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PubMed1987

Potential of urinary neopterin excretion in differentiating chronic non-A, non-B hepatitis from fatty liver.

Urinary neopterin excretion was measured in 26 patients with histologically proven chronic non-A, non-B hepatitis (16 chronic persistent hepatitis, 10 chronic active hepatitis) and in 16 patients with steatosis. The potential of neopterin levels to discriminate between the two patient groups was compared with that of standard laboratory variables. Neopterin levels and triglycerides were shown to be the best variables for discriminating between the hepatitis and fatty liver patients, neopterin being the more specific of the two. Neopterin excretion in chronic persistent hepatitis was not statistically different from that in chronic active hepatitis. In the absence of specific tests, increased neopterin excretion seems to be a useful marker for diagnosing chronic non-A, non-B hepatitis and particularly in differentiating it from fatty liver.

Adult↗
PubMed1998

Effects of hemoperfusion with polymyxin B-immobilized fibre on serum neopterin and soluble interleukin-2 receptor concentrations in patients with septic shock.

OBJECTIVE: the aim of the present study was to determine whether serum neopterin and soluble interleukin (IL)-2 receptor levels were related to the development of septic shock and whether polymyxin B-immobilized fibre (PMX-F) treatment affects these levels. METHODS: we examined 24 patients admitted to our intensive care unit with Gram-negative septic shock. Serum neopterin and soluble IL-2 receptor levels were measured using commercially available test kits. Patients were treated with direct hemoperfusion using PMX-F columns. RESULTS: fifteen out of 24 patients (63%) survived and were discharged from our hospitals within 30 days after PMX-F treatment. Blood endotoxin levels decreased significantly from 49.2+/-8.6 pg/ml to 13.2+/-4.4 pg/ml after PMX-F treatment. The pretreatment serum concentrations of neopterin and IL-2 receptor were significantly higher in the nine non-surviving patients with septic shock than in the 15 surviving patients (P<0.01) and 20 control subjects (P<0.001). Serum concentrations of neopterin and IL-2 receptor in patients with septic shock decreased significantly after PMX-F treatment (P<0.01). CONCLUSIONS: these data suggest that serum neopterin and IL-2 receptor concentrations may be prognostic indicators in patients with septic shock. PMX-F treatment may be effective for reducing serum neopterin and IL-2 receptor concentrations.

Adult↗
PubMed1996

Streptococcal erythrogenic toxins induce neopterin formation in human peripheral blood mononuclear cells but not in the human myelomonocytoma cell line THP-1.

We tested whether the exposure of human monocytic cells to streptococcal erythrogenic toxins A, B, C and a streptococcal-derived Mitogert BX is associated with synthesis of neopterin in vitro. Neopterin production was not induced when the human myelomono-cytoma cell line THP-1 was stimulated with these toxins, and there was only a slight co-stimulatory effect of streptococcal erythrogenic toxin A together with interferon-gamma stimulation. However, these toxins induced interferon-gamma and further neopterin production in peripheral blood mononuclear cells of three healthy individuals. This neopterin formation could be blocked by anti-human interferon-gamma. From our investigations we conclude that there is no direct effect of streptococcal erythrogenic toxins on neopterin production by monocytic cells. However, the data obtained in peripheral blood mononuclear cell culture imply that these toxins are able to stimulate neopterin production in humans via the induction of huge amounts of interferon-gamma.

Biopterins↗
PubMed2003

Neopterin as a potential modulator of tumor cell growth and proliferation.

The present article proposes tumor-promoting biochemical effects of the immunologically active pteridine-compound neopterin. Based on previous findings of interactions between neopterin and the cellular redox state, two major pathways of tumor progression are presented: (1) the inhibition of nitric oxide-induced apoptotic death of tumor cells via suppression of nitric oxide synthesis in the presence of neopterin; (2) the stimulatory effects of neopterin on the production and release of angiogenic growth factors. High serum neopterin concentrations are a common finding in tumor patients and correlate well with the fatal outcome of the disease. Affection of tumor tissue growth as well as formation of metastases by neopterin may provide an explanation for these clinical observations.

Apoptosis↗
PubMed1982

Determination of neopterine in human urine by reversed-phase high-performance liquid chromatography.

Since the analysis of urinary neopterine is important in diagnosing malignancy, a method has been developed for its rapid and sensitive separation and quantitation using high-performance liquid chromatography (HPLC) on reversed phase. Eluted neopterine is monitored by fluorescence at a excitation wavelength of 353 nm and measured at 438 nm. Separation was optimized by elution with 15 mmol/l potassium phosphate (pH 6.4) at a flow-rate of 0.8 ml/min. Urinary neopterine was related to creatinine with the aim of reducing variations due to fluctuating urinary concentrations. The proposed method has good performance characteristics and is not influenced by the presence of reduced neopterine in urine. Using this HPLC method, urinary neopterine related to creatinine was determined for 148 healthy male adults (mean neopterine/creatinine 113 mumol/mol), 146 healthy female adults (mean neopterine/creatinine 140 mumol/mol) 60 healthy children (mean neopterine/creatinine 163 mumol/mol). The neopterine levels for four healthy individuals were measured daily over a period of one month.

Adolescent↗
PubMed1999

Clinical and immunological significance of neopterin measurement in cerebrospinal fluid in patients with febrile convulsions.

Neopterin is synthesized mainly by monocytes/macrophages and is considered to be a marker for activation of the cellular immune system. It has been reported that cerebrospinal fluid (CSF) neopterin levels are significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or non-pleocytotic CSF. In this study levels of neopterin and interferon-gamma (IFN-gamma) were measured in children with non-pleocytotic CSF. The CSF neopterin levels were significantly higher in patients with typical febrile convulsions (FCs) (15.0 +/- 4.5 nmol/l) than in those with pyrexia without convulsions (6.5 +/- 2.7 nmol/l) or convulsions without pyrexia, namely, epilepsy (4.8 +/- 2.4 nmol/l). The CSF neopterin/serum neopterin ratio (C/S ratio) was also higher in patients with typical FCs (1.54 +/- 0.83) than in those with pyrexia without convulsions (0.32 +/- 0.18) or convulsions without pyrexia (0.77 +/- 0.28). Patients with prolonged FCs tended to have higher CSF neopterin levels than those with typical FCs. There was also a tendency for CSF IFN-gamma levels to be higher in patients with FCs than in those with pyrexia without convulsions or convulsions without pyrexia. The results of the present study suggest that some immune activation in the central nervous system (CNS) compartment may be related to the mechanisms of FCs.

Child, Preschool↗
PubMed2000

Neopterin and interleukin-8--prognosis in alcohol-induced cirrhosis.

BACKGROUND: Neutrophil cytotoxity and activated macrophages have been implicated in the pathogenesis of alcohol-induced liver disease. The aim of this study was to relate plasma levels of neopterin, a marker of activation of the cellular immune system, and IL-8, a neutrophil chemotactic factor, with severity of liver disease and prognosis in patients with alcohol-induced cirrhosis. METHODS: Plasma concentrations of neopterin and IL-8 were assessed in 81 patients with alcohol-induced cirrhosis admitted to the Department of Medicine B, Bispebjerg Hospital, Copenhagen, Denmark, and in 16 healthy controls. After a median follow-up period of 5 years, mortality and death causes were registered. The patients were divided into groups according to the major contributing cause of death: infection, upper gastrointestinal bleeding or hepatic coma. RESULTS: Neopterin and IL-8 levels were increased in the cirrhosis patients, but not significantly related to Child-Pugh classification. Five-year mortality was 67%. High neopterin levels (>upper quartile) were an independent predictor of death (p=0.01, Log rank and p<0.02, Cox). High IL-8 levels (>upper quartile) were of no significant prognostic value for overall mortality. Causes of death related mortality were as follows (Log rank): Neopterin; p=0.009, p=0.84 and p=0.94, and IL-8; p=0.36, p=0.002 and p=0.27, respectively, according to infection, bleeding and coma as causes of death. CONCLUSIONS: Neopterin and IL-8 plasma levels are raised in patients with alcohol-induced cirrhosis, and are predictive of mortality associated with infections and upper gastrointestinal bleeding, respectively.

Cause of Death↗
PubMed2002

Neopterin as a marker of immunostimulation: an investigation in anaesthetic workplaces.

Personnel working in operating theatres and recovery rooms are exposed to a variety of noxious substances. The results of studies of the effects of occupational exposure on immune parameters are conflicting. Neopterin is an acknowledged marker of immunostimulation. Urinary neopterin levels of 58 anaesthetists and anaesthetic nurses were measured over a 3-week period. Neopterin analyses were performed using high performance liquid chromatography. Neopterin levels were within the normal range for all subjects. Younger subjects (aged < or = 35 years) had significantly higher urinary neopterin concentrations than older subjects (aged > 35 years). The present study is the first to investigate the influence of anaesthetic exposure on neopterin levels. No evidence of immunostimulation was found.

Adult↗
PubMed2003

Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN).

BACKGROUND: Balkan endemic nephropathy (BEN) is of great clinical importance in restricted areas of Bulgaria, Serbia, Croatia, Bosnia, Herzegovina, and Romania, since the etiology of BEN is still unknown. METHODS: In urine samples from 48 patients (41 females and 7 males, aged 65.6 +/- 6.87 years) with BEN living in an endemic area of Vratza district, Bulgaria, neopterin concentrations were measured by high-pressure liquid chromatography (HPLC) and compared with other clinical and laboratory investigations, including creatinine, hemoglobin, and erythrocyte sedimentation rates (ESRs). RESULTS: Urinary neopterin concentrations were 263 +/- 128 (mean +/- SD; range, 78 to 786 micromol/mol creatinine), 24 (50%) of BEN patients presented with increased concentrations as compared to the established normal ranges. Average ESRs were increased (1 hour, 29.0 +/- 14.7 mm/hour) and hemoglobin was decreased (109.3 +/- 16.4 g/L). Hemoglobin correlated inversely with ESRs (rs = -0.787 and -0.780) and creatinine concentrations (r = -0.690, all P < 0.001), but not with neopterin concentrations. Neopterin concentrations also did not correlate with serum creatinine levels. There existed an age relationship of ESR, creatinine, and hemoglobin, but not of neopterin. Neopterin concentrations were slightly lower in five females with low titers of antibodies against local B1 hantavirus strain (P < 0.05). CONCLUSION: The findings can support an immune-mediated inflammatory process in the pathogenesis of BEN only in a subgroup of patients.

Aged↗
PubMed2002

Neopterin inhibits ATP-induced calcium release in alveolar epithelial cells in vitro.

BACKGROUND: Serum neopterin concentrations rise during activation of the cellular immune system. It is suggested that neopterin interacts with cellular redox mechanisms. This induces oxidative stress, which inhibits intracellular Ca2+ transients in various cell types. In type II alveolar epithelial cells, Ca2+ increase is considered involved in the exocytosis of surfactants. This exocytosis is disturbed during inflammation. AIMS: To clarify whether neopterin affects adenosine triphosphate (ATP)-induced Ca2+ transients in an alveolar epithelial cell line (L2). METHODS: Ca2+ transients were detected as fura-2 fluorescence by an image analysis system. RESULTS: Cells were exposed for 100 sec to ATP (1 microM, repeated four times). The first application of ATP induced an increase of the fluorescence ratio by approximately 100%, while the following stimulations resulted in smaller transients. In a second set of experiments, L2 cells were exposed to ATP or ATP + neopterin (100 nM), alternately. Simultaneous application of neopterin inhibited Ca2+ transients almost completely. CONCLUSIONS: Inhibition of Ca2+ transients by neopterin may lead to suppressed exocytosis of surfactant proteins in alveolar epithelial cells. This might contribute to the deterioration of pulmonary functions in the course of inflammatory processes.

Adenosine Triphosphate↗
PubMed1999

Neopterin derivatives modulate toxicity of reactive species on Escherichia coli.

Neopterin and 7,8-dihydroneopterin are released by human monocytes/macrophages upon stimulation with interferon-gamma. In parallel, a panel of highly reactive species is produced by macrophages as part of their cytotoxic armature, which is directed against microbial and viral challenge and against malignant growth. Recently, neopterin and 7,8-dihydroneopterin were shown to modulate the action of reactive species in vitro. In this study we investigated the impact of neopterin and 7,8-dihydroneopterin on the toxicity of reactive species, namely chloramine-T, H2O2, hypochlorite, nitrite, and formaldehyde, respectively. We studied the growth inhibition of Escherichia Coli (E. coli) by these toxic agents and its modulation by neopterin and 7,8-dihydroneopterin. Bacterial growth was monitored by optical density of suspension cultures at 600 nm. Compared to control experiments, neopterin enhanced toxicity of all reactive species tested except formaldehyde, while 7,8-dihydroneopterin reduced activity of hypochlorite and chloramine-T. No significant impact of the pteridines could be established for H2O2-mediated and formaldehyde-mediated growth inhibition. The data support the concept that neopterin and 7,8-dihydroneopterin produced during immune response in humans could be important to modulate the action of reactive species released in parallel.

Anti-Bacterial Agents↗
PubMed1999

Changes of serum and urinary neopterin concentrations in rats after partial hepatectomy.

OBJECTIVE: To investigate the changes in serum and urinary neopterin concentrations over time after partial hepatectomy in rats, and to find out if neopterin can be used as a marker of immunological response during the regulation of liver regeneration. DESIGN: Randomised experiment. SETTING: University hospital, Taiwan, R.O.C. SUBJECTS: 84 male Wistar rats weighing about 200g. INTERVENTIONS: Partial hepatectomy (67%) or sham operation (n = 42 in each group). MAIN OUTCOME MEASURES: Serum and urinary neopterin concentrations measured by radioimmunoassay preoperatively and on days 1, 2, 3, 5, 7, and 10 postoperatively. RESULTS: Serum neopterin concentrations increased and reached their peak on days 5 and 7 after partial hepatectomy. The urinary neopterin concentration showed a similar trend, but with a more pronounced increase on days 5 and 7. CONCLUSIONS: Serum and urinary neopterin concentrations can be used as markers of activated cell-mediated immunity in rats after partial hepatectomy.

Animals↗
PubMed2002

Human parvovirus Bb19 detection in asymptomatic blood donors: association with increased neopterin concentrations.

Serum neopterin concentrations were determined in 20,000 blood donations. For the 400 donations with neopterin concentrations above the 98 th percentile and another 1200 donations with neopterin concentrations in the lower range, results of human parvovirus (HPV) B19 tests were compared. Infectious specimens were identified by dot blot hybridization assay and polymerase chain reaction (PCR) that used the outer primers and detected 1 pg of HPV B19 DNA, corresponding to approximately 10(5) copies of the genome, in the specimens and by a nested PCR that detected 1-10 fg of DNA, corresponding to 10(2)-10(3) copies of the genome. Of 400 specimens with neopterin concentrations > or =12 nmol/L (98th percentile, current cutoff), 10 tested positive by dot blot hybridization assay (9 of these were confirmed by nested PCR). Among 1200 specimens with low neopterin concentrations (<12 nmol/L), no specimen containing HPV B19 DNA was detected. These findings suggest an association between elevated neopterin concentrations and HPV B19 infectivity.

Blood Donors↗
PubMed1993

Cerebrospinal fluid neopterin levels in 159 neurologically asymptomatic persons infected with the human immunodeficiency virus (HIV-1): relationship to immune status.

Monocytes and brain macrophage-microglial cells are thought to play a crucial role in the neurologic dysfunction associated with HIV-1 disease. Since neopterin is produced by monocytes-macrophages, we asked whether cerebrospinal fluid (CSF) neopterin levels increase before the onset of HIV-1 neurologic disease and whether they correlate with other CSF and peripheral blood immunologic parameters. In this study, CSF neopterin levels from 159 neurologically asymptomatic HIV-positive persons were found to increase as the blood CD4+ T-cell count decreased and as CSF IgG, IgG synthesis, IgG index, and beta 2-microglobulin increased. Neopterin levels in the CSF exceeded those in the serum in 32% of patients, while 25% had CSF levels > 13.5 nmol/liter. CSF neopterin levels vary with immune status, may reflect intrathecal production, and can be elevated in asymptomatic HIV-positive patients with normal neurologic examinations. Long-term follow-up of this patient population should be able to define the clinical correlation between CSF neopterin levels during the asymptomatic phase of HIV-1 disease and the risk of subsequent neurologic disease.

Biopterins↗
PubMed2005

Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris.

AIMS: Serum levels of neopterin, an immune modulator secreted by activated macrophages, are elevated in patients with acute coronary syndromes compared with stable angina patients and control subjects. In unstable angina, serum neopterin levels correlate with the presence of vulnerable coronary stenosis, multiple complex coronary lesions, and patient outcome. The present study assessed the prognostic significance of raised serum neopterin concentrations in patients with stable angina pectoris. METHODS AND RESULTS: We carried out a 1-year follow-up prospective study in 297 patients with chronic stable chest pain undergoing diagnostic coronary angiography. The primary study endpoint was the composite of non-fatal myocardial infarction, unstable angina, and cardiac death. Fifty-one patients (17.2%) had adverse coronary events during follow-up. Mean serum neopterin levels were significantly higher in patients with events compared with those without (P=0.02). On multiple regression analysis, neopterin levels (P=0.021), severity of coronary artery disease (P=0.009), and a history of previous myocardial infarction (P=0.001) were independent predictors of adverse events. CONCLUSIONS: Serum neopterin is an independent predictor of major adverse coronary events in patients with chronic stable angina pectoris. This marker of macrophage activation may be useful for risk stratification in patients with chronic stable angina.

Aged↗
PubMed1990

Immune activation during measles: interferon-gamma and neopterin in plasma and cerebrospinal fluid in complicated and uncomplicated disease.

To study T cell and macrophage activity during measles, levels of interferon-gamma (IFN-gamma) and neopterin in plasma and cerebrospinal fluid (CSF) were measured. Plasma levels of IFN-gamma were elevated in measles (1.17 +/- 0.27) compared with healthy adults (0.13 +/- 0.06, P less than .05) and children (0.14 +/- 0.06, P less than .01). Plasma levels of neopterin were elevated in measles (32.5 +/- 2.7) compared with healthy adults (5.3 +/- 2.9, P less than .0001), healthy children (12.1 +/- 4.0, P less than .001), and children with other infectious diseases (20.6 +/- 4.0, P less than .02). IFN-gamma was increased in measles primarily during rash; neopterin remained elevated for several weeks. Levels of neopterin showed a significant positive correlation with plasma levels of soluble interleukin-2 receptor and soluble CD8, two other parameters of T cell activation. Children with measles complicated by pneumonia had higher levels of neopterin in serum than those with uncomplicated disease. Children with measles complicated by autoimmune encephalomyelitis had higher levels of neopterin in CSF than those with noninflammatory neurologic disease but lower than those with central nervous system infections. Thus, IFN-gamma seems to be produced in vivo during acute measles virus infection; deficiency of this lymphokine does not appear to correlate with increased susceptibility to secondary infections.

Adolescent↗
PubMed1991

Cerebrospinal fluid and serum neopterin and biopterin in D-retrovirus-infected rhesus macaques (Macaca mulatta): relationship to clinical and viral status.

Increases in serum and cerebrospinal fluid (CSF) neopterin concentrations accompany many inflammatory diseases, including infection with HIV-1 and may reflect activation of guanosine triphosphate (GTP) cyclohydrolase 1 by gamma-interferon and other cytokines. In the present study, macaques with clinical simian AIDS (SAIDS) infected with the immunosuppressive type-D retrovirus D/1/California had increased concentrations of CSF neopterin but not of biopterin beginning soon after seroconversion. Normal neopterin concentrations in the CSF were found in macaques with SAIDS-related complex as well as asymptomatic, viremic macaques. CSF biopterin, serum neopterin and serum biopterin concentrations of D/1/California-infected macaques were not different from the levels in control animals. The increase in CSF neopterin may reflect local inflammatory responses and paralleled previously documented changes in L-tryptophan metabolism in these macaques. However, the absence of macrophage infiltrates in the brain of the infected macaques suggests a non-macrophage source of both increased CSF neopterin and tryptophan metabolites in the SAIDS macaques.

Animals↗
PubMedDate not supplied

Intraperitoneal fluid neopterin, nitrate, and tryptophan after regional administration of interleukin-12.

Activated monocytes-macrophages may be associated with antitumor activity, and activation of these cells by certain cytokines, primarily interferon gamma (IFN-gamma), can be indicated by alterations in the concentrations of neopterin, nitrate, or tryptophan. Specimens of peritoneal fluid were obtained from patients with intra-abdominal neoplasia who were undergoing treatment in a phase I trial of weekly intraperitoneal recombinant interleukin-12 (rhIL-12), an inducer of IFN-gamma. Concentrations of neopterin, nitrate, tryptophan, IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) were determined at various times during the first 48 hours in 11 patients who received intraperitoneal rhIL-12 in doses ranging from 100 to 1,500 ng/kg. An increase in peritoneal fluid nitrate concentrations was observed in nine of these patients. Increased concentrations of TNF-alpha and IFN-gamma were detected in 3 of 9 and 8 of 11 patients, respectively. Increased peritoneal fluid neopterin concentrations were detected by 24 hours after the injection in all patients studied. A significant increase in the ascitic fluid neopterin level could still be detected after 1 or 2 weeks of treatment (mean +/- standard error, 7.8 +/- 1.5 nM vs. 4.6 +/- 0.3 nM; Wilcoxon test, p = 0.0019), which is consistent with monocyte-macrophage activation. In contrast, the tryptophan concentration was lower (4.7 +/- 1.1 microM vs. 6.1 +/- 1.2 microM; p = 0.0428) after 1 or 2 weeks of treatment. There was a significant correlation between the dose of rhIL-12 and posttreatment neopterin concentrations (r(s) = 0.559, p = 0.0102). The intraperitoneal delivery of rhIL-12 appears to be associated with an immediate, sustained, and dose-dependent increase in peritoneal fluid neopterin, associated in most patients by an increase in IFN-gamma and in certain patients by an increase in nitrate and a decrease in tryptophan concentrations.

Abdominal Neoplasms↗