Neopterin (Np) is a metabolite of guanosine triphosphate in human body, which is produced by stimulation of interferon gamma (IFN-γ) released by activated T cells by monocyte-macrophages. A low molecular pyrimidine compound. It is stable in body fluids such as blood, urine, cerebrospinal fluid and pleural and ascites. It lasts for a long time and is not easily inactivated or degraded in the body. It reflects the "lymphocyte-macrophage axis". A good indicator of the state of cellular immune status. Clinical data show that organ transplantation, malignant tumors, infectious diseases, autoimmune diseases and cardiovascular diseases can be seen in the level of new fluids. Monitor the cellular immune activation and inflammatory response status, and then understand the disease progression and its activity.
Xinyi's biological function, also known as 6-D-red trihydroxypropionamidine, is not fully understood in its biological properties. It is mainly produced by mononuclear-macrophages in the body, and other cells, such as umbilical vein endothelium. Cells and cultured kidney epithelial cells can also release Np under the stimulation of IFN-γ, but the total amount of release is much less than that produced by macrophages. The stimulated T cell supernatant can stimulate the addition of macrophages. Each unit of IFN-γ can detect Np in the supernatant, while the addition of anti-IFN-γ monoclonal antibody can completely block Np release. In vitro, IFN-α can also induce Np, but IFN-α is required. The dose is at least 1000 times higher than IFN-γ to produce a considerable amount of Np. Other macrophage activation substances such as zymosan, phorbol ester, colony stimulating factor and IFN-β are unable to induce the formation of a considerable amount of Np, so activation IFN-γ produced by T cells is the most effective stimulator of Np release. However, lipopolysaccharide and tumor necrosis factor alpha (TNF-α) can enhance the release of Np by IFN-γ, in patients. Cytokines such as interleukin-2 (IL-2) induce T cell release of IFN-γ, thereby stimulating Np
IFN-γ and IL-2 are representative cytokines secreted by T helper cell 1 (TH1), which activate cellular immune system by regulating cytotoxic T cells, thus, viral infection, intracellular bacterial infection and Cells with predominantly cellular immune responses such as intracellular parasite infection may be associated with a significant increase in Np levels, so determination of Np levels in patients with these diseases can be used to monitor cellular immune activation status, while acute bacterial infections have only moderate Np levels. Elevated, at this time, the humoral immune response involving helper T cell type II (Th2) is dominant, and the characteristic factors are IL-4, -5, -6, -9, -10, -13. These cytokines cannot Induction of Np is induced.
Clinical application of new sputum determination Application in organ transplantation: The main clinical application to date for the determination of Np body fluids is to monitor whether recipients of organ transplantation have immune-related complications (rejection or infection). A continuous increase in morning urine or serum Np concentration often indicates a rejection or infection after organ transplantation. In the kidney transplantation, it is found that the elevation of Np is 4 days earlier than the clinical diagnosis. The high level of Np in the early stage after transplantation indicates that the survival time of the transplanted organ is very short. Np can also identify rejection and infection. Increased serum Np/creatinine ratio and rejection and infection (mainly cytomegalovirus infection) in the early stage of lung transplantation (within 21 days), but recurrence after 3 weeks The serum Np/creatinine ratio of the responding patients did not increase. At this time, the high Np/creatinine ratio was associated with infection, and the Np/creatinine ratio of the lung transplanted patients was significantly correlated with the soluble interleukin-2 receptor. Parallel measurement of Np concentration in urine and bile in liver transplantation can identify rejection and infection, because excessive excretion of Np in bile sweat is only seen in rejection after liver transplantation, rarely seen in cytomegalovirus infection or hepatitis. Similarly, the determination of Np concentration in the pancreatic secretion of pancreatic transplant patients can provide similar identification information. For bone marrow transplant patients, Np can be used to monitor the destruction of the immune system and the process of hematopoietic tissue reconstruction. It is also possible to predict the Np level after hematopoietic tissue reconstruction. Whether graft-versus-host reactions or viral infections can occur. In addition, patients receiving dead body transplants had significantly higher plasma Np levels 8 to 10 days after surgery than those receiving live organ transplants, indicating that the former had stronger cellular immune activation [1].
2. Np and malignant tumors: Malignant tumor cells behave differently from benign tumor cells and normal cell surfaces, thus activating the cellular immune system with elevated levels of Np. Almost all kinds of malignant tumors have blood and urine Np try to increase. However, serum Np levels in cervical carcinoma in situ are not elevated, and there may be no systemic cellular immune activation in patients with carcinoma in situ. The increase of serum Np level in patients with ovarian cancer has nothing to do with the stage of ovarian cancer. Wei Qichun et al [2] also showed that serum Np levels in lung cancer patients with different stages of disease were not statistically significant. Although Np levels and tumor size are ineffective, Np levels are significantly reduced or even up to normal levels, and when raised again, predicting tumor recurrence, in hematological malignancies, cervical or ovarian cancer, colon cancer, lung cancer, prostate cancer, In the study of hepatocellular carcinoma and oral squamous cell carcinoma, Np was found to independently predict the prognosis of the middle layer. High urine or serum Np concentration indicates poor prognosis and short survival time [3]. This may be due to the invasive malignant tumor, the stronger the cellular immune response stimulated, or the stronger the cellular immune response that the body uses to fight, but ultimately the body's immune system still cannot overcome the malignant progression of the tumor, and it is strong. The immune response leads to damage to the body, anemia, and cachexia are common complications of malignant tumors. Traditional tumor markers are the products or metabolites of tumor cells themselves, and their correlation with tumor growth and development is better than Np, but it can not predict the prognosis of patients [4].
3. The value of Np in infectious diseases: 100% increase in Np levels in viral infections, and is associated with disease activity, such as influenza, acute viral hepatitis, acute mumps, rubella, Epstein-Barr virus and cytomegalovirus infection, etc. The patient has an elevated level of Np before the onset of clinical symptoms, and serum antibodies can be detected before reaching the peak. Generally, serum antibodies can be detected 2 to 4 weeks after the elevation of Np, and Np levels are detected when serum antibodies appear. Reduced, if the pathogen has been cleared, Np can be reduced to normal levels. In chronic viral infections such as HIV (HIV) infection, when antibodies appear in serum, Np does not fall to normal levels. About 3/4 of HIV-infected patients have high clinical symptoms but still have higher The Np concentration, the higher the Np level in the incubation period, the faster the disease progresses. When the clinical symptoms of the acquired immunodeficiency syndrome (AIDS) break out, the Np level is further increased, and the quantitative polymerase chain reaction technique is used. Polymerase chain reaction (PCR) assay for HIV-1 RNA found that Np levels are also associated with viral load in vivo and reflect the efficacy of anti-HIV therapy.
Intracellular bacterial infection and viral infection mainly stimulate the cellular immune system, and the level of Np in patients is significantly increased. For example, the Np level in serum, urine and alveolar lavage fluid of patients with pulmonary tuberculosis is significantly higher than that of lung cancer and pneumonia patients, especially Urine Np is most obvious and is associated with tuberculosis lesions and mobility [5]. Horak was to be tested for urine Np levels in 7 children with pulmonary tuberculosis. It was found that children with drug resistance were nearly five times more common than those with non-resistant children. As for whether Np can reflect the drug resistance of tuberculosis, it needs more cases to confirm.
Intracellular parasitic infections such as acute malaria also have a higher concentration of Np, and Np levels can rapidly drop to normal within a few days after effective treatment against malaria. It is worth noting that the internal parasite load is negatively correlated with the Np body fluid level, indicating that when there are many parasites in the body, when the condition is serious, the cellular immunity of the body is converted to humoral immunity.
For acute non-intracellular bacterial infections, Np concentrations are usually at a lower level, so this humoral immunity predominates, so Np can be used to identify acute infections of viruses and bacteria with sensitivity and specificity superior to ESR and white blood cell counts. , but not as good as C-reactive protein and severe systemic infection (such as sepsis) patients with high levels of serum neopterin and are closely related to the occurrence and development of sepsis [6,7], may be a large number of bacterial toxins, lipids The plasma peroxide activates the cellular immune system.
4. Application of Np in autoimmune diseases: Clinical data show that Np levels are closely related to disease activity in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Wegener's granulomatosis and cutaneous muscle. Cao Yuelan et al [8] confirmed that the urinary Np level in patients with systemic lupus erythematosus was significantly positively correlated with disease activity index and erythrocyte sedimentation rate, and was related to clinical treatment effect. Cao Jianping [9] also found that serum and urine Np levels in patients with rheumatoid arthritis were significantly positively correlated with changes in erythrocyte sedimentation rate, soluble interleukin-2 receptor, and Stoke index, and were also associated with clinical efficacy. The new sputum in the human body is excreted by the kidneys. The collection of urine specimens is non-invasive and convenient, but the effect of renal function changes on the concentration of urinary neopterin should be excluded first. The influence of the research changes of Cao Yuelan et al [8], in order to eliminate the interference of different concentrations of urine on the concentration of new sputum, the results are expressed by urinary neoplasm (umol) / urine creatinine (mol), ie umol / molCr.
5. Application of Np in cardiovascular diseases: Coronary atherosclerosis and acute and chronic coronary syndromes, the release of various cytokines in the body activates the cellular immune system, and neutrophils and mononuclear cells are visible in the blood vessel wall and myocardium. - Macrophage infiltration, elevated serum Np levels, and associated with disease activity, Np can be used as an indicator of coronary disease activity [10]. Other infection indicators such as neutrophil counts and C-reactive protein have evidenced the role of inflammatory factors in atherosclerosis, but their correlation with disease activity is weaker than Np [11,12]. In addition, a follow-up survey of patients with hypertension [13] and chronic stable angina [14] found that patients with unstable angina or secondary myocardial infarction, sudden cardiac death and other cardiovascular events were less likely to have cardiovascular events than those with no cardiovascular events. The level of Np was high in the group, while the C-reactive protein was not significantly different between the two groups. It can be seen that Np is an independent predictor of cardiovascular events in patients with hypertension and chronic stable angina. This conclusion also confirms the hypothesis that there is cellular immune activation in the pathological process of acute coronary syndrome and acute myocardial infarction. Then, whether mononuclear/macrophage activation also triggers the occurrence and progression of cardiovascular events remains to be seen. Further research. Increased levels of Np are also seen in dilated cardiomyopathy and chronic myocarditis and are associated with graded cardiac function. 80% of patients with acute rheumatic fever have elevated Np concentrations, and Np concentrations can be used to assess cardiac involvement in patients with acute rheumatic fever.
6. Screening Np for blood donors can help improve blood transfusion safety factor: In recent years, with the development of serum technology and the clinical application of molecular biology techniques (such as PCR technology), there has been a great improvement in blood transfusion safety, but blood transfusion The risk of infection is still high. One is the existence of unknown pathogens or mutant new pathogens. Second, the window period or pathogens and their antibodies are concealed and missed. How to solve the above problems? In 1994, Austria recommended the use of Np as an adjunct to screening blood donors. Np is a non-specific cellular immune activation indicator. Almost all levels of Np infection are elevated and have increased before clinical symptoms appear. Earlier than regular laboratory tests. By screening the blood donors for Np levels, subclinical infections or potential immune system disorders are detected with increased chances, suspicious blood is excluded, thereby improving blood transfusion safety. Studies have shown that blood donors with serum Np concentrations above 10 nmol/L The cytomegalovirus infection rate is 19 times higher than that of 10 nmol/L or less, and the EB virus and parvovirus B19 infection rate is 3 times higher, and the hepatitis C infection rate is 7 times higher. It can be seen that the Np measurement is effective in screening blood donors for virus infection. It is effective. Of course, this application of Np is still controversial in the inter-medical world. The safety of blood transfusion in China needs to be systematically evaluated after in-depth research.
The summary has a slightly more immune-stimulated disease, and the level of Np in the body fluid is increased. Np is an early, sensitive indicator of cellular immune activation, which is often seen earlier than routine laboratory tests, and is associated with disease progression, especially activity. Sex is closely related. Monitoring Np levels also helps to understand the pathogenesis of related diseases. Np exists in a variety of body fluids, its properties are stable, and detection is convenient, thus overcoming the defects of some similar diagnostic indicators.
Xinyi's biological function, also known as 6-D-red trihydroxypropionamidine, is not fully understood in its biological properties. It is mainly produced by mononuclear-macrophages in the body, and other cells, such as umbilical vein endothelium. Cells and cultured kidney epithelial cells can also release Np under the stimulation of IFN-γ, but the total amount of release is much less than that produced by macrophages. The stimulated T cell supernatant can stimulate the addition of macrophages. Each unit of IFN-γ can detect Np in the supernatant, while the addition of anti-IFN-γ monoclonal antibody can completely block Np release. In vitro, IFN-α can also induce Np, but IFN-α is required. The dose is at least 1000 times higher than IFN-γ to produce a considerable amount of Np. Other macrophage activation substances such as zymosan, phorbol ester, colony stimulating factor and IFN-β are unable to induce the formation of a considerable amount of Np, so activation IFN-γ produced by T cells is the most effective stimulator of Np release. However, lipopolysaccharide and tumor necrosis factor alpha (TNF-α) can enhance the release of Np by IFN-γ, in patients. Cytokines such as interleukin-2 (IL-2) induce T cell release of IFN-γ, thereby stimulating Np
IFN-γ and IL-2 are representative cytokines secreted by T helper cell 1 (TH1), which activate cellular immune system by regulating cytotoxic T cells, thus, viral infection, intracellular bacterial infection and Cells with predominantly cellular immune responses such as intracellular parasite infection may be associated with a significant increase in Np levels, so determination of Np levels in patients with these diseases can be used to monitor cellular immune activation status, while acute bacterial infections have only moderate Np levels. Elevated, at this time, the humoral immune response involving helper T cell type II (Th2) is dominant, and the characteristic factors are IL-4, -5, -6, -9, -10, -13. These cytokines cannot Induction of Np is induced.
Clinical application of new sputum determination Application in organ transplantation: The main clinical application to date for the determination of Np body fluids is to monitor whether recipients of organ transplantation have immune-related complications (rejection or infection). A continuous increase in morning urine or serum Np concentration often indicates a rejection or infection after organ transplantation. In the kidney transplantation, it is found that the elevation of Np is 4 days earlier than the clinical diagnosis. The high level of Np in the early stage after transplantation indicates that the survival time of the transplanted organ is very short. Np can also identify rejection and infection. Increased serum Np/creatinine ratio and rejection and infection (mainly cytomegalovirus infection) in the early stage of lung transplantation (within 21 days), but recurrence after 3 weeks The serum Np/creatinine ratio of the responding patients did not increase. At this time, the high Np/creatinine ratio was associated with infection, and the Np/creatinine ratio of the lung transplanted patients was significantly correlated with the soluble interleukin-2 receptor. Parallel measurement of Np concentration in urine and bile in liver transplantation can identify rejection and infection, because excessive excretion of Np in bile sweat is only seen in rejection after liver transplantation, rarely seen in cytomegalovirus infection or hepatitis. Similarly, the determination of Np concentration in the pancreatic secretion of pancreatic transplant patients can provide similar identification information. For bone marrow transplant patients, Np can be used to monitor the destruction of the immune system and the process of hematopoietic tissue reconstruction. It is also possible to predict the Np level after hematopoietic tissue reconstruction. Whether graft-versus-host reactions or viral infections can occur. In addition, patients receiving dead body transplants had significantly higher plasma Np levels 8 to 10 days after surgery than those receiving live organ transplants, indicating that the former had stronger cellular immune activation [1].
2. Np and malignant tumors: Malignant tumor cells behave differently from benign tumor cells and normal cell surfaces, thus activating the cellular immune system with elevated levels of Np. Almost all kinds of malignant tumors have blood and urine Np try to increase. However, serum Np levels in cervical carcinoma in situ are not elevated, and there may be no systemic cellular immune activation in patients with carcinoma in situ. The increase of serum Np level in patients with ovarian cancer has nothing to do with the stage of ovarian cancer. Wei Qichun et al [2] also showed that serum Np levels in lung cancer patients with different stages of disease were not statistically significant. Although Np levels and tumor size are ineffective, Np levels are significantly reduced or even up to normal levels, and when raised again, predicting tumor recurrence, in hematological malignancies, cervical or ovarian cancer, colon cancer, lung cancer, prostate cancer, In the study of hepatocellular carcinoma and oral squamous cell carcinoma, Np was found to independently predict the prognosis of the middle layer. High urine or serum Np concentration indicates poor prognosis and short survival time [3]. This may be due to the invasive malignant tumor, the stronger the cellular immune response stimulated, or the stronger the cellular immune response that the body uses to fight, but ultimately the body's immune system still cannot overcome the malignant progression of the tumor, and it is strong. The immune response leads to damage to the body, anemia, and cachexia are common complications of malignant tumors. Traditional tumor markers are the products or metabolites of tumor cells themselves, and their correlation with tumor growth and development is better than Np, but it can not predict the prognosis of patients [4].
3. The value of Np in infectious diseases: 100% increase in Np levels in viral infections, and is associated with disease activity, such as influenza, acute viral hepatitis, acute mumps, rubella, Epstein-Barr virus and cytomegalovirus infection, etc. The patient has an elevated level of Np before the onset of clinical symptoms, and serum antibodies can be detected before reaching the peak. Generally, serum antibodies can be detected 2 to 4 weeks after the elevation of Np, and Np levels are detected when serum antibodies appear. Reduced, if the pathogen has been cleared, Np can be reduced to normal levels. In chronic viral infections such as HIV (HIV) infection, when antibodies appear in serum, Np does not fall to normal levels. About 3/4 of HIV-infected patients have high clinical symptoms but still have higher The Np concentration, the higher the Np level in the incubation period, the faster the disease progresses. When the clinical symptoms of the acquired immunodeficiency syndrome (AIDS) break out, the Np level is further increased, and the quantitative polymerase chain reaction technique is used. Polymerase chain reaction (PCR) assay for HIV-1 RNA found that Np levels are also associated with viral load in vivo and reflect the efficacy of anti-HIV therapy.
Intracellular bacterial infection and viral infection mainly stimulate the cellular immune system, and the level of Np in patients is significantly increased. For example, the Np level in serum, urine and alveolar lavage fluid of patients with pulmonary tuberculosis is significantly higher than that of lung cancer and pneumonia patients, especially Urine Np is most obvious and is associated with tuberculosis lesions and mobility [5]. Horak was to be tested for urine Np levels in 7 children with pulmonary tuberculosis. It was found that children with drug resistance were nearly five times more common than those with non-resistant children. As for whether Np can reflect the drug resistance of tuberculosis, it needs more cases to confirm.
Intracellular parasitic infections such as acute malaria also have a higher concentration of Np, and Np levels can rapidly drop to normal within a few days after effective treatment against malaria. It is worth noting that the internal parasite load is negatively correlated with the Np body fluid level, indicating that when there are many parasites in the body, when the condition is serious, the cellular immunity of the body is converted to humoral immunity.
For acute non-intracellular bacterial infections, Np concentrations are usually at a lower level, so this humoral immunity predominates, so Np can be used to identify acute infections of viruses and bacteria with sensitivity and specificity superior to ESR and white blood cell counts. , but not as good as C-reactive protein and severe systemic infection (such as sepsis) patients with high levels of serum neopterin and are closely related to the occurrence and development of sepsis [6,7], may be a large number of bacterial toxins, lipids The plasma peroxide activates the cellular immune system.
4. Application of Np in autoimmune diseases: Clinical data show that Np levels are closely related to disease activity in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Wegener's granulomatosis and cutaneous muscle. Cao Yuelan et al [8] confirmed that the urinary Np level in patients with systemic lupus erythematosus was significantly positively correlated with disease activity index and erythrocyte sedimentation rate, and was related to clinical treatment effect. Cao Jianping [9] also found that serum and urine Np levels in patients with rheumatoid arthritis were significantly positively correlated with changes in erythrocyte sedimentation rate, soluble interleukin-2 receptor, and Stoke index, and were also associated with clinical efficacy. The new sputum in the human body is excreted by the kidneys. The collection of urine specimens is non-invasive and convenient, but the effect of renal function changes on the concentration of urinary neopterin should be excluded first. The influence of the research changes of Cao Yuelan et al [8], in order to eliminate the interference of different concentrations of urine on the concentration of new sputum, the results are expressed by urinary neoplasm (umol) / urine creatinine (mol), ie umol / molCr.
5. Application of Np in cardiovascular diseases: Coronary atherosclerosis and acute and chronic coronary syndromes, the release of various cytokines in the body activates the cellular immune system, and neutrophils and mononuclear cells are visible in the blood vessel wall and myocardium. - Macrophage infiltration, elevated serum Np levels, and associated with disease activity, Np can be used as an indicator of coronary disease activity [10]. Other infection indicators such as neutrophil counts and C-reactive protein have evidenced the role of inflammatory factors in atherosclerosis, but their correlation with disease activity is weaker than Np [11,12]. In addition, a follow-up survey of patients with hypertension [13] and chronic stable angina [14] found that patients with unstable angina or secondary myocardial infarction, sudden cardiac death and other cardiovascular events were less likely to have cardiovascular events than those with no cardiovascular events. The level of Np was high in the group, while the C-reactive protein was not significantly different between the two groups. It can be seen that Np is an independent predictor of cardiovascular events in patients with hypertension and chronic stable angina. This conclusion also confirms the hypothesis that there is cellular immune activation in the pathological process of acute coronary syndrome and acute myocardial infarction. Then, whether mononuclear/macrophage activation also triggers the occurrence and progression of cardiovascular events remains to be seen. Further research. Increased levels of Np are also seen in dilated cardiomyopathy and chronic myocarditis and are associated with graded cardiac function. 80% of patients with acute rheumatic fever have elevated Np concentrations, and Np concentrations can be used to assess cardiac involvement in patients with acute rheumatic fever.
6. Screening Np for blood donors can help improve blood transfusion safety factor: In recent years, with the development of serum technology and the clinical application of molecular biology techniques (such as PCR technology), there has been a great improvement in blood transfusion safety, but blood transfusion The risk of infection is still high. One is the existence of unknown pathogens or mutant new pathogens. Second, the window period or pathogens and their antibodies are concealed and missed. How to solve the above problems? In 1994, Austria recommended the use of Np as an adjunct to screening blood donors. Np is a non-specific cellular immune activation indicator. Almost all levels of Np infection are elevated and have increased before clinical symptoms appear. Earlier than regular laboratory tests. By screening the blood donors for Np levels, subclinical infections or potential immune system disorders are detected with increased chances, suspicious blood is excluded, thereby improving blood transfusion safety. Studies have shown that blood donors with serum Np concentrations above 10 nmol/L The cytomegalovirus infection rate is 19 times higher than that of 10 nmol/L or less, and the EB virus and parvovirus B19 infection rate is 3 times higher, and the hepatitis C infection rate is 7 times higher. It can be seen that the Np measurement is effective in screening blood donors for virus infection. It is effective. Of course, this application of Np is still controversial in the inter-medical world. The safety of blood transfusion in China needs to be systematically evaluated after in-depth research.
The summary has a slightly more immune-stimulated disease, and the level of Np in the body fluid is increased. Np is an early, sensitive indicator of cellular immune activation, which is often seen earlier than routine laboratory tests, and is associated with disease progression, especially activity. Sex is closely related. Monitoring Np levels also helps to understand the pathogenesis of related diseases. Np exists in a variety of body fluids, its properties are stable, and detection is convenient, thus overcoming the defects of some similar diagnostic indicators.
API (Active Pharmaceutical Ingredient) refers to a substance or substance combination used in manufacturing a drug product. API also refers to the active or central ingredient in the product which causes the direct effect on the disease diagnosis, prevention, treatment or cure. While API is the active component of a drug, excipients are the inactive or inert substances present in a drug.
An API starting material, usually a defined chemical property purchased in the market place or produced in-house, is used in the production of an API.
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