Influence of pegylated interferon-α therapy on plasma levels of citrulline and arginine in melanoma patients

Department of Neuroscience, Erasmus MC, The Netherlands.
Amino Acids (Impact Factor: 3.29). 02/2007; 32(1):121-6. DOI: 10.1007/s00726-006-0284-3
Source: PubMed


The aim of this study was to evaluate the effect of pegylated interferon-alpha (PEG-IFN-alpha) on the plasma citrulline/arginine ratio, regarded as an index of nitric oxide (NO) synthesis, in patients with high-risk melanoma. Forty patients were randomly assigned to either PEG-IFN-alpha treatment (n = 22) or to observation only (control group, n = 18). The treatment group received 6 microg PEG-IFN-alpha/kg once a week during 8 weeks, followed by a maintenance dose of 3 microg/kg/wk. Blood was collected at different time points, plasma concentrations of citrulline and arginine were measured and the ratio of citrulline/arginine was calculated. Patients treated with PEG-IFN-alpha showed a significant decrease in the concentrations of citrulline and in the citrulline/arginine ratio during the whole study period, both compared to baseline values and to the control group. The data suggest that therapy with PEG-IFN-alpha results in a marked decrease in the synthesis of NO in melanoma patients.

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Available from: Alexander Maximiliaan Eggermont, Feb 11, 2015
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    • "On the one hand, one could doubt the validity of the use of the amino acids CIT and ARG as indices for NO production as the metabolism of CIT and ARG is complex. This has already been discussed earlier (Fekkes et al. 2007). On the other hand, the assay of NOx is fraught with technical difficulties and blood concentrations of nitrite/nitrate are influenced by factors as diet, physical activity and antioxidants taken (Tsikas and Frölich 2004; Dusse et al. 2005). "
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    ABSTRACT: Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-α (IFN-α). Animal studies showed that IFN-α administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H2O2 generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-α. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-α, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-α are unlikely to contribute to definite psychiatric disturbance.
    Full-text · Article · Oct 2009 · Amino Acids
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    • "In this process tetrahydrobiopterin (BH4) is a necessary cofactor. We have shown that the ratio of the plasma concentrations of citrulline (Cit) and arginine (Arg), the so-called Cit/Arg ratio, can be regarded as an index of NO synthesis (Fekkes et al. 2007). One of the key players in the production of NO in AD may be the inflammation and immune activation that characterize the pathology of AD. "
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    ABSTRACT: Subjects with Down syndrome (DS) have abnormalities in virtually all aspects of the immune system and almost all will be affected with Alzheimer's disease (AD). It is thought that nitric oxide (NO) is involved in the pathophysiology of AD. In the present study, including a total of 401 elderly DS subjects, the spectrum of plasma amino acids and neopterin was investigated and related to development of AD. Concentrations of nearly all amino acids in DS subjects differed significantly from those of healthy controls. Neopterin was increased in DS subjects, especially in dementia. The production of NO as reflected by an increased citrulline/arginine ratio (Cit/Arg ratio) was enhanced during development of clinical dementia. Neopterin concentrations correlated to the Cit/Arg ratio only in the group of prevalent demented subjects (rho = 0.48, P = 0.006). The results of this study are suggestive for an increase in oxidative processes in DS subjects with AD.
    Full-text · Article · Jun 2009 · Amino Acids
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    ABSTRACT: There is an increasing interest in the role of nitric oxide (NO) and pterines in the pathophysiology of neuropsychiatric disorders. The results so far show an inconsistent pattern. In the present study, neopterin and a measure of NO synthesis in plasma of symptomatic and euthymic bipolar affective patients were compared to those of patients with a major depression and healthy controls. As an index of NO synthesis, the ratio of the amino acids citrulline and arginine (Cit-Arg ratio) was calculated. Neopterin is a bypass product in the synthesis of tetrahydrobiopterin, which is a cofactor of NO synthase. The results indicate that both neopterin and the Cit-Arg ratio are decreased in bipolar affective patients, irrespective of their symptomatic status. In addition, an association between the values of the Cit-Arg ratio and the neopterin level was observed, which is suggestive for a low tetrahydrobiopterin activity. NO formation may be endangered in bipolar affective disorder.
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