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PubMed1994

Serum and urinary neopterin as markers in renal transplant patients.

For monitoring neopterin levels, serial serum and urinary samples were obtained from 21 renal transplant patients. In renal transplant patients, serum neopterin levels were significantly higher than in healthy volunteers, even though in a clinically stable state urinary neopterin levels were also higher than in healthy volunteers, but statistically not significantly. In cases with rejection, both serum and urinary neopterin levels were significantly more elevated than in the stable state. In contrast, serum and urinary neopterin levels were not elevated in nephrotoxicity events. These results suggest that serum and urinary neopterin levels might be valuable indicators of acute rejection. Moreover, they could be useful for differentiating acute rejection from nephrotoxicity episode.

Acute Disease↗
PubMed1997

Neopterin, beta 2-microglobulin, and acute phase proteins in HIV-1-seropositive and -seronegative Zambian patients with tuberculosis.

Neopterin is a biochemical marker for the activation of the cell-mediated immune system. We measured neopterin, beta 2-microglobulin, and acute phase proteins in 31 HIV-seropositive and -seronegative Zambian patients with tuberculosis, using stored sera that had been obtained at the beginning and at end of antituberculosis treatment. In both HIV-seropositive and -seronegative patients neopterin and acute phase proteins were elevated when tuberculosis was initially diagnosed and fell during treatment. In contrast, the mean beta 2-microglobulin level increased during antituberculous therapy in the HIV-seropositive group. Serum neopterin levels at diagnosis were correlated with other parameters of disease activity (fever, anemia, and weight loss). In both groups, patients with persistently elevated neopterin levels at the end of treatment were more likely to suffer relapse of tuberculosis or other adverse health events in the subsequent follow-up period. Neopterin can be used to monitor the response to antituberculous therapy in both HIV-seropositive and -seronegative patients and may have a prognostic value for the patients' wellbeing in the follow-up period.

AIDS-Related Opportunistic Infections↗
PubMed2000

Effect of sepsis and cardiac surgery with cardiopulmonary bypass on plasma level of nitric oxide metabolites, neopterin, and procalcitonin: correlation with mortality and postoperative complications.

OBJECTIVES: To examine the hypothesis that nitrite/nitrate, neopterin, and procalcitonin (PCT) levels can be useful predictors of sepsis-associated mortality and predictors of the postoperative complications after cardiopulmonary bypass (CPB). DESIGN: Prospective clinical study. SETTING: Intensive care unit of the Medical University Hospital. PATIENTS: 41 patients with sepsis, 42 patients subjected to open heart surgery with CPB, and 30 healthy volunteers. MEASUREMENTS AND RESULTS: Nitrite/nitrate, neopterin, and PCT levels were measured in septic patients as soon as sepsis was recognized and then on the 2nd, 3rd, and 5th days of treatment. Statistically significant differences between survivors and nonsurvivors were found for neopterin and PCT. The area under receiver operating characteristic curve (AUC) for both parameters as predictors of mortality was above 0.8. The nitrite/nitrate level was also higher in nonsurvivors, but the AUC remained below 0.8, which indicates poor predictive power. The same parameters were measured in patients undergoing cardiac surgery before, during and after CPB establishment. The development of post-operative complications was correlated with increased postoperative neopterin and PCT levels. Additionally, neopterin was found as an early marker for the prognosis of postoperative complications, since patients who developed organ dysfunction had had elevated concentration of this parameter even before surgery (AUC 0.83). Measurement of NO metabolite levels was less specific and less sensitive. CONCLUSIONS: Our results confirm the value of PCT and neopterin measurement as diagnostic tools in monitoring the clinical course of patients in intensive care units.

Area Under Curve↗
PubMed1998

Urinary neopterin excretion and dihydropteridine reductase activity in rheumatoid arthritis.

Neopterin and biopterin are two products of the pteridine pathway. Even though their roles and interrelationships have not been exactly clarified, neopterin is known as a biomarker of cell-mediated immunity. In this case, the highly elevated neopterin levels are parallel to the slightly elevated biopterin levels. On the other hand, the reduced form of biopterin-tetrahydrobiopterin is an essential cofactor of aromatic monoxygenases that leads to synthesis of tyrosine, tryptophan and dopamine neurotransmitters and its concentration in body fluids and tissues is maintained by the enzyme dihydropteridine reductase (DHPR). Increased numbers of activated lymphocytes can be found in peripheral blood, in the synovial fluid and synovial membranes or patients with rheumatoid arthritis (RA). Since the present study was undertaken to evaluate the role of the pteridine pathway in RA, we measured urine neopterin levels and dried blood DHPR activities in 36 patients with RA and in 20 healthy volunteers, in parallel with other clinical parameters. We found that neopterin excretion was significantly increased in RA patients compared with controls. The means were 433 +/- 216, 153 +/- 43 and 111 +/- 34 mumol/mol creatinine for patients in active stage, in remission and controls, respectively. Our results suggest that urine neopterin levels were strongly dependent on the stage and activity of RA. Either as an effect of the disease itself or of drug administration, slightly reduced DHPR activities were detected (3.484 +/- 0.304 for control, 2.974 +/- 0.255 in active stage RA, and 3.048 +/- 0.302 red cytochrome C/min/5 mm disc in remission).

Adult↗
PubMed2002

Increased neopterin production and tryptophan degradation in advanced Parkinson's disease.

Large amounts of neopterin are produced by interferon-(IFN)-gamma-stimulated human monocytes/macrophages, and increased neopterin concentrations indicate cellular immune activation. In parallel, IFN-gamma induces indoleamine 2,3-dioxygenase which degrades 1-tryptophan to kynurenine. Increased tryptophan degradation rates are indicated by an increased kynurenine/tryptophan ratio (kyn/trp-ratio), reflecting immune system activation, too. In 22 patients with Parkinson's disease (PD) and in 11 age-matched controls, serum and cerebrospinal fluid (CSF) neopterin concentrations were measured by ELISA. Tryptophan and kynurenine concentrations were determined by HPLC. Neopterin concentrations and kyn/trp-ratios were increased both in serum and CSF of patients as compared to controls. Serum tryptophan was lower in patients. Patients with the highest disease activity presented with highest degree of immune activation. Significant correlations existed between neopterin concentrations and kyn/trp-ratios in serum and CSF. Increased formation of neopterin and enhanced degradation of tryptophan suggest activated cell-mediated immune response in a subgroup of patients with advanced Parkinson's disease.

Aged↗
PubMed1993

Neopterin modulates toxicity mediated by reactive oxygen and chloride species.

Neopterin, a pyrazino-pyrimidine derivative, is synthesized in excess by human monocytes/macrophages upon stimulation with interferon-gamma, a cytokine derived from activated I cells. Neopterin is furthermore produced constitutively. A relatively constant ratio between neopterin and its reduced form. 7,8-dihydroneopterin, has been described in human serum. In the study presented here we tested the ability of neopterin and its reduced form to modulate the effects of cytotoxic substances like hydrogen peroxide or hypochlorous acid and N-chloramine derivatives. We show that 7,8-dihydroneopterin potently reduces biological and chemical effects of these substances independently from the pH value. In contrast, at slightly alkaline pH (pH 7.5) neopterin enhances hydrogen peroxide and chloramine-T activity. This is demonstrated by increase of signal intensity in a luminol assay and also by enhancement of toxicity towards bacteria. Thus, the macrophage derived substance neopterin is able both to enhance and to reduce cytotoxicity in dependence of pH value and its oxidation state, and it may have a pivotal role in modulation of macrophage mediated effector mechanism.

Animals↗
PubMed1995

Induction of inducible nitric oxide synthase expression by neopterin in vascular smooth muscle cells.

The pteridine compounds neopterin and 7,8-dihydroneopterin serve as valuable indicators for the stimulation of the cellular immune system. Whether they exhibit distinct biochemical functions in the immunological process is at present under discussion. We show that neopterin, but not 7,8-dihydroneopterin, is a stimulus for iNOS gene expression in rat vascular smooth muscle cells in vitro. At a concentration of 20 microM, neopterin leads to an iNOS mRNA expression of 2.5 amol iNOS cDNA/micrograms total RNA. When cells were coincubated with 20 microM neopterin and 5 micrograms/ml lipopolysaccharide derived from Escherichia coli, at least an additive effect on iNOS mRNA expression could be detected (iNOS cDNA concentration was 5.0 amol/micrograms total RNA). We speculate that neopterin enhances the macrophage-induced extracellular toxicity. This might be of relevance in situations associated with excessive release of cytokines, neopterin, and nitric oxide, as observed in septic shock.

Animals↗
PubMed1996

Neopterin activates transcription factor nuclear factor-kappa B in vascular smooth muscle cells.

We have previously shown that the pteridine compound neopterin stimulates inducible nitric oxide synthase (iNOS) gene expression in vascular smooth muscle cells in vitro. The mechanisms whereby neopterin exhibits these effects remained unclear. The present study demonstrates that neopterin induces the translocation of the transcription factor nuclear factor-kappa B (NF-kappa B) to the nucleus. Pretreatment of cells with the antioxidant pyrrolidine dithiocarbamate completely suppressed the effects of neopterin on NF-kappa B activation, iNOS gene expression, and nitric oxide release. From these data we conclude that neopterin activates the translocation of NF-kappa B subunits to the nucleus by modulating the intracellular redox state. This is one possible explanation for the impact of neopterin on iNOS gene expression.

Animals↗
PubMedDate not supplied

Urinary neopterin in volunteers experimentally infected with Plasmodium falciparum.

To investigate the kinetics of monocyte/macrophage activation in falciparum malaria we determined urinary neopterin values serially in experimentally infected volunteers. Three subjects who had been immunized with irradiated sporozoites via mosquito bites served as controls. These individuals remained aparasitaemic, afebrile and without a rise in neopterin after challenge by infective mosquitoes. Four non-immune subjects developed Plasmodium falciparum parasitaemia, fever (3 of 4) and sharp rises in neopterin. Parasite densities reached 10-100 parasitized erythrocytes per microliter before elevations in temperature or neopterin levels were detected. Onset of fever preceded the rise in neopterin excretion by one day. Prompt chemotherapy was associated with the clearance of parasites from the blood and the return of temperature and neopterin levels to normal.

Biopterins↗
PubMed1992

Serum kynurenine and neopterin concentrations in patients with cardiomyopathy.

Serum kynurenine and neopterin concentrations were determined in patients with hypertrophic (n = 22) and dilated (n = 23) cardiomyopathy. Significantly increased kynurenine and neopterin levels have been observed in cases of dilated cardiomyopathy. In these patients we found a positive correlation between serum kynurenine and neopterin levels (RS = 0.52, P less than 0.001). There existed several associations between the laboratory parameters neopterin and kynurenine and clinical findings, such as left ventricle (LV) systolic volume and LV circumferential fiber shortening velocity in patients with dilated cardiomyopathy (all P less than 0.05). In vitro, interferon-gamma induces the formation of neopterin in human monocytes/macrophages. Also the degradation of tryptophan via the kynurenine pathway is induced by interferon-gamma. Our data show that increased kynurenine as well as neopterin accumulation in serum are associated with severity of dilated cardiomyopathy. Thus, the data point to a role of immune activation in the pathogenesis of the disease.

Biopterins↗
PubMed2004

Influence of neopterin on generation of reactive species by myeloperoxidase in human neutrophils.

Increased neopterin concentrations in human serum indicate activation of cell-mediated immune response. Earlier we have shown that neopterin enhanced generation of singlet oxygen, hydroxyl radical and nitric oxide in human peripheral blood neutrophils by NADPH-independent pathways. To further investigate a participation of neopterin in reactive species production by neutrophils, we studied its influence on myeloperoxidase (MPO) activity. MPO was isolated from human peripheral blood neutrophils from healthy donors. Generation of reactive species by MPO/H(2)O(2) in Earl's solution (pH=7.2) at 37 degrees C was investigated by monitoring of chemiluminescence using luminol as light emitter. In the MPO/H(2)O(2) system, neopterin increased singlet oxygen in a concentration-dependent manner, but it decreased formation of other oxidizing species. Comparing several oxygen scavengers, formation of reactive species was totally blocked by sodium azide (NaN(3)), both in the presence and in the absence of neopterin. Superoxide dismutase (SOD) and d-mannitol insignificantly decreased chemiluminescence of this reaction, but diazabicyclo[2.2.2]octane (DABCO) strongly inhibited it. We conclude that the effects of neopterin on neutrophils' MPO are directed to increase singlet oxygen and to decrease other reactive species via inhibition of MPO and/or scavenging of reactive species.

Humans↗
PubMed2005

Relationship between homocysteine and neopterin concentrations in patients with gynecological cancer.

Elevated concentrations of vascular risk factor homocysteine have been described in patients with malignant diseases, and homocysteine was supposed to be useful as tumor marker. Likewise, elevated concentrations of Th1-type immune activation marker neopterin are frequently observed in patients suffering from cancer and serve as prognostic marker for the survival of patients. In this study, the relationship between homocysteine and neopterin concentrations was examined in 18 patients with gynecological cancer. Concentrations of homocysteine and cysteine were measured by HPLC in sera of patients, folic acid and vitamin B(12) levels were determined by radioimmunoassay, and neopterin concentrations were measured by ELISA. Median homocysteine concentration was 11.2 microM (interquartile range: 9.9-13.2 microM), 3 patients had levels higher than 15 microM, the upper limit of the normal range. Neopterin concentrations were increased in 13 patients (median: 11.6; 7.7-24.9 nM), cysteine (median: 234; 216-255 microM), folate (median: 7.8; 6.2-11.7 ng/ml) and vitamin B(12) (median: 352; 258-570 pg/ml) concentrations were all within reference ranges although rather at the lower side. Higher homocysteine concentrations correlated inversely with low folate concentrations (r(s)=-0.605; P<0.01) and tended to be higher in patients with higher cysteine levels (r(s)=0.457; P<0.06; ). No correlation was found between homocysteine and immune activation marker neopterin, although the three patients with elevated homocysteine concentrations tended to have higher neopterin levels as well (P<0.07). In conclusion, only a few patients with gynecological cancer present with elevated homocysteine concentrations and hyperhomocysteinemia seems only weakly related to immune activation phenomena, tumor cell proliferation probably is more important for the increase of homocysteine.

Aged↗
PubMed2005

Elevated urine neopterin levels in nonalcoholic steatohepatitis.

OBJECTIVES: The aim of this study was to relate urine levels of neopterin, a marker of activation of the cellular immune system, with grading and staging of NASH. DESIGN AND METHODS: Urine concentrations of neopterin, routine tests, insulin and C-peptide levels were assessed in 50 patients with NASH, 25 patients with chronic viral hepatitis (CVH), and in 26 healthy controls. RESULTS: Urine neopterin levels were found elevated in the NASH and CVH groups compared with controls. There was no significant correlation between urine neopterin levels and inflammation grade in the liver. CONCLUSIONS: Urine neopterin levels are a marker of cellular immunity and are higher in patients with NASH. However, neopterin levels were not significantly associated with histopathological grade and stage of disease.

Adult↗
PubMed2005

Usefulness of neopterin levels and left ventricular function for risk assessment in survivors of acute myocardial infarction.

BACKGROUND: Results of previous studies have shown that serum neopterin levels are higher in patients with acute myocardial infarction (AMI). However, little is known regarding the prognostic value of neopterin in survivors of AMI. The present study analyzes the prognostic value of neopterin serum concentration and left ventricular ejection fraction in survivors of AMI. METHODS: The additional prognostic information provided by neopterin to parameters of left ventricular function in survivors of AMI was investigated through 82 patients with ST-segment elevation. RESULTS: Binary logistic regression analysis identified the following predictors of 6-month cardiac death: Killip class >I at presentation (OR=2.4, 95% CI: 1.2 to 3.8, p=0.001), a reduced ejection fraction (OR=1.9, 95% CI: 1.3 to 2.2, p=0.001), and greater neopterin (OR=1.4, 95% CI: 1.1 to 1.6, p=0.01). CONCLUSIONS: Neopterin is associated with mortality, in addition to parameters of ventricular function (Killip class and ejection fraction) in survivors of AMI.

Aged↗
PubMed2003

Neopterin levels in patients with coronary artery disease are independent of Chlamydia pneumoniae seropositivity.

BACKGROUND: Chronic infection with Chlamydia pneumoniae (Cpn) has been associated with atherosclerotic cardiovascular disease in sero-epidemiological, pathological and animal-model studies. Inflammation and immune activation has been proposed as the pathophysiological link between chronic infection and atherosclerosis. The aim of this study was to assess whether Cpn seropositivity is associated with serum neopterin concentrations, a marker of macrophage activation, in patients with stable and unstable angina pectoris. METHODS: We examined 100 patients with angiographically documented coronary artery disease: 60 patients had chronic stable angina and 40 had Braunwald class III unstable angina. Neopterin concentrations were measured with a commercially available immunoassay. Cpn titres were measured with a microimmunofluorescence (MIF) assay. RESULTS: Neopterin concentrations were significantly higher in patients with unstable angina compared to those with chronic stable angina (6.30 [4.85-8.80] nmol/L vs 4.95 [3.35-7.05] nmol/L, P =.004), even after adjustment for variables that were significantly different between the 2 groups on univariate analysis. In contrast, the prevalence of positive Cpn serology did not differ significantly between the 2 angina patient groups (65% v 58%, P =.50). Neopterin levels were similar between Cpn-negative and Cpn-positive patients (P =.40) in both stable and unstable angina groups. CONCLUSIONS: Patients with unstable angina had higher neopterin concentrations than patients with chronic stable angina, probably reflecting the higher degree of immune activation in acute coronary syndromes. Neopterin levels, however, were independent of Cpn serostatus when combining both stable and unstable angina patients. Thus, immune activation in patients with acute coronary syndromes appears to be unrelated to Cpn seropositivity.

Analysis of Variance↗
PubMed1999

Serum neopterin levels and the angiographic extent of coronary arterial narrowing in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

Systemic serum markers of inflammation are elevated in diseases due to atherosclerosis, but have not been associated with the extent of atherosclerotic disease. We examined the role of neopterin, a byproduct of activated macrophage metabolism, in patients with unstable angina. Baseline neopterin samples and clinical histories were obtained in 52 patients admitted with unstable angina pectoris. Coronary angiograms of 27 patients were reviewed using Sullivan's method to assess the total atherosclerotic burden in the coronary arteries. Twenty-six of the 52 patients were eventually diagnosed with a non-Q-wave acute myocardial infarction (AMI) and had higher neopterin levels (10.1 +/- 6.7 vs 7.2 +/- 4.0 nmol/L, p = 0.06) than patients with a final diagnosis of unstable angina. Patients with neopterin >8.7 were more likely to be diagnosed with a non-Q-wave AMI (75% vs 39%, p = 0.035) and were more likely to have significantly more severe and extensive angiographically determined atherosclerosis than patients with low neopterin levels. Neopterin levels correlated with the score of atherosclerotic extension (Spearman's rank correlation coefficient 0.4807, p = 0.034). This study demonstrates a correlation between immune cell activation and the extent of angiographically determined atherosclerosis and the degree of myocardial ischemia.

Aged↗
PubMed1982

Urinary neopterine excretion in patient with genital cancer.

Urinary neopterine values in 96 healthy women were compared with those in a group of 63 patients with cancer of the genitals who had not yet undergone treatment. Significantly higher median neopterine levels were found in the patients with carcinoma (p less than 0.001). In the 63 cancer patients who had not yet been treated, the diagnosis was made correctly in 65% of the cases by monitoring neopterine levels. In the follow-up of 72 patients with cancer of the genitals in 74% the neopterine values corresponded with the clinico-roentgenological findings. In 22%, false positive neopterine values (no recurrence of the tumor), and in 4% false negative values (recurrence, or progression of the carcinoma) were observed. These results confirm previous reports concerning the significance of pteridine excretion in patients with cancer. However, more investigations have to be performed to establish the value of neopterine sampling in monitoring patients with malignant tumors.

Adult↗
PubMed1996

Neopterin and 7,8-dihydroneopterin induce apoptosis in the rat alveolar epithelial cell line L2.

The neopterin derivatives, neopterin and 7,8-dihydroneopterin, modulate the cellular oxidant-antioxidant balance as well as the expression of the inducible nitric oxide synthase (iNOS) gene. Since apoptosis can be induced by reactive oxygen intermediates and nitric oxide (NO) we investigated whether these neopterin derivatives induce apoptotic cell death. As model we selected the rat alveolar epithelial cell line L2. 24 h incubation of neopterin (1-1000 microM) as well as 7,8-dihydroneopterin (1-1000 microM) resulted in a significant increase of percent apoptotic cells (measured by FACS analysis). Coincubation of both pteridines with the cytomix (interferon-gamma plus tumor necrosis factor-alpha) led to a significantly higher apoptosis than the cytomix alone. In contrast to the cytomix, no iNOS gene expression and no NO release could be detected after incubation with neopterin or 7,8-dihydroneopterin. We conclude that neopterin and 7,8-dihydroneopterin are per se inducers of apoptosis which is not mediated by nitric oxide. This may be of importance in inflammatory pulmonary diseases associated with an activation of the cellular immune system.

Animals↗