatment of head and neck cancer. In this paper a clinical application of chemotherapy in combination with radiotherapy was evaluated from the point of the cure rate and also preservation of the structures and the functions of the head and neck region. In order to test the advantage or usefulness of initial chemotherapy followed by radiotherapy (= pre-radiation chemotherapy), the experimental study on combination of chemotherapy and radiotherapy was designed by using ICR mice and Ehrlich solid carcinoma. Cisplatin and peplomycin, a newly developed derivative of bleomycin, were used as chemotherapeutic agents. Tumor growth delay rate was chosen as a parameter to indicate the effectiveness. Results obtained are as follows. 1. Combination chemotherapy of cisplatin and peplomycin was more effective than each single agent on Ehrlich solid carcinoma. Synergistic effect was obtained by higher dose. So, the combination of cisplatin and peplomycin was proved to be eligible for pre-radiation chemotherapy. 2. Synergistic effect of chemotherapy and radiotherapy was observed when chemotherapy was used prior to radiotherapy on Ehrlich solid carcinoma. 3. Even their additional effect was not recognized when radiotherapy preceded to chemotherapy on Ehrlich solid carcinoma. 4. No severe toxic effect was seen in the mice. The experimental results made it clear that pre-radiation chemotherapy is beneficial to the treatment of head and neck cancer. (author)

  12. Induction Chemotherapy for p16 Positive Oropharyngeal Squamous Cell Carcinoma

    OpenAIRE

    Saito, Yuki; Ando, Mizuo; Omura, Go; Yasuhara, Kazuo; Yoshida, Masafumi; Takahashi, Wataru; Yamasoba, Tatsuya

    2016-01-01

    Objectives/Hypothesis We aimed to determine the effectiveness of induction chemotherapy for treating p16?positive oropharyngeal cancer in our department. Study Design This was a retrospective case series to assess treatment effectiveness. Methods We administered induction chemotherapy to patients with stage III to IV oropharyngeal p16?positive squamous cell carcinoma between 2008 and 2013. Induction chemotherapy was administered using combinations of docetaxel, cisplatin, and 5?fluorouracil. ...

  13. Management of hepatitis B reactivation in patients receiving cancer chemotherapy

    OpenAIRE

    Huang, Yi-Wen; Chung, Raymond T.

    2012-01-01

    Hepatitis B virus (HBV) reactivation is well documented in previously resolved or inactive HBV carriers who receive cancer chemotherapy. The consequences of HBV reactivation range from self-limited conditions to fulminant hepatic failure and death. HBV reactivation also leads to premature termination of chemotherapy or delay in treatment schedules. This review summarizes current knowledge of management of HBV reactivation in patients receiving cancer chemotherapy. HBV surface antigen (HBsAg) ...

  14. Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice.

    Science.gov (United States)

    Adén, Ulrika; Halldner, Linda; Lagercrantz, Hugo; Dalmau, Ishar; Ledent, Catherine; Fredholm, Bertil B

    2003-03-01

    Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant. Adenosine is believed to protect against HI brain damage. However, the roles of the different adenosine receptors are unclear, particularly in young animals. We examined the role of adenosine A2A receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI. HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated with the use of histopathological scoring and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured during HI. Reduction in cortical cerebral blood flow during HI and rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild-type mice. The A2AR(-/-) mice subjected to HI displayed increased forward locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+) mice subjected to HI, whereas beam-walking performance was similarly defective in both groups. These results suggest that, in contrast to the situation in adult animals, A2AR play an important protective role in neonatal HI brain injury.

  15. Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Kazuhiro; Yoshida, Katsuya [Chiba Univ. (Japan). School of Medicine; Tadokoro, Hiroyuki [and others

    2000-12-01

    The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg{center_dot}kg{sup -1}{center_dot}min{sup -1}) in 8 WHHL rabbits (13.8{+-}0.5 months) with {sup 13}N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml{center_dot}min{sup -1}{center_dot}g{sup -1}) did not differ significantly between control and WHHL groups both at baseline (3.67{+-}0.72 vs 4.26{+-}1.12 ml{center_dot}min{sup -1}{center_dot}g{sup -1}, p=NS) and with adenosine (7.92{+-}2.00 vs 9.27{+-}2.91 ml{center_dot}min{sup -1}{center_dot}g{sup -1}, p=NS), nor did coronary flow reserve (2.16{+-}0.37 vs 2.18{+-}0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model. (author)

  16. Adenosine-induced coronary flow reserve in Watanabe heritable hyperlipidemic rabbits

    International Nuclear Information System (INIS)

    Shimada, Kazuhiro; Yoshida, Katsuya; Tadokoro, Hiroyuki

    2000-01-01

    The Watanabe heritable hyperlipidemic (WHHL) rabbit develops coronary atherosclerosis and hypercholesterolemia because of a genetic deficiency of low-density lipoprotein receptors and is therefore a good animal model for studying the relationships of coronary atherosclerosis, hypercholesterolemia and coronary flow reserve. The aim of the present study was to assess myocardial perfusion at baseline and during adenosine infusion (0.2 mg·kg -1 ·min -1 ) in 8 WHHL rabbits (13.8±0.5 months) with 13 N-ammonia, small-animal positron emission tomography (PET) and colored microspheres. Results were compared with those from 6 age-matched Japanese white rabbits. Plaque distribution was also examined in the extramural coronary arteries. All 8 WHHL rabbits had coronary plaques, with 6 showing multiple plaques. Mean global myocardial blood flow (ml·min -1 ·g -1 ) did not differ significantly between control and WHHL groups both at baseline (3.67±0.72 vs 4.26±1.12 ml·min -1 ·g -1 , p=NS) and with adenosine (7.92±2.00 vs 9.27±2.91 ml·min -1 ·g -1 , p=NS), nor did coronary flow reserve (2.16±0.37 vs 2.18±0.41, p=NS). None showed evidence of regional perfusion abnormalities by visual and semiquantitative analyses of PET images. It was concluded that WHHL rabbits preserve adenosine-induced coronary flow reserve despite coronary atherosclerosis and hypercholesterolemia, suggesting that a compensatory mechanism develops in this animal model. (author)

  17. Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function.

    Science.gov (United States)

    Bjursell, Magnus K; Blom, Henk J; Cayuela, Jordi Asin; Engvall, Martin L; Lesko, Nicole; Balasubramaniam, Shanti; Brandberg, Göran; Halldin, Maria; Falkenberg, Maria; Jakobs, Cornelis; Smith, Desiree; Struys, Eduard; von Döbeln, Ulrika; Gustafsson, Claes M; Lundeberg, Joakim; Wedell, Anna

    2011-10-07

    Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. Human Adenosine A2A Receptor: Molecular Mechanism of Ligand Binding and Activation

    Directory of Open Access Journals (Sweden)

    Byron Carpenter

    2017-12-01

    Full Text Available Adenosine receptors (ARs comprise the P1 class of purinergic receptors and belong to the largest family of integral membrane proteins in the human genome, the G protein-coupled receptors (GPCRs. ARs are classified into four subtypes, A1, A2A, A2B, and A3, which are all activated by extracellular adenosine, and play central roles in a broad range of physiological processes, including sleep regulation, angiogenesis and modulation of the immune system. ARs are potential therapeutic targets in a variety of pathophysiological conditions, including sleep disorders, cancer, and dementia, which has made them important targets for structural biology. Over a decade of research and innovation has culminated with the publication of more than 30 crystal structures of the human adenosine A2A receptor (A2AR, making it one of the best structurally characterized GPCRs at the atomic level. In this review we analyze the structural data reported for A2AR that described for the first time the binding of mode of antagonists, including newly developed drug candidates, synthetic and endogenous agonists, sodium ions and an engineered G protein. These structures have revealed the key conformational changes induced upon agonist and G protein binding that are central to signal transduction by A2AR, and have highlighted both similarities and differences in the activation mechanism of this receptor compared to other class A GPCRs. Finally, comparison of A2AR with the recently solved structures of A1R has provided the first structural insight into the molecular determinants of ligand binding specificity in different AR subtypes.

  19. Cerebral A{sub 1} adenosine receptors (A{sub 1}AR) in liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Boy, Christian [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); University Hospital Essen, Department of Nuclear Medicine, Essen (Germany); Meyer, Philipp T. [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Kircheis, Gerald; Haussinger, Dieter [University of Duesseldorf, Clinic for Gastroenterology, Hepatology and Infectiology, Duesseldorf (Germany); Holschbach, Marcus H.; Coenen, Heinz H. [Research Centre Juelich, Institute of Nuclear Chemistry, Juelich (Germany); Herzog, Hans; Elmenhorst, David [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); Kaiser, Hans J. [University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Zilles, Karl [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); C. and O. Vogt Institute of Brain Research, Duesseldorf (Germany); Bauer, Andreas [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); University of Duesseldorf, Department of Neurology, Duesseldorf (Germany)

    2008-03-15

    The cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A{sub 1} adenosine receptors (A{sub 1}AR), is likely to be involved. The present study investigates changes of cerebral A{sub 1}AR binding in cirrhotic patients by means of positron emission tomography (PET) and [{sup 18}F]CPFPX, a novel selective A{sub 1}AR antagonist. PET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan's non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to B{sub max}/K{sub D}). Cortical and subcortical regions showed lower A{sub 1}AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p < 0.05, U test with Bonferroni-Holm adjustment for multiple comparisons) in cingulate cortex (-50.0%), precentral gyrus (-40.9%), postcentral gyrus (-38.6%), insular cortex (-38.6%), thalamus (-32.9%), parietal cortex (-31.7%), frontal cortex (-28.6), lateral temporal cortex (-28.2%), orbitofrontal cortex (-27.9%), occipital cortex (-24.6), putamen (-22.7%) and mesial temporal lobe (-22.4%). Regional cerebral adenosinergic neuromodulation is heterogeneously altered in cirrhotic patients. The decrease of cerebral A{sub 1}AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A{sub 1}AR density or affinity, as well as blockade of the A{sub 1}AR by endogenous adenosine or exogenous xanthines. (orig.)

  20. Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy.

    Science.gov (United States)

    Aronica, Eleonora; Zurolo, Emanuele; Iyer, Anand; de Groot, Marjolein; Anink, Jasper; Carbonell, Caterina; van Vliet, Erwin A; Baayen, Johannes C; Boison, Detlev; Gorter, Jan A

    2011-09-01

    Adenosine kinase (ADK) represents the key metabolic enzyme for the regulation of extracellular adenosine levels in the brain. In adult brain, ADK is primarily present in astrocytes. Several lines of experimental evidence support a critical role of ADK in different types of brain injury associated with astrogliosis, which is also a prominent morphologic feature of temporal lobe epilepsy (TLE). We hypothesized that dysregulation of ADK is an ubiquitous pathologic hallmark of TLE. Using immunocytochemistry and Western blot analysis, we investigated ADK protein expression in a rat model of TLE during epileptogenesis and the chronic epileptic phase and compared those findings with tissue resected from TLE patients with mesial temporal sclerosis (MTS). In rat control hippocampus and cortex, a low baseline expression of ADK was found with mainly nuclear localization. One week after the electrical induction of status epilepticus (SE), prominent up-regulation of ADK became evident in astrocytes with a characteristic cytoplasmic localization. This increase in ADK persisted at least for 3-4 months after SE in rats developing a progressive form of epilepsy. In line with the findings from the rat model, expression of astrocytic ADK was also found to be increased in the hippocampus and temporal cortex of patients with TLE. In addition, in vitro experiments in human astrocyte cultures showed that ADK expression was increased by several proinflammatory molecules (interleukin-1β and lipopolysaccharide). These results suggest that dysregulation of ADK in astrocytes is a common pathologic hallmark of TLE. Moreover, in vitro data suggest the existence of an additional layer of modulatory crosstalk between the astrocyte-based adenosine cycle and inflammation. Whether this interaction also can play a role in vivo needs to be further investigated. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

  1. A comparison of N-methyl-D-aspartate-evoked release of adenosine and [3H]norepinephrine from rat cortical slices

    International Nuclear Information System (INIS)

    Hoehn, K.; Craig, C.G.; White, T.D.

    1990-01-01

    Tetrodotoxin reduced N-methyl-D-aspartate (NMDA)-evoked release of adenosine by 35% but virtually abolished [3H]norepinephrine release. Although [3H]norepinephrine release from rat cortical slices evoked by 500 microM NMDA was abolished by 1.2 mM Mg++, which produces a voltage-sensitive, uncompetitive block of NMDA-channels, adenosine release was increased in the presence of Mg++. Partial depolarization with 12 mM K+ relieved the Mg++ block of 500 microM NMDA-evoked [3H]norepinephrine release but did not affect adenosine release, indicating that a Mg++ requirement for the adenosine release process per se cannot account for this discrepancy. NMDA was 33 times more potent in releasing adenosine than [3H]norepinephrine. At submaximal concentrations of NMDA (10 and 20 microM), adenosine release was augmented in Mg+(+)-free medium. Although a high concentration of the uncompetitive NMDA antagonist MK-801 [(+)-5-methyl-10,11,dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate] (3 microM) blocked NMDA-evoked release of [3H]norepinephrine and adenosine, a lower concentration (300 nM) decreased NMDA-evoked [3H]norepinephrine release by 66% without affecting adenosine release. These findings suggest that maximal adenosine release occurs when relatively few NMDA receptors are activated, raising the possibility that spare receptors exist for NMDA-evoked adenosine release. Rather than acting as a protectant against excessive NMDA excitation, released adenosine might provide an inhibitory threshold which must be overcome for NMDA-mediated neurotransmission to proceed

  2. Clinical application of radiotherapy combined with chemotherapy

    International Nuclear Information System (INIS)

    Morita, Kozo

    1978-01-01

    In clinical application of radiation therapy combined with chemotherapy, it is important to gain the maximal therapeutic benefit. At present we have no agents that improve the therapeutic ratio by enhancing the effect of radiation on the tumor cell selectively. Therefore, it is necessary to use combining some or all of following procedures: (1) the intraarterial infusion of the agents, (2) the selective localization by reason of the biological affinity of the agents, (3) the surgical removal of the non-sensitized tumor residue and (4) the selective sensitization of the tumor due to its shorter cell cycle. (author)

  3. Intestinal lymphangiectasia secondary to radiotherapy and chemotherapy

    International Nuclear Information System (INIS)

    Rao, S.S.; Dundas, S.; Holdsworth, C.D.

    1987-01-01

    We report a case of intestinal lymphangiectasia secondary to radiotherapy and chemotherapy. The patient also had small bowel bacterial overgrowth and pancreatic insufficiency. Lymphatic ectasia as a histological feature has been described previously in association with postradiotherapy malabsorption, but radiation-induced lymphangiectasia producing clinical manifestations has hitherto not been reported. Replacement of dietary long-chain fats with medium-chain triglycerides, pancreatic enzyme supplements, and a short course of oxytetracycline, resulted in dramatic clinical improvement. The possibility of intestinal lymphangiectasia should be borne in mind in patients with postradiotherapy malabsorption. A low serum albumin and lymphocyte count should draw attention to this possibility

  4. Combined modality treatment with radiotherapy and chemotherapy

    International Nuclear Information System (INIS)

    Tannock, I.F.; Toronto Univ., ON

    1989-01-01

    The present paper discusses some of the methodological issues which can confound the interpretation of clinical trials of combined modality treatment. It reviews some of the larger randomized trials which have evaluated combined modality treatment in cancers of the head and neck, lung, gastrointestinal tract and bladder. It concludes that adequate trials have yet to be performed in many of thses sites, but that at present, evidence for long-term benefit from adjunctivechemotherapy is meagre. Finally, it suggests some possible mechanisms which might heve limited the benefit of chemotherapy when added to radiation treatment. (Author). 87 refs.; 4 figs.; 4 tabs

  5. Extracellular Adenosine Triphosphate Associated with Amphibian Erythrocytes: Inhibition of ATP Release by Anion Channel Blockers.

    Science.gov (United States)

    1986-01-01

    Paddle and Burnstock (326), Williams and Forrester (463), Forrester and Williams (151) and Clemens and Forrester (82) provide evidence that hypoxia may...an ATp4 - receptor. Fed. Proc. 45:208, 1986. (abstr) 99. Dahlen , S.E. and Hedqvist, P. ATP, B,y-methylene ATP andN adenosine inhibit non-cholinergic...regulation of skeletal muscle blood low. Circ Res. 29:375-384, 1971. 117. Dodd, J., Jahr, C.E., Hamilton, P.N., Heath, M.J., Matthew , W.P., and Jessell, T.M

  6. Effects of adenosine triphosphate concentration on motor force regulation during skeletal muscle contraction

    Science.gov (United States)

    Wei, J.; Dong, C.; Chen, B.

    2017-04-01

    We employ a mechanical model of sarcomere to quantitatively investigate how adenosine triphosphate (ATP) concentration affects motor force regulation during skeletal muscle contraction. Our simulation indicates that there can be negative cross-bridges resisting contraction within the sarcomere and higher ATP concentration would decrease the resistance force from negative cross-bridges by promoting their timely detachment. It is revealed that the motor force is well regulated only when ATP concentration is above a certain level. These predictions may provide insights into the role of ATP in regulating coordination among multiple motors.

  7. The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects

    DEFF Research Database (Denmark)

    Birk, S; Petersen, K.A.; Kruuse, Christina Rostrup

    2005-01-01

    . Headache was rated on a verbal scale (0-10). Regional cerebral blood flow (rCBF) with 133Xe inhalation and single-photon emission computed tomography (SPECT) and MCA flow velocity (V(MCA)) with transcranial Doppler, were measured in direct sequence. Six participants developed headache during 80 microg kg.......16) were found between treatments. A significant dilation of the superficial temporal artery (STA) was seen (P circulating adenosine has no effect on rCBF or V(MCA), while it dilates the STA and causes very mild headache....

  8. Endogenous activation of adenosine A(1) receptors accelerates ischemic suppression of spontaneous electrocortical activity

    DEFF Research Database (Denmark)

    Ilie, Andrei; Ciocan, Dragos; Zagrean, Ana-Maria

    2006-01-01

    Cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis. It was found in vitro during ischemia that the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, may inhibit synaptic transmission via the A(1......) receptor subtype. The link between endogenous A(1) receptor activation during ischemia and the suppression of spontaneous electrocortical activity has not yet been established in the intact brain. The aim of this study was to investigate in vivo the effects of A(1) receptor antagonism by 8-cyclopentyl-1...

  9. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function

    OpenAIRE

    Kara, Firas M.; Chitu, Violeta; Sloane, Jennifer; Axelrod, Matthew; Fredholm, Bertil B.; Stanley, E. Richard; Cronstein, Bruce N.

    2010-01-01

    Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A1R, A2AR, A2BR, and A3R). Because A1R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A1R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A1R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the pre...

  10. Adenosine A2b receptor promotes progression of human oral cancer

    International Nuclear Information System (INIS)

    Kasama, Hiroki; Sakamoto, Yosuke; Kasamatsu, Atsushi; Okamoto, Atsushi; Koyama, Tomoyoshi; Minakawa, Yasuyuki; Ogawara, Katsunori; Yokoe, Hidetaka; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

    2015-01-01

    Adenosine A2b receptor (ADORA2B) encodes an adenosine receptor that is a member of the G protein-coupled receptor superfamily. This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. Little is known about the relevance of ADORA2B to human malignancy including oral squamous cell carcinoma (OSCC). We aimed to characterize the expression state and function of ADORA2B in OSCC. The ADORA2B expression levels in nine OSCC-derived cells were analyzed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting analyses. Using an ADORA2B knockdown model, we assessed cellular proliferation and expression of hypoxia-inducible factor1α (HIF-1α). We examined the adenosine receptor expression profile under both normoxic and hypoxic conditions in the OSCC-derived cells. In addition to in vitro data, the clinical correlation between the ADORA2B expression levels in primary OSCCs (n = 100 patients) and the clinicopathological status by immunohistochemistry (IHC) also was evaluated. ADORA2B mRNA and protein were up-regulated significantly (p < 0.05) in seven OSCC-derived cells compared with human normal oral keratinocytes. Suppression of ADORA2B expression with shRNA significantly (p < 0.05) inhibited cellular proliferation compared with the control cells. HIF-1α also was down-regulated in ADORA2B knockdown OSCC cells. During hypoxia, ADORA2B expression was induced significantly (p < 0.05) in the mRNA and protein after 24 hours of incubation in OSCC-derived cells. IHC showed that ADORA2B expression in primary OSCCs was significantly (p < 0.05) greater than in the normal oral counterparts and that ADORA2B-positive OSCCs were correlated closely (p < 0.05) with tumoral size. Our results suggested that ADORA2B controls cellular proliferation via HIF-1α activation, indicating that ADORA2B may be a key regulator of tumoral progression in OSCCs. The online version of this article (doi:10.1186/s12885-015-1577-2) contains

  11. Delayed emesis: moderately emetogenic chemotherapy (single-day chemotherapy regimens only)

    DEFF Research Database (Denmark)

    Roila, Fausto; Warr, David; Aapro, Matti

    2011-01-01

    An update of the recommendations for the prophylaxis of delayed emesis induced by moderately emetogenic chemotherapy discussed during the third Perugia Consensus Conference (June 2009) sponsored by MASCC-ESMO was presented. The review considered new studies published since the second consensus...

  12. Inhibitory effect of sequential combined chemotherapy and radiotherapy on growth of implanted tumor in mice

    International Nuclear Information System (INIS)

    Okada, Kouji

    1983-01-01

    Sequential chemotherapy using FT-207, adriamycin and mitomycin C followed by radiotherapy was attempted to achieve effective inhibition against implanted tumor in C57BL/6 black mice bearing YM-12 tumors. Sequential combined chemotherapy was more effective than single drug chemotherapy or combined chemotherapy of other drugs. Addition of radiotherapy to the sequential combined chemotherapy was successful for enhancing therapeutic effect. (author)

  13. Regulation of Maltodextrin Phosphorylase Synthesis in Escherichia coli by Cyclic Adenosine 3′, 5′-Monophosphate and Glucose1

    Science.gov (United States)

    Chao, Julie; Weathersbee, Carolyn J.

    1974-01-01

    Cyclic adenosine 3′, 5′-monophosphate (AMP) stimulates maltodextrin phosphorylase synthesis in Escherichia coli cells induced with maltose. A maximal effect occurs at 2 to 3 mM cyclic AMP. The action of cyclic AMP is specific, inasmuch as adenosine triphosphate, 3′-AMP, 5′-AMP, adenosine, and dibutyryl cyclic AMP are inactive. Glucose, α-methyl glucoside, 2-deoxyglucose, and pyridoxal 5′-phosphate repress maltodextrin phosphorylase synthesis. This repression is reversed by cyclic AMP. The action of cyclic AMP appears to be at the transcriptional level, since cyclic AMP fails to stimulate phosphorylase production in induced cells in which messenger ribonucleic acid synthesis has been arrested by rifampin or by inducer removal. The two other enzymes involved in the metabolism of maltose, amylomaltase and maltose permease, are also induced in this strain of E. coli and affected by glucose and cyclic AMP in a manner similar to phosphorylase. PMID:4358043

  14. Reconsideration of the sequence of rigor mortis through postmortem changes in adenosine nucleotides and lactic acid in different rat muscles.

    Science.gov (United States)

    Kobayashi, M; Takatori, T; Iwadate, K; Nakajima, M

    1996-10-25

    We examined the changes in adenosine triphosphate (ATP), lactic acid, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in five different rat muscles after death. Rigor mortis has been thought to occur simultaneously in dead muscles and hence to start in small muscles sooner than in large muscles. In this study we found that the rate of decrease in ATP was significantly different in each muscle. The greatest drop in ATP was observed in the masseter muscle. These findings contradict the conventional theory of rigor mortis. Similarly, the rates of change in ADP and lactic acid, which are thought to be related to the consumption or production of ATP, were different in each muscle. However, the rate of change of AMP was the same in each muscle.

  15. Non-linear quantitative structure-activity relationship for adenine derivatives as competitive inhibitors of adenosine deaminase

    International Nuclear Information System (INIS)

    Sadat Hayatshahi, Sayyed Hamed; Abdolmaleki, Parviz; Safarian, Shahrokh; Khajeh, Khosro

    2005-01-01

    Logistic regression and artificial neural networks have been developed as two non-linear models to establish quantitative structure-activity relationships between structural descriptors and biochemical activity of adenosine based competitive inhibitors, toward adenosine deaminase. The training set included 24 compounds with known k i values. The models were trained to solve two-class problems. Unlike the previous work in which multiple linear regression was used, the highest of positive charge on the molecules was recognized to be in close relation with their inhibition activity, while the electric charge on atom N1 of adenosine was found to be a poor descriptor. Consequently, the previously developed equation was improved and the newly formed one could predict the class of 91.66% of compounds correctly. Also optimized 2-3-1 and 3-4-1 neural networks could increase this rate to 95.83%

  16. Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia.

    Directory of Open Access Journals (Sweden)

    Mei Cui

    Full Text Available Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC or 6 days (E6d HPC. Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC. Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1. An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.

  17. Non-enzymolytic adenosine barcode-mediated dual signal amplification strategy for ultrasensitive protein detection using LC-MS/MS.

    Science.gov (United States)

    Yang, Wen; Li, Tengfei; Shu, Chang; Ji, Shunli; Wang, Lei; Wang, Yan; Li, Duo; Mtalimanja, Michael; Sun, Luning; Ding, Li

    2018-05-10

    A method is described for the determination of proteins with LC-MS/MS enabled by a small molecule (adenosine) barcode and based on a double-recognition sandwich structure. The coagulation protein thrombin was chosen as the model analyte. Magnetic nanoparticles were functionalized with aptamer29 (MNP/apt29) and used to capture thrombin from the samples. MNP/apt29 forms a sandwich with functionalized gold nanoparticles modified with (a) aptamer15 acting as thrombin-recognizing element and (b) a large number of adenosine as mass barcodes. The sandwich formed (MNP/apt29-thrombin-apt15/AuNP/adenosine) can ben magnetically separated from the sample. Mass barcodes are subsequently released from the sandwiched structure for further analysis by adding 11-mercaptoundecanoic acid. Adenosine is then detected by LC-MS/MS as it reflects the level of thrombin with impressively amplified signal. Numerous adenosines introduced into the sandwich proportional to the target concentration further amplify the signal. Under optimized conditions, the response is linearly proportional to the thrombin concentration in the range of 0.02 nM to 10 nM, with a detection limit of 9 fM. The application of this method to the determination of thrombin in spiked plasma samples gave recoveries that ranged from 92.3% to 104.7%. Graphical abstract Schematic representation of a method for the determination of thrombin with LC-MS/MS. The method is based on a double-recognition sandwiched structure. With LC-MS/MS, mass barcodes (adenosine) are detected to quantify thrombin, which amplifies the detection signal impressively.

  18. Effects of the repeated administration of adenosine and heparin on myocardial perfusion in patients with chronic stable angina pectoris.

    Science.gov (United States)

    Barron, H V; Sciammarella, M G; Lenihan, K; Michaels, A D; Botvinick, E H

    2000-01-01

    The mechanism by which ischemia stimulates angiogenesis is unknown. Adenosine is released during myocardial ischemia and may be a mediator of this process. Experimental data suggest that heparin may enhance this effect. The purpose of this open-labeled, placebo-controlled trial was to determine whether repeated intravenous administration of adenosine and heparin could mimic physiologic angiogenesis and reduce the amount of exercise-induced myocardial ischemia in patients with coronary artery disease. Subjects with chronic stable angina refractory to conventional medical therapy and not suitable for revascularization received either adenosine (140 microg/kg/min for 6 minutes) and heparin (10,000 U bolus), (n = 14), or placebo, (n = 7) daily for 10 days. All patients underwent baseline and follow-up exercise testing with thallium-201 single-photon emission computed tomography myocardial perfusion imaging. A semiquantitative assessment of the extent and severity of the perfusion abnormalities was calculated by 2 blinded investigators. There was no significant change in exercise duration or in the peak heart rate systolic blood pressure product associated with adenosine and heparin compared with placebo treatment. There was, however, a 9% reduction in the extent (60.6 +/- 4.0 vs 54.9 +/- 4.1, p = 0.03) and a 14% improvement in severity (41.5 +/- 3.2 vs 35.7 +/- 2.9, p = 0.01) of the myocardial perfusion abnormalities seen in patients who received adenosine and heparin compared with placebo. Thus, in this pilot study, repeated administration of adenosine and heparin reduced the amount of exercise-induced ischemia in patients with chronic stable angina refractory to conventional treatment.

  19. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Pospisil, M.; Hofer, M.; Netikova, J.; Hola, J.; Vacek, A. [Academy of Sciences of the Czech Republic, Inst. of Biophysics, Brno (Czech Republic); Znojil, V.; Vacha, J. [Masaryk Univ., Medical Faculty, Brno (Czech Republic)

    1998-03-01

    The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of {sup 60}Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in combination, were evaluated. The drugs were injected to mice in a 4-d treatment regimen starting on d 3 after irradiation and the haematopoietic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cells, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combination therapy occurred in the post-irradiation recovery phase which is dependent on the repopulation of haematopoietic stem cells. This was indicated by the significant elevation of counts of granulocyte-macrophage progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood. These effects suggest that the repopulation potential of the combination therapy lies in a common multi-lineage cell population. The results of this study implicate the promising possibility to enhance the curative effects of G-CSF under conditions of myelosuppressive state induced by radiation exposure. (au) 43 refs.

  20. Granulocyte colony-stimulating factor and drugs elevating extracellular adenosine synergize to enhance haematopoietic reconstitution in irradiated mice

    International Nuclear Information System (INIS)

    Pospisil, M.; Hofer, M.; Netikova, J.; Hola, J.; Vacek, A.; Znojil, V.; Vacha, J.

    1998-01-01

    The activation of adenosine receptors has recently been demonstrated to stimulate haematopoiesis. In the present study, we investigated the ability of drugs elevating extracellular adenosine to influence curative effects of granulocyte colony-stimulating factor (G-CSF) in mice exposed to a sublethal dose of 4 Gy of 60 Co radiation. Elevation of extracellular adenosine in mice was induced by the combined administration of dipyridamole, a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), an adenosine prodrug. The effects of dipyridamole plus AMP, and G-CSF, administered either alone or in combination, were evaluated. The drugs were injected to mice in a 4-d treatment regimen starting on d 3 after irradiation and the haematopoietic response was evaluated on d 7, 10, 14, 18 and 24 after irradiation. While the effects of G-CSF on the late maturation stages of blood cells, appearing shortly after the completion of the treatment, were not influenced by dipyridamole plus AMP, positive effects of the combination therapy occurred in the post-irradiation recovery phase which is dependent on the repopulation of haematopoietic stem cells. This was indicated by the significant elevation of counts of granulocyte-macrophage progenitor cells (GM-CFC) and granulocytic cells in the bone marrow (d 14), of GM-CFC (d 14), granulocytic and erythroid cells (d 14 and 18) in the spleen, and of neutrophils (d 18), monocytes (d 14 and 18) and platelets (d 18) in the peripheral blood. These effects suggest that the repopulation potential of the combination therapy lies in a common multi-lineage cell population. The results of this study implicate the promising possibility to enhance the curative effects of G-CSF under conditions of myelosuppressive state induced by radiation exposure. (au)