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  1. Article ; Online: Kynurenine metabolism predicts cognitive function in patients following cardiac bypass and thoracic surgery.

    Forrest, Caroline M / Mackay, Gillian M / Oxford, Lynn / Millar, Keith / Darlington, L Gail / Higgins, Michael J / Stone, Trevor W

    Journal of neurochemistry

    2011  Volume 119, Issue 1, Page(s) 136–152

    Abstract: Cardiac surgery involving extra-corporeal circulation can lead to cognitive dysfunction. As such surgery is associated with signs of inflammation and pro-inflammatory mediators activate tryptophan oxidation to neuroactive kynurenines which modulate NMDA ... ...

    Abstract Cardiac surgery involving extra-corporeal circulation can lead to cognitive dysfunction. As such surgery is associated with signs of inflammation and pro-inflammatory mediators activate tryptophan oxidation to neuroactive kynurenines which modulate NMDA receptor function and oxidative stress, we have measured blood concentrations of kynurenines and inflammatory markers in 28 patients undergoing coronary arterial graft surgery and, for comparison, 28 patients undergoing non-bypass thoracic surgery. A battery of cognitive tests was completed before and after the operations. The results show increased levels of tryptophan with decreased levels of kynurenine, anthranilic acid and 3-hydroxyanthranilic acid associated with bypass, and a later increase in kynurenic acid. Levels of neopterin and lipid peroxidation products rose after surgery in non-bypass patients whereas tumour necrosis factor-α and S100B levels increased after bypass. Changes of neopterin levels were greater after non-bypass surgery. Cognitive testing showed that the levels of tryptophan, kynurenine, kynurenic acid and the kynurenine/tryptophan ratio, correlated with aspects of post-surgery cognitive function, and were significant predictors of cognitive performance in tasks sensitive to frontal executive function and memory. Thus, anaesthesia and major surgery are associated with inflammatory changes and alterations in tryptophan oxidative metabolism which predict, and may play a role in, post-surgical cognitive function.
    MeSH term(s) Adult ; Aged ; Biomarkers/metabolism ; Chromatography, High Pressure Liquid ; Cognition/physiology ; Coronary Artery Bypass/psychology ; Enzyme-Linked Immunosorbent Assay ; Extracorporeal Circulation ; Female ; Humans ; Inflammation/metabolism ; Kynurenine/blood ; Lipid Peroxidation ; Male ; Middle Aged ; Neopterin/blood ; Nerve Growth Factors/metabolism ; Neuropsychological Tests ; Postoperative Complications/diagnosis ; Postoperative Complications/psychology ; Predictive Value of Tests ; Psychomotor Performance/physiology ; Reproducibility of Results ; S100 Calcium Binding Protein beta Subunit ; S100 Proteins/metabolism ; Stroop Test ; Thoracic Surgical Procedures/psychology ; Trail Making Test ; Tryptophan/metabolism ; Tumor Necrosis Factor-alpha/blood ; Verbal Learning
    Chemical Substances Biomarkers ; Nerve Growth Factors ; S100 Calcium Binding Protein beta Subunit ; S100 Proteins ; S100B protein, human ; Tumor Necrosis Factor-alpha ; Kynurenine (343-65-7) ; Neopterin (670-65-5) ; Tryptophan (8DUH1N11BX)
    Language English
    Publishing date 2011-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/j.1471-4159.2011.07414.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment.

    Forrest, Caroline M / Mackay, Gillian M / Oxford, Lynn / Stoy, Nicholas / Stone, Trevor W / Darlington, L Gail

    Clinical and experimental pharmacology & physiology

    2006  Volume 33, Issue 11, Page(s) 1078–1087

    Abstract: 1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine ... ...

    Abstract 1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2. Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3. In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4. The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate.
    MeSH term(s) 3-Hydroxyanthranilic Acid/chemistry ; 3-Hydroxyanthranilic Acid/metabolism ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Female ; Humans ; Indomethacin/therapeutic use ; Kynurenic Acid/chemistry ; Kynurenic Acid/metabolism ; Kynurenine/blood ; Kynurenine/chemistry ; Kynurenine/metabolism ; Lipid Peroxidation ; Male ; Middle Aged ; Molecular Structure ; Neopterin/blood ; Osteoporosis/drug therapy ; Osteoporosis/metabolism ; Sodium Salicylate/therapeutic use ; Tryptophan/chemistry ; Tryptophan/metabolism ; ortho-Aminobenzoates/chemistry ; ortho-Aminobenzoates/metabolism
    Chemical Substances Anti-Inflammatory Agents, Non-Steroidal ; ortho-Aminobenzoates ; anthranilic acid (0YS975XI6W) ; 3-Hydroxyanthranilic Acid (1UQB1BT4OT) ; Kynurenine (343-65-7) ; Neopterin (670-65-5) ; Tryptophan (8DUH1N11BX) ; Kynurenic Acid (H030S2S85J) ; Sodium Salicylate (WIQ1H85SYP) ; Indomethacin (XXE1CET956)
    Language English
    Publishing date 2006-11
    Publishing country Australia
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 189277-0
    ISSN 1440-1681 ; 0305-1870 ; 0143-9294
    ISSN (online) 1440-1681
    ISSN 0305-1870 ; 0143-9294
    DOI 10.1111/j.1440-1681.2006.04490.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Adenosine and cytokine levels following treatment of rheumatoid arthritis with dipyridamole.

    Forrest, Caroline M / Stoy, Nicholas / Stone, Trevor W / Harman, Gillian / Mackay, Gillian M / Oxford, Lynn / Darlington, L Gail

    Rheumatology international

    2006  Volume 27, Issue 1, Page(s) 11–17

    Abstract: Adenosine can suppress the release of tumour necrosis factor-alpha (TNF-alpha) from activated monocytes and macrophages, and may contribute to the anti-inflammatory activities of methotrexate and sulphasalazine. Dipyridamole inhibits the cellular uptake ... ...

    Abstract Adenosine can suppress the release of tumour necrosis factor-alpha (TNF-alpha) from activated monocytes and macrophages, and may contribute to the anti-inflammatory activities of methotrexate and sulphasalazine. Dipyridamole inhibits the cellular uptake and metabolism of adenosine and we have, therefore, examined the effects of dipyridamole in patients with rheumatoid arthritis in an attempt to alleviate their symptoms. Forty patients aged 18-75 years were randomised to receive dipyridamole 400 mg/day or placebo. Blood samples were taken at baseline and at monthly intervals for 6 months. Purines were determined by HPLC and cytokines by ELISA. After 3 months of treatment there were significant reductions in neopterin levels and in the modified Health Assessment Questionnaire score, but these were not maintained. Dipyridamole had no effect on disease severity or the levels of purine metabolites, interleukin-1beta (IL-1beta), IL-6, TNF-alpha, lipid peroxidation products, erythrocyte sedimentation rate or C-reactive protein. In conclusion, rheumatoid arthritis patients showed no clinical improvement following treatment with dipyridamole for 6 months.
    MeSH term(s) Adenosine/blood ; Adolescent ; Adult ; Aged ; Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/drug therapy ; Cytokines/blood ; Dipyridamole/pharmacology ; Dipyridamole/therapeutic use ; Dose-Response Relationship, Drug ; Humans ; Interleukin-1beta/blood ; Interleukin-6/blood ; Lipid Peroxidation/drug effects ; Middle Aged ; Neopterin/blood ; Platelet Aggregation Inhibitors/pharmacology ; Platelet Aggregation Inhibitors/therapeutic use ; Treatment Outcome ; Tumor Necrosis Factor-alpha/blood ; Young Adult
    Chemical Substances Cytokines ; Interleukin-1beta ; Interleukin-6 ; Platelet Aggregation Inhibitors ; Tumor Necrosis Factor-alpha ; Dipyridamole (64ALC7F90C) ; Neopterin (670-65-5) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2006-11
    Publishing country Germany
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 8286-7
    ISSN 1437-160X ; 0172-8172
    ISSN (online) 1437-160X
    ISSN 0172-8172
    DOI 10.1007/s00296-006-0212-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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