Effect of Long-Term Anti-CD4 or Anti-CD8 Treatment on the Development

人参皂苷G-Rh2通过调节脂质代谢与免疫改善小鼠代谢综合征①黄容容②张子君解梦园苟静李晴马坤向明（华中科技大学同济医学院药学院生物药学系，武汉430030）中图分类号R967文献标志码A文章编号1000-484X（2022）09-1030-07［摘要］目的：研究人参皂苷G-Rh2对高脂饮食（HFD）诱导小鼠代谢综合征（MS）的治疗效果和作用机制。

方法：从小鼠体质量、胰岛素敏感性、血脂水平和肝脏功能方面评价G-Rh2对MS小鼠的治疗效果，广靶脂质代谢组学检测肝脏中脂质代谢物变化，ELISA检测血清中TNF-α、IL-6水平，流式细胞术检测脾脏、胸腺中CD4+T、CD8+T细胞、NK细胞和骨髓来源的抑制性细胞（MDSCs）数量。

结果：G-Rh2明显减少MS小鼠的体质量和脂肪量，提高胰岛素敏感性，降低血脂总胆固醇（TC）、游离脂肪酸（NEFA）和低密度脂蛋白胆固醇（LDL-C）水平，防止肝脏脂质堆积。

G-Rh2改变肝脏中脂质代谢模式，下调74种脂质代谢物，主要包括三酰甘油（TGs）和磷脂酰胆碱（PCs）两大类。

G-Rh2降低血清中TNF-α和IL-6含量，平衡脾脏中CD4+T/MDSCs比例，减少肝脏中炎症细胞浸润。

结论：G-Rh2对HFD诱导的小鼠MS有治疗作用，通过调节肝脏脂质代谢和抑制炎症双重途径实现。

［关键词］代谢综合征；人参皂苷G-Rh2；脂质代谢；免疫Ginsenoside Rh2ameliorates metabolic syndrome in high-fat diet induced obese mice by regulating lipid metabolism and immunityHUANG Rongrong，ZHANG Zijun，XIE Mengyuan，GOU Jing，LI Qing，MA Kun，XIANG Ming.Department of Biological Medicine，School of Pharmacy，Tongji Medical College，Huazhong University of Science and Technology，Wuhan430030，China［Abstract］Objective：To explore the therapeutic effect and mechanism of G-Rh2on metabolic syndrome（MS）in high-fat diet（HFD）induced obese mice.Methods：The therapeutic effect of G-Rh2on MS mice was evaluated by body weight，insulin sensi⁃tivity，blood lipid level and liver function.The changes of lipid metabolites in liver were investigated by non-targeted lipid metabolo⁃mics technology.ELISA kits were used to detect TNF-αand IL-6in serum.Immune cells CD4+T，CD8+T，NK cells and bone marrow-derived suppressor cells（MDSCs）in spleen and thymus were detected by flow cytometer.Results：G-Rh2significantly reduced body weight，and serum lipids level especially TC，NEFA，LDL-C of MS mice.It simultaneously alleviated insulin resistance and protected liver from steatohepatitis.Further，G-Rh2down-regulated74lipid metabolites in liver，mainly including triglycerides（TGs）and phos⁃phatidylcholine（PCs），which suggested G-Rh2changed the liver metabolism pattern.On the other hand，G-Rh2reduced the inflam⁃matory cells infiltration in liver and TNF-α，IL-6in serum.And it balanced the ratio of CD4+T cells/MDSCs in spleen，which played an anti-inflammatory effect.Conclusion：G-Rh2has a therapeutic effect on MS in HFD induced obese mice by regulating liver lipid metabolism and inhibiting regional inflammation.［Key words］Metabolic syndrome；Ginsenoside Rh2；Lipid metabolism；Immunity代谢综合征（metabolic syndrome，MS）是多种代谢紊乱症候群在同一个体聚集的慢性疾病，表现为高血糖、高血压、血脂异常、腹部肥胖等，易诱发糖尿病、脂肪肝病以及心血管疾病［1-2］。

Genes, autoimmunity and pathogenesis of rheumatic heart diseaseL Guilherme1, KF Köhler1, E Postol1, J Kalil21 Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo;Institute for Immunology Investigation, National Institute for Science and Technology, University of São Paulo, São Paulo, Brazil2 Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo;Institute for Immunology Investigation, National Institute for Science and Technology, University of São Paulo, São Paulo;Clinical Immunology and Allergy Division, School of Medicine, University of São Paulo, São Paulo, BrazilClick here for correspondence address and emailAbstractPathogenesis of rheumatic heart disease (RHD) remains incompletely understood. Several genes associated with RHD have been described; most of these are involved with immune responses. Single nucleotide polymorphisms in a number of genes affect patients with RHD compared to controls. Molecular mimicry between streptococcal antigens and human proteins, including cardiac myosin epitopes, vimentin and other intracellular proteins is central to the pathogenesis of RHD. Autoreactive T cells migrate from the peripheral blood to the heart and proliferate in the valves in response to stimulation with specific cytokines. The types of cells involved in the inflammation as well as different cytokine profiles in these patients are being investigated. High TNF alpha, interferon gamma, and low IL4 are found in the rheumatic valve suggesting an imbalance between Th1 and Th2 cytokines and probably contributing to the progressive and permanent valve damage. Animal model of ARF in the Lewis rat may further contribute towards understanding the ARF.Keywords: Autoimmunity, rheumatic Heart disease, susceptibility genesHow to cite this URL:Guilherme L, Köhler KF, Postol E, Kalil J. Genes, autoimmunity and pathogenesis of rheumatic heart disease. Ann Pediatr Card [serial online] 2011 [cited 2012 Nov 2];4:13-21. Availablefrom: /text.asp?2011/4/1/13/79617Rheumatic heart disease (RHD) is still a major health problem in several countries due to the heart lesions that follow a rheumatic fever (RF) episode in 30-45% of patients. The incidence of acute RF (ARF) in some developing countries exceeds 50 per 100,000 children. The worldwide prevalence of RHD is at least 15.6 million cases, and this disease is responsible for around 233,000 deaths/year. [1] RHD results from autoimmune reactions triggered by an untreated S. pyogenes throat infection leading to severe valvular damage in genetically susceptible individuals. Recurrences of ARF play an important role in the worsening of valvularlesionss. [2],[3]In the present review, we focus on genetic susceptibility factors, their role in the development of RF and RHD, and the mechanisms that lead to autoimmune reactions and permanent valvular damage. Animal models of the disease will also be discussed, as will prospective vaccines for the prevention of RF and RHD.Innate and Adaptive Immune Responses : A Brief ReviewProtection against pathogens in the humans relies on complex interactions between innate and adaptive immunity. Most of the pathogens that enter the body are recognized initially by the innate immune system. [4]This defense mechanism is not antigen-specific and is instead focused on the recognition of a limited number of specific patterns that are shared by groups of pathogens (pathogen-associated molecular patterns - PAMPs) by pattern recognition receptors (PRRs) in the host. These PRRs can be soluble in human serum or cell-associated. [5],[6]The molecules that initiate the complement cascade are examples of soluble PRRs. The complement system is part of the innate immune system and consists of many proteins involved in a cascade of proteolysis and protein complex assembly that culminates in the elimination of invading pathogens. [6] Several components of the bacterial cell surface combine with PRRs such as Ficolin family of proteins, or Mannan binding lectins (MBL). These complexes, in turn combine with serine proteases and lead to complement activation via lectin pathway resulting in opsonophagocytosis of the invading pathogen, apoptosis, or modulation of inflammation. [7],[8],[9],[10]Toll-like receptors (TLRs) are pivotal cell-associated PRRs in the innate immune system. These receptors are capable of recognizing a wide spectrum of organisms, including viruses, bacteria and other parasites, and are classified into different groups based on their localization (cell surface or intracellular) and the type of PAMPs they recognize. TLR activation leads to the production of proinflammatory cytokines that enable macrophages and dendritic cells (DC) to eliminate invading pathogens. DCs can stimulate T cell expansion and differentiation, initiating an adaptive immune response. [4] The molecules produced during the innate immune response act as signals to activate adaptive immune responses. Antigen presenting cells (APCs), such as DCs, are activated and express costimulatory (CD80 and CD86) and MHC molecules on their cell surface that enable these cells to present processed antigens to T cells through the T cell receptor (TCR). Class I MHC molecules, such as HLA-A, -B and -C, present peptides derived from intracellular pathogens to CD8 + T cells, while class II MHC molecules, such as HLA-DR, -DQ and -DP, present peptides derived from extracellular pathogens to CD4 + T cells, which secrete a wide range of cytokines and have both effector and regulatory roles. Cytokines such as TNF-a and IFN-g act at the site of infection and can affect pathogensurvival and control the immune response. Activation of CD4 + T cells not only leads to the expansion of CD4 + effector cells, but also can promote the expansion and differentiation of antigen-specific CD8 + T cells and B cells. [4]CytokinesCytokines seem to play a pivotal role in the activation of immunological and inflammatory responses in RF. It has been shown that peripheral blood mononuclear cells (PBMC) from children with RF produce more TNF-α than heal thy controls. [20] Moreover, interleukin-6 (IL-6) and TNF-α are considered inducers of the acute phase of RF and are strongly correlated with C-reactive protein. [21],[22]TNF-α is a proinflammatory cytokine that has been associated with the severity of different autoimmune and inflammatory diseases. The gene that encodes this cytokine is located within the MHC region on chromosome 6p21.3. This region is highly polymorphic, and the TNF-alpha gene also contains a large number of polymorphisms. [23] Some of these were investigated in RF/RHD patients in different countries. An SNP in the promoter region of TNF-alpha (-308A) was associated with susceptibility to RHD in Mexico, Turkey, Brazil, and Egypt. [21],[22],[23],[24],[25],[26] The TNF-alpha -238G allele was also associated with RHD in Mexican and Brazilian patients. [24],[25] The TNF-alpha gene has a proinflammatory effect and is probably associated with the exacerbation of the inflammatory response in RF/RHD patients who present with high serum TNF-α levels[20],[22],[27],[28] and large numbers of TNF-α-producing cells in the throat and valves. [29]Polymorphisms in other cytokine genes have also been investigated and seem to be involved with the disease. These include TGF beta1, [30],[31] interleukin-1 receptor antagonist (IL1Ra), [32] interleukin 10, [21] amongst others. In Taiwanese RHD patients, both the -509T and 869T alleles of TGF beta 1 were found to be risk factors for the development of valvular RHD lesions. [30] Similar results were found in Egyptian patients. [31] RHD patients from Egypt and Brazil with severe carditis showed low frequencies of allele 1 for IL1Ra, suggesting the absence of control of the inflammatory process. [21],[32]Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines, together with TGF-β and IL-35. It is produced by activated immune cells, especially monocytes/macrophages and T cell subsets, including regulatory T cells (Tr1 and Treg) and Th1 cells. IL-10 acts through a transmembrane receptor complex, and regulates the functions of many different immune cells. [33]The gene encoding human IL-10 is located on chromosome 1. A large number of polymorphisms have been identified in the IL-10 gene promoter. The genotype IL-10 -1082G/A that is overrepresented in RHD Egyptian patients is associated with the development of multiple valvular lesions (MVL) and with the severity of RHD. [21] More recently, polymorphism in cytotoxic T cell Lymphocyte antigen 4 (CTLA-4), which is a negative regulator of T cell proliferation has also been shown in Turkish RHD patients.[34]Human Leucocyte AntigenHuman leucocyte antigen (HLA) molecules are encoded by the HLA genes (-A, -B, -C, -DR, -DQ and -DP), which are located on the short arm of human chromosome 6. Early studies of susceptibility for RF/RHD pointed out the association of the disease with several HLA class II alleles, mainly those encoded by the DR and DQ genes.Several HLA class II alleles were described in locations around the world [Figure 2]. [35],[36]Figure 2: RF/RHD associated HLA class II alleles:distribution around the world Several identifiedalleles by serology in the 80`s and/or molecularbiology after the 90`s were shown. Americas: (USA,Mexico, Martinique, South of Brazil); Asia:(Paquistan-Kashmir, North India, Latvia, Japan,South China), United Arab Emirates: (Saudi Arabia)Europe-Asia: (Turkey), Africa: (South Africa andEgypt)Click here to viewThe HLA-DR7 allele that was found in Brazilian, Turkish, Egyptian, and Latvian patients could be considered the HLA class II gene that is most consistently associated with RF/RHD. HLA-DR4 and -DR7 are associated with HLA-DR53 [Figure 2]. In addition, the association of HLA-DR7 with some HLA-DQB or -DQA alleles may be related to the development of multiple valvular lesions (MVL) in RHD patients in Egypt and in Latvia. [37],[38],[39]The molecular mechanism by which HLA class II molecules confer susceptibility to autoimmune diseases is not clear. As mentioned above, the role of HLA class II molecules is to present antigens to the TCR, leading to the recruitment of large numbers of CD4 + T cells that specifically recognize antigenic peptides from extracellular pathogens and the activation of adaptive immune responses. Therefore, the associated alleles probably encode molecules that facilitate the presentation of some streptococcal peptides to T cells that later trigger autoimmune reactions mediated by molecular mimicry.In summary, several alleles of the HLA class II genes appear to be the dominant contributors to the development of RF and RHD. Polymorphisms (SNPs and variable number of tandem repeat sequences of nucleotides) in genes involved with inflammatory responses and host defenses against pathogens that are associated with disease probably contribute to the development of valvular lesions and can determine the type of rheumatic valvular lesions(stenosis, regurgitation, or both) that occur in RHD patients.Rheumatic Fever and Rheumatic Heart Disease areMediated by Molecular Mimicry Between S.Pyogenes andHuman ProteinsMolecular mimicry between components of B hemolyticus streptococci and human heart tissues is the central problem in the pathogenesis of ARF and RHD. The precise mechanisms are being investigated for many years, and some real progress in the understanding of the pathogenesis is occurring slowly. [40],[41],[42],[43]Both T and B lymphocytes can recognize pathogenic and self antigens via four different types of molecular mimicry: (1) identical amino acid sequences, (2) homologous but non-identical sequences, (3) common or similar amino acid sequences of different molecules (proteins, carbohydrates) and (4) structural similarities between the microbe or environmental agent and its host.[43],[44] Autoimmune diseases from molecular mimicry may be facilitated because of the phenomena of epitope spreading and TCR degeneracy. Epitope spreading is the mechanism by which an ongoing immune response leads to reactivity against epitopes that are distinct from the original disease-inducing epitope [43],[45] and degeneracy of TCRs, which allows the recognition of a broad spectrum of antigens (self and microbial antigens) by the same T lymphocyte through it`s receptor. [41],[42],[46]The M protein is the most important antigenic structure of the S. pyogenes and shares structural homology with a-helical coiled-coil human proteins such as cardiac myosin, tropomyosin, keratin, laminin, vimentin and several valvular proteins. [40],[41],[42],[47]Several studies done in the last 50 years described the presence of cross-reactivity between human proteins and streptococcal antigens recognized by antibodies. [40] Among these human proteins, cardiac myosin and vimentin seem to be the major targets of cross-reactive reactions, along with other intracellular valvular proteins. N-acetyl ß-D-glucosamine, a polysaccharide present in streptococcal cell wall, induces cross-reactivity against laminin, an extracellular matrix alpha helical coiled-coil protein present in the valves. [40] By using affinity purified anti-myosin antibodies, Cunningham΄s group identified a five amino acid (Gln-Lys-Ser-Lys-Gln) epitope of the N-terminal M proteins of serotypes 5 and 6 (M5, M6) as being cross-reactive with cardiac myosin. [40]The interplay of humoral and cellular immune responses in RHD was recently demonstrated by Cunningham΄s group through two elegant studies. They showed that, in rheumatic carditis, antibodies that cross-react with streptococcal and human proteins bind to the endothelial surface and upregulate the adhesion molecule VCAM-1 [48] , leading to inflammation, cellular infiltration and valve scarring. [49] These data suggest that ARF may result from initial antibody mediated damage that later may be perpetuated by cell mediated inflammation. [50]Although antibodies in the sera of RF/RHD patients cross-react with several human proteins, we demonstrated that rheumatic heart disease lesions are mediated mainly by inflammatory cells and CD4 + T lymphocytes. [51]Studies performed in the last 25 years showed that CD4 + T cells are the major effectors of autoimmune reactions in the heart tissue in RHD patients. [51],[52],[53] The in vitro reactivity of peripheral T cells from RHD patients was evaluated in an early study that showed that these cells were able to recognize a 50- to 54-kDa myocardial protein fraction indicating autoreactivity to heart antigens, which was probably caused by streptococcal infection. [54] The role of T cells in the pathogenesis of RF and RHD was demonstrated through the analysis of heart-tissue infiltrating T cell clones. We demonstrated for the first time that M5 protein peptides (residues 81-96 and 83-103) displayed cross-reactivity with valvular proteins by molecular mimicry. [51] We also showed that valve-infiltrating T cells recognized cardiac myosin peptides by molecular mimicry and epitope spreading mechanisms. [55]These immunodominant M5 epitopes were preferentially recognized by peripheral T lymphocytes from RHD patients, when compared with normal individuals, mainly in the context of HLA-DR7. [56] These results suggested that autoreactive T cells migrate from the periphery to the site of heart lesions. Similarly, Yoshinaga et al. [57] reported that T cell lines derived from heart valve specimens and PBMC from RF and RHD patients react with cell wall and membrane streptococcal antigens. These lymphocytes, however, did not cross-react with the M protein or mammalian cytoskeletal proteins. [57]Recently, two studies demonstrated mimicry between cardiac myosin and the streptococcal M protein and pointed out different patterns of T cell antigen cross-recognition. One of them focused on peripheral T cell clones from one patient with RHD, which recognized different alpha helical coiled-coil proteins, such as the streptococcal M protein, myosin, laminin and tropomyosin. [58]The other study focused on the reactivity of intralesional T cell clones derived from myocardium and valvular tissue of six RHD patients against cardiac myosin, the streptococcal M5 protein and valve-derived proteins. A high frequency of reactive T cell clones was found (63%). These T cells displayed three patterns of cross-reactivity: (1) cardiac myosin and valve-derived proteins; (2) cardiac myosin and streptococcal M5 peptides; and (3) cardiac myosin, streptococcal M5 peptides and valve-derived proteins.[55]Using a proteomics approach, we showed that T cells recognize vimentin, further supporting the role of this protein as a putative autoantigen involved in rheumatic lesions. In addition, we identified myocardial and valvular autoantigens that were recognized by heart-infiltrating and peripheral T cells from RF/RHD patients. Novel heart tissue proteins were identified, including disulfide isomerase ER-60 precursor (PDIA3) protein and a 78-kDa glucose-regulated protein precursor (HSPA5). [59] However, their role in RHD pathogenesis and other autoimmune diseases is not clear.As mentioned above, both epitope spreading and the degeneracy of T cell receptors contributed to the amplification of cross-reactivity that leads to tissue damage.By using a molecular approach, we evaluated Vb chain usage by TCRs and the degree of clonality of heart-tissue infiltrating T cells. In RHD, the autoreactive T lymphocytes that infiltrate both the myocardium and the valves were identified in oligoclonal expansions by analyzing their TCRs. A high number of T cell oligoclonal expansions were found in the valvular tissue, indicating that specific and cross-reactive T cells migrate to the valves. [49]An effective immune response depends on cytokine production. CD4 + T helper cells are crucial regulators of the adaptive immune response. Antigen-activated CD4 + T cells become polarized toward a Th1 or Th2 phenotype based on the cytokines they secrete. Th1 cells are involved with cellular immune response and produce IL-2, IFN-γ and TNF-α. Th2 cells mediate humoral and allergic immune responses and produce IL-4, IL-5 and IL-13. A new lineage of CD4 + T cells (Th17) was recently described and is characterized by the production of IL-17. In vitro studies indicated a proinflammatory function for IL-17, and its expression was found to be associated with some inflammatory and autoimmune diseases. [60],[61]The role of cytokines in RF/RHD was first evaluated by examining the sera of patients and peripheral mononuclear cells stimulated by streptococcal antigens. These samples showed increased amounts of proinflammatory cytokines (IL-1, IL-6, TNF-a and IFN-g). [62] Immunohistochemistry on heart tissue (myocardium and valves) from acute and chronic RHD patients, showed a large number of mononuclear cells able to secrete TNF-a, IFN-g and the regulatory cytokine IL-10. Importantly, while a significant number of IL-4 + cells were found in the myocardium, these cells were very scarce in valve lesions in RHD patients. It is important to remember that valve damage and not myocarditis is the main problem in ARF. These observations indicated a role for balanced Th1/Th2 cytokines in healing myocarditis and in the induction of progressive and permanent valve damage. [29] IL-17 and Il-23 (Th17 cytokines) were recently analyzed by immunohistochemistry in both myocardium and valvular tissue from RHD patients. We observed a large number of IL-17 + and IL-23 + heart-tissue infiltrating cells (unpublished results), showing that these cytokines also play an important role in the development of heart lesions.Animal Models of RF/RHDHumans are unique hosts for S. pyogenes infections.Several studies (in mice, rats, hamsters, rabbits and primates) have been done to find a suitable animal model in which to examine the autoimmune process leading to RF/RHD with little success. [63] In the last decade, a model in Lewis rats has been developed that appears to be useful for the study of RF/RHD. These rats have already been used to induce experimental autoimmune myocarditis and study the pathogenesis of RF/RHD. [64],[65],[66]Immunization of Lewis rats with recombinant M6 protein induced focal myocarditis, myocyte necrosis and valvular heart lesions in three out of six animals. The disease in these animalsincluded verruca-like nodules and the presence of Anitschkow cells, which are large macrophages (also known as caterpillar cells), in mitral valves. Lymph node cells from these animals showed a proliferative response against cardiac myosin, but not skeletal myosin or actin. A CD4 + T cell line responsive to both the M protein and cardiac myosin was also obtained. Taken together, these results confirm the cross-reactivity between the M protein and cardiac myosin triggered by molecular mimicry, as observed in humans, possibly causing a break in tolerance leading to autoimmunity. [67],[68]Similarly, immunizing the Lewis rats with synthetic peptides from the conserved regions of M5 protein, or from B and C regions , or a recombinant M5 proteins have yielded focal myocarditis, infiltration with CD4+T cells, CD68 + macrophage but no typical aschoff`s nodule. [69],[70],[71],[72]Thus the Lewis Rat model could be considered a model of autoimmune valvulitis akin to ARF.Prospective Vaccines against S.PyogenesMany studies have focused on developing a vaccine against S. pyogenes in order to prevent infection and its complications. There are four anti-group A streptococci (GAS) vaccine candidates based on the M protein and eight more candidates based on other streptococci antigens, including group A CHO, C5a peptidase (SCPA), cysteine protease (Spe B), binding proteins similar to fibronectin, opacity factor, lipoproteins, Spes (super antigens) and streptococcal pili. [73]A multivalent vaccine, currently under phase II clinical trials, combines the amino acid sequences of the N-terminal portion of the M protein from the 26 most common strains of GAS in the US as a recombinant protein. [74],[75],[76]Because the C-terminal portion of the M protein is conserved among the 200 strains identified by their emm-types, vaccines based on this region are expected to provide broad coverage. The first attempt to develop a vaccine based on the C-terminal portion of the M protein was performed by Fischetti et al. [77] This vaccine was able to induce protection against S. pyogenes containing homologous (M6) and heterologous (M14) M protein, demonstrating that the use of conserved region-derived peptides could induce protection against different serotypes. [78]Conserved epitopes from the M protein have been also studied by a group from Australia, where the incidence of streptococcal infections in aboriginal communities is very high. Two synthetic peptides from the M5 protein (J8 and J14) were selected, and several formulations presented promising results. [79],[80],[81],[82] A combination of J8 and the fibronectin-binding repeats region (FNBR) of fibronectin I (SfbI) provided enhanced protection against S. pyogenes in mice. [83]We developed a vaccine epitope (StreptInCor) composed of 55 amino acid residues of the C-terminal portion of the M protein that encompasses both T and B cell protective epitopes. [84]The structural, chemical and biological properties of this peptide were evaluated and have shown that StreptInCor is a very stable molecule, an important property for a vaccine candidate. [85] Furthermore, experiments with mice showed that this construct is immunogenic and safe. [86]The greatest challenge for the development of a GAS vaccine resides in the promotion of immunity without generating cross-reactivity with human tissue. An effective and safe vaccine is still needed, most of all in developing countries.ConclusionSeveral genes involved in the control of infection and the immune response play a role in the development of RF and RHD. Some genes are associated with the innate immune response, and others with the adaptive immune response. Many of these genes are responsible for the inflammatory process and autoimmune reactions.In rheumatic carditis, antibodies that cross-react with streptococcal and human proteins upregulate adhesion molecules, leading to inflammation and increased cellular infiltration. CD4 + T cells that cross-react with heart tissue and streptococcal antigens are the major effectors of heart lesions.Large numbers of mononuclear cells that infiltrate rheumatic heart lesions produce inflammatory cytokines (TNF-a and IFN-g) and the imbalance between these cells and the IL-4-producing Th2 cells in the valve tissue might contribute to the progression and maintenance of rheumatic valvular lesions. Th17 cells also play a role in the development of autoimmunity.Several pathogenic M protein epitopes were identified that can induce cross-reactive responses against human proteins. Both epitope spreading and TCR degeneracy increase the possibility of cross-reactivity between infectious agents and self antigens.An animal model of Lewis rat displays similar heart lesions to RHD and is considered a good model of the disease.The development of a vaccine against S. pyogenes is an important goal and, given the number of ongoing studies, will probably be a reality in the near future.。

·论著·肾移植术后抗HLA-Ⅱ类抗体阳性患者与移植肾功能和长期存活的研究康颖1，贾保祥1，2，刘杰1，徐秀红 2（1. 北京诺诗康瀛医学科技有限公司移植免疫研究中心，北京100050；2. 首都医科大学附属北京友谊医院泌尿科，北京100050）【摘要】目的研究肾移植术后抗人类白细胞抗原（HLA）-Ⅱ类抗体阳性患者与移植肾功能和长期存活。

方法对2007年在首都医科大学附属北京友谊医院已检测出抗HLA-Ⅱ类抗体阳性的肾移植术后107例患者，于2010年和2011年再次检测其抗HLA-Ⅱ类抗体，并在2014年10月前后进行肾功能和长期存活观察。

结果2007年检测出107例肾移植术后抗HLA-Ⅱ类抗体阳性患者，其中19例患者肾功能正常，2010-2011年检测仍阳性，2014年检测肾功能正常。

43例患者肾功能正常，2010-2011年检测抗HLA-Ⅱ类抗体转阴性，2014年肾功能正常。

2例患者肾功能正常，2010-2011年查抗体转阴性，肾功能正常，2014年肾功能下降。

3例患者肾功能正常，2010-2011年查抗体转阴性，肾功能下降，2014年肾功能无再次下降趋势。

18例患者肾功能正常，2010-2011年查抗HLA-Ⅱ类抗体阳性，大部分患者肾功能下降，2014年时肾功能全部下降。

22例患者肾功能正常，2～3年后移植肾失功或失联。

结论抗HLA-Ⅱ类抗体对移植肾功能的影响因人而异，也可能存在保护性抗体。

【关键词】肾移植；抗HLA-Ⅱ抗体；肾功能；长期存活Anti-HLA-Ⅱantibody-positive patients with transplanted renal function and long-term survivalKang ying1，Jia baoxiang1，2，Liu jie1，Xu xiuhong2. 1. Rose Kang Ying，Beijing Medical Technology TransplantImmune Research Center,Beijing 100050，China.； 2.Beijing Friendship Hospital， Capital Medical University，Beijing100050，China.Corresponding author：Jia Baoxiang，Email：********************【Abstract】Objective This study focuses on the effect of anti HLA-Ⅱ antibody on kidney function andlong-term survival of kidney transplantation patients. Methods A total number of 107kidney transplantationpatients from Capital Medical University Affiliated Beijing Friendship Hospital, whose anti HLA class Ⅱ antibodieshad been detected to be positive and transplantation operation had been performed in 2007. In 2010-2011, these patients’HLA class Ⅱantibodies were detected again. In October 2014, these patients were detected for renalfunction and long-term survival. Results The detection results in 2007showed that 107kidney transplantationpatients had positive anti HLA-Ⅱantibody. 19patients had normal renal function with positive anti HLA-Ⅱantibody in the detection of 2010 and 2011, and normal renal function in 2014. 43 of these patients had normal renalfunction but their HLA class Ⅱ antibodies turn to be negative in 2010-2011， and they had normal kidney functionin 2014. There were 2 of these patients who had normal renal function with negative antibody in 2010-2011, but theirrenal function reduced in 2014. There were 3 patients who had renal function reduced in 2010-2011 with negative antibody， but their renal function didn’t show downward trend in 2014. A total number of 18 patients lost most renal DOI：10.3969/j.issn.2095-5332.2016.01.004 基金项目：国家火炬计划项目（2014GH010024） 通讯作者：贾保祥，Email：********************肾移植术后产生抗人类白细胞抗原（HLA）抗体，可使肾移植患者发生急性和慢性排斥，从而导致移植肾功能下降或丧失，是肾移植手术失败的重要因素之一［1］，因此，肾移植术后关注和检测抗HLA抗体的产生是预测和诊断移植肾体液性排斥的重要手段。

药剂学常用物质英文缩写1-NEP N-乙基吡咯酮1-NMP N-甲基吡咯酮2G-β-CYD 二葡糖基－β－环糊精2-HP-β-CYD 2－羟丙基－β－环糊精5-NCP 5-羧基吡咯酮5-NMP 5-甲基吡咯酮Accelerated testing 加速试验Acrylic acid resin 丙烯酸树酯Active targeting preparation 主动靶向制剂Adersive dispersion-type TTS 粘胶分散型TTS Adhersive strength 粘附力Adhesion 粘附性Adhesives 粘合剂Aerosil 微粉硅胶Aerosol 气雾剂Aerosol of micropowders for inspiration 吸入粉雾剂Aethylis oleas 油酸乙酯Agglomerate 聚结物Aggregation 聚集Air suspension 空气悬浮法Alarm clock 闹钟Alcohol 乙醇All-trans 全反式Alterntae addition method 两相交替加入法Amebocyte lysate 变形细胞溶解物Amorphous forms 无定型Angle of repose 休止角Antiadherent 抗粘剂Antioxidants 抗氧剂Antisepesis 防腐Apparent solubility 表现溶解度Aprotinin 抑酞酶Aquacoat 乙基纤维素水分散体Aromatic waters 芳香水剂Arrhenius 方程阿仑尼乌斯方程Ascabin 苯甲酸酯Aseptic technique 无菌操作法Azone 氮酮Ball mill 球磨机Base adsorption 基质吸附率Bases 基质Beeswax 蜂蜡Bending 弯曲力BHA 叔丁基对羟基茴香醚BHT 二叔丁基对甲酚Bioavailability 生物利用度Biochemical approach 生物学方法Biopharmaceutics 生物药剂学Biotechnology 生物技术Bond学说中等粉碎（粒径）Bound water 结合水分Breakage (Bk) 脆碎度Brij 泽、聚氧乙烯脂肪醇醚Brij 聚氧乙烯脂肪醇醚Buccal tablets 颊额片Bulk density 松密度Bulk density 松密度、堆密度Burst effect 突释效应CA 醋酸纤维素CAB 醋酸纤维素丁酸酯Cabomer 羟基乙烯共聚物Caking 结饼CAP 醋酸纤维素酞酸酯CAP 邻苯二甲酸醋酸纤维素Capillary state 毛细管状Capsules 胶囊剂Carbomer 卡波姆、羧基乙烯共聚物Carbopol 卡波普Carbopol 934 卡波普Carboxymethyl cellulose sodium 羟甲基纤维素钠Carboxymethyl starch sodium CMS-Na羧甲基淀粉纳Carboxymethylcellulose sodium CMC-Na羧甲基纤维素纳CAT 醋酸纤维素苯三酸酯CD 圆二色谱法Cellulose acetate (CA) 醋酸纤维素Cellulose acetate phthalate (CAP) 醋酸纤维素酞酸醋Central composite design (CCD) 星点设计Cera aseptical pro osse bone wax 骨蜡Ceramide 神经酰胺Cetomacrogol 聚乙二醇与十六醇缩合Chemical approach 化学方法Chewable tablets 咀嚼片Chitin 壳多糖Chitosan 壳聚糖Chronopathology 时辰病理学Chronopharmacology 时辰药理学Clausius-Clapeyron方程克劳修斯－克拉珀龙方程Clinical pharmaceutics 临床药剂学Cloud point 对聚氧乙烯型非离子表面活性剂CMC-Na 羧甲基纤维素纳CMEC 羧甲乙纤维素CMS 羧甲基淀粉CMS-Na 羧甲基淀粉钠Coadminiatration of skin Meta Inh 皮肤代谢抑制剂的合用Coadministraition of chem. P Enh 化学吸收促进剂的合用Coagulation 聚沉Coated tablets 包衣片Coating material 表材Cocoa butter 可可豆脂Cohesion 凝聚性、粘着性Cohesive strength 内聚力Cold compression method 汽压法Cold-homogenization 冷却一匀化法Colon-targeted capsules 结肠靶向胶囊剂Compactibility 成形性Complex coacervation 复凝聚法Compliance 顺应性Compressed tablets 普通片Compressibility 压缩度Compression 压缩力Compressive work 压缩功Cone and plate viscometer 圆椎平板粘度计Consistency curve 稠度曲线Controllability 可控性Controlled release tablets 控释片Controlled-release preparation 控释制剂Convective mixing 对流混合Convective transport 传递透过Coordination number 配位数Copoly (latic/glycolic) acid 聚乳酸乙醇酸共聚物Core material 表心物Cosolvency 潜溶Cosolvent 潜溶剂Coulter counter method 库尔特计数法Count basis 个数基准CP 聚羧乙烯CPVP 交联聚乙烯比咯烷酮CRacemization 外消旋作用Creams 乳青剂Creep 蠕变性Cremolphore EL 聚氧乙烯蓖麻油甘油醚Critical relative humidity (CRH) 临界相对湿度Critical relative humidity（CRH）临界相对湿度Critical velocity 临界速度Critrical micell concentration CMC临界胶束浓度Croscarmellose sodium CCNa交联羧甲基纤维素纳Croscarmellose sodium (CCNa) 交联甲基纤维素钠Crospovidone 交联聚维酮Cross-liked polyvinyl pyrrolidone PVPP交联聚维酮Crushing 粉碎Crystal form 晶型Crystal habit 晶态、晶癖、结晶习性CTS 普通栓剂Cumulative size distribution 累积分布Cutting 剪切力Cyclodextrin (CYD) 环糊精Cylinder model 圆栓体模型Cytotoxicity 细胞素DDS 药物传递系统Decoction 汤剂Degree of circularity 圆形度Degree of sphericility 球形度Delipidization 角质层去脂质化Dextrin 糊精Dialysis cell method 渗析池法Dicetyl phosphate 磷酸二鲸蜡脂Dielectric constant 介电常数Differential scanning calorimetry DSC差示扫描显热法Differential thermal analysis DTA差示热分析法Diffusive mixing 扩散混合Dilatant flow 胀性流动Diluents 稀释剂、填充剂Dimethicone (silicones) 二甲基硅油、硅油、硅酮Dimethyl sulfoxide(DMSO) 二甲基亚砜Dimethylacetamide (DMA) 二甲基乙酰胺Disinfection 消毒Disintegrants 崩解剂Disk assemble method 圆盘法Disperse medium 分散介质Disperse phase 分散相Disperse system 分散体系Dispersed phase 分散相、内相、非连续相Dispersible tablets 分散片Displacement value (DV) 置换价Distilled water 蒸馏水DL-phenylalanine ethyl acetoacetate DL苯基苯胺乙醚乙酸乙酯DLVO理论引力势能与斥力势能DME 二甲醚DMSO 二甲基亚矾DM-β-CYD 二甲基－β－环糊精Donor cell 供给宝DOPE 二油酰磷脂酰乙醇胺Dosage form 药物剂型DPPC 二棕榈酰磷脂酰胆碱Drop dentifrices 滴牙剂Drug carrier 药物载体Drug-loading rate 载药量Dry bulb temperature 干球温度DSPC 二硬脂酰磷脂酰胆碱DSPE 二硬脂酰磷脂酰乙醇胺Dumping effect 突释效应EA 乙基纤维素Ear drops 滴耳剂EC 乙基纤维素EC 毛细管电泳Effect diameter Dsk,有效径Effectiveness 有效性Effervescent disintegrants 泡腾崩解剂Effervescent tablets 泡腾片Elastic deformation 弹性变形Elastic recovery (ER) 弹性复原率Elastic work 弹性功Elasticity 弹性Electro phoresis 电泳Electroporesis 电致孔法Electuary 煎膏剂EMA 甲丙烯酸乙酯Emolphor 聚氧乙烯蓖麻油化合物Emulsifer in water method 水中乳化剂法、湿胶法Emulsifier in oil method 油中乳化剂法、干胶法Emulsion 普通乳Emulsions 乳剂Enamine 烯胺Endocytosis 内呑Endotoxin 内毒素Enteric capsules 肠溶胶囊剂Enteric coated tablets 肠溶衣片Entrapment rate 包封率Epidermis 表皮Epimerization 差向异构作用EPR效应促渗滞留作用Equilibrium solubility 平衡溶解度Equilibrium water 平衡水分Equivalent specific surface DSVEquivalent volume diameter Dv，体积等价径，球相当径Ethanol 乙醇Ethical (prescription) drug 处方药Ethycellulose (EC) 乙基纤维素Ethylcellulose EC乙基纤维素Ethylene vilnylacetate copolymer 乙烯-醋酸乙烯共聚物Ethylene vinylacetate copolymer 乙烯－醋酸乙烯共聚物Eu L, Eu S 聚甲基丙烯酸Eu RL, Eu RS 聚甲基丙烯酸酯Eu RL100, Eu RS100 甲基丙烯酸酯共聚物（不溶）Eu RL100, Eu SL100 聚丙烯酸树脂系列Eu S100, Eu L100 甲基丙烯酸共聚物（肠溶）Eudragit (E, RL, RS) 甲基丙烯酸酯共聚物Eudragit L100 甲基丙烯酸共聚物Eudragit RS100, RL100, NE30D 甲基丙烯酸酸共聚物- Eudragit S100 甲基丙烯酸共聚物EV A 乙烯－醋酸乙烯共聚物Evaporation 蒸发Excipients (adjuvants) 辅料External phase 分散介质、外相、连续相Extracts 浸膏剂Eye drop 滴眼剂Eye ointments 眼膏剂Factorial design 析因设计Fatty oils 脂肪油Feret diameter 定方向接线径Ficks第一扩散公式药材提取Fillers 填充剂Film coated tablets 薄膜衣片Film dispersion method 薄分散法Films 膜剂First-pass effect 首过效应Fliud extracts 流浸膏剂Flocculation 絮凝Flocculation value 絮凝度Flow curve 流动曲线Flow velocity 流出速度Flowability 流动性Fluid-energy mills 流能磨、气流式粉碎机Fluidity buffer 流动性缓冲剂Fluidized bed coating 流化床包衣法Free water 自由水分Freely movable liquid 自由流动液体Freon 氟氯烷烓类、氟里昂Frequency size distribution 频率分布Funicular state 索带状Fusion 融合Fusion method 热烙法Garles 含潄剂GAS 气体反溶剂技术Gas adsorption method 气体吸附法Gas antisolution GASGas permeability method 气体透过法GCP 药物临床试验管理规范Gelatin 胫胶Gelatin 明胶Gelatin glycerin 甘油胫胶Gelatinization 糊化General acid-base catalysis 广义酸碱催化Geometric diameter 几何学粒子径Geometric isomerization 几何异构Ghost cell 影细胞Glidants 助流剂GLP 药物非临床研究管理规范Glycerin 甘油Glycerins 甘油剂Glyceryl monostearate 硬脂酸、甘油酯Glycolic acid 羟基乙酸GMP 药品生产质量管理规范Granule density 颗粒密度Granules 颗粒剂Graton-Fraser模型颗粒的排列模型Group number HLB基团数Guest molecules 客分子G-β-CYD 葡糖－－环糊精Half life 半衰期Handerson-Hasselbach公式解离状态、pkc、ph的关系Hard capsules 硬胶囊剂Hardness 硬度HCO 氢仪蓖麻油HEC 羟乙基纤维素HEMA 甲基丙烯酸羟乙酯HES 羟乙基淀粉Heywood diameter Dh，投影面积圆相当径Higuchi方程希古契方程Host molecules 主分子HPC 羟丙纤维素HPMA 羟丙甲丙烯酸甲酯HPMC 羟丙甲基纤维素HPMC 羟丙甲纤维素HPMCAS 醋酸羟丙甲纤维素琥珀酸酯HPMCP 羟丙甲基纤维素酞酸酯HPMCP (HP-50, HP-55) 羟丙甲纤维酸酯Humidity 湿度Hydration of stratum corneum 角质层的水化作用Hydrogel 水性凝胶Hydrophile-lipophile balance 亲水亲油平衡值Hydrotropy 助溶Hydrotropy agent 助溶剂Hydroxypropyl methylcellulose 羟丙甲纤维素Hydroxypropyl methylcellulose acetate succinate 醋酸羟丙甲纤维素琥珀酸酯Hydroxypropyl methylcellulose phthalate 羟丙甲纤维素酞酸醋Hydroxypropylcellulose (HPC) 羟丙基纤维素Hydroxypropylmethyl cellulose HPMC羟丙甲基纤维素Hygroscopicity 吸湿性Hypodermic tablets 皮下注射用片ICH 国际协调会议IDDS 植入给药系统IEC 离子交换色谱法IEF 等电点聚焦Immobile liquid 不可流动液体Impact 冲击力Impact mill 冲击式粉碎机Implant tablets 植入片Inclusion compound 包含物Industrial pharmaceutics 工业药剂学Infusion solution 输液Injection 注射液In-liquid drying 液中干燥法（乳化－溶剂挥发法）Interface polycondensation 界面缩聚法intra-arterial route 动脉内注射Intradermal (ID) route 皮内注射Intramuscular (IM) route 肌肉注射Intravenous (IV) route 静脉注射Intrinsic dissolution rate 特性溶出速率Intrinsic solubility 特性溶解度Inverse targeting 反向靶向Iontophoresis 离子渗透法IR 红外Isoclectric focusing IEF等电点聚焦Isoosmotic solution 等渗溶液Isopropylpalmitate 异丙酸棕榈酯Isostearylisostearate 异硬脂酸异硬酯Isotonic solution 等张溶液Journal of Drug Targeting 药物靶向杂志Kick学说粗粉碎（体积）Krafft point 对离子型表面活性剂而言Krummbein diameter 定方向最大径Lactic acid 乳酸Lactose 乳糖Lag time 滞留时间Large unilamellar vesicles 大单室脂质体Laurocapam 月桂氮草酮Length basis 长度基准L-HPC 低取代羟丙基纤维素Limulus lysate test 鲎试验法Liniments 搽剂Liposomes 脂质体Liquid immersion method 液浸法Liquid injection 无针液体注射器Liquid paraffin 液体石蜡Long-circulating liposome 长循环脂质体Long-circulating liposomes 长循环脂质体Long-term testing 长期试验Loo-Rigelman方程双宝血药浓度－吸收率换算Lotions 洗剂Lubricants 润滑剂LUVs 大单宝脂质体。

黄芪促进中枢神经系统再生与修复的研究进展张力【摘要】黄芪具有免疫调节、抗菌、利尿、强心等多方面药理作用.中医认为神经功能缺损通常是由肾精不足所致.黄芪作为补益中药可提高机体对创伤的修复能力,增加损伤部位血供,有利于神经再生,促进神经干细胞增殖及定向分化,从中提取的单体或有效成分对中枢神经系统再生与修复具有保护作用,形成功能性神经元,为治疗神经功能缺损疾病提供了临床应用前景.该文依据黄芪对神经再生不同作用并最终促进功能性神经再生的思路对其综述.【期刊名称】《医学综述》【年(卷),期】2014(020)003【总页数】3页(P398-400)【关键词】黄芪;中枢神经系统;再生;修复;神经干细胞;神经保护【作者】张力【作者单位】西安医学院解剖教研室,西安,710021【正文语种】中文【中图分类】R282.71中医药学对神经功能缺损疾病的治疗有较深刻的认识。

神经再生已成为当前国际神经科学和脑科学研究的热点,同时也成为中医药现代化发展的一个切入点。

近年来的研究表明,中药不仅可以保护神经细胞,提高神经元抵抗损伤的能力[1],还可以促进神经干细胞(neural stem cell,NSC)增殖及定向分化,形成功能性神经元,达到治疗神经功能缺损疾病的目的[2]。

了解中药的作用机制,有助于为中药的临床应用拓展思路。

1 黄芪的有效成分及作用《中国药典》中收载蒙古黄芪或膜荚黄芪的干燥根作为药用黄芪正品。

中国黄芪属特有植物——淡紫花黄芪可当做膜荚黄芪使用。

常见的药用黄芪及制品多为蒙古黄芪。

其注射液是经提取后制成的灭菌水溶液。

目前对黄芪药材及含君药黄芪的中成药均以黄芪皂苷Ⅳ(黄芪甲苷)作为质量评价指标[3]。

药理研究表明,黄芪注射液中不同化学成分具有不同的药理活性,主要有3种:黄芪皂苷、黄芪酮、黄芪多糖[4]。

此外,有研究发现一些中药配伍黄芪可提高机体对创伤的修复能力,增加损伤部位血供,有利于神经再生和修复[5]。

黄芪作为祖国医学常用的中药材之一,其药用历史悠久。

浅论β受体阻断药治疗青光眼的研究概况【关键词】青光眼/ 治疗;β受体阻断药青光眼是世界第二大致盲眼病。

据统计[1]，2000年全世界共有6 680万青光眼患者，其中670万患者因此而双目失明;我国大约有500～600万青光眼患者，致盲人数也有50万左右。

目前治疗青光眼的药物主要是降眼压药，分五类：β受体阻断药、α受体激动药、碳酸酐酶抑制药、前列腺素类药物、拟胆碱能药。

其中β受体阻断药又是临床治疗青光眼的一线用药。

笔者主要介绍β受体阻断药治疗青光眼的研究进展。

1 噻吗洛尔噻吗洛尔是1978年被美国FDA批准第一个用于治疗青光眼的β受体阻断药，其抗青光眼机制有以下几方面：减少房水生成来降低眼压;减少Ca2+和Na+内流从而保护视网膜神经[2，3]。

在长达6个月的随机双盲、多中心临床试验中，%噻吗洛尔滴眼液降眼压达～，与1%布林佐胺滴眼液为～相似，但明显弱于1%布林佐胺、%噻吗洛尔复方制剂～。

另外一项临床试验中，噻吗洛尔降低眼压平均达(～)，与拉坦前列素疗效相同(～)。

研究证实每天予%噻吗洛尔眼用凝胶液滴眼1次与每天滴眼2次的疗效相当[6, 7]。

由于噻吗洛尔能结合于虹膜黑色素，所以噻吗洛尔治疗虹膜色素沉着病人效果较差;噻吗洛尔能减少脉络膜和视神经盘血液供应，这对青光眼治疗有害。

噻吗洛尔常见局部不良反应有结膜充血、上皮点状着色、干眼症等;全身不良反应有心动过缓、心律失常、房室传导阻滞、心力衰竭、支气管痉挛;中枢神经系统不良反应有抑郁、焦虑、阳萎、疲劳、幻觉等。

2 卡替洛尔卡替洛尔降眼压机制和噻吗洛尔一样，也是通过减少房水生成来降低眼压。

临床研究从(±)kPa降至(±)kPa，优于尼普洛尔的(±)kPa至(±)kPa。

表明，拉坦前列腺素治疗3个月的青光眼患者中，卡替洛尔能进一步降低眼压。

在146例原发性青光眼及眼高压患者参与的随机双盲试验中，1%长效卡替洛尔滴眼液降眼压效果(每日1次)与1%常规卡替洛尔滴眼液(每日2次)基本相同。

药物经济学评价是基于对药品卫生成本和健康产出的全面分析，从而对药品经济性进行评价和优选的学科技术［1］。

虽然在药物经济学评价中探讨的是整体成本，但药品价格和费用是构成卫生成本的重要内容。

因此，药品价格的改变可能会显著影响经济学评价的结果。

现实中，医药价格具有易变性［2］，药物经济学评价结果也会有相应的动态改变，需要及时更新经济学评价结果，以更好地支持决策。

德谷门冬双胰岛素是由70%的德谷胰岛素和30%的门冬胰岛素组成的可溶性双胰岛素制剂，于2019年在我国上市，并在2020年中完成和发表了该药对比甘精胰岛素的药物经济学研究报告［3］。

2020年底，德谷门冬双胰岛素通过国家医保谈判进入了医保用药目录［4］，其医保支付价格有了明显下降。

为此，本文基于该药品新的价格水平，采作者简介：陶立波，博士，研究员。

研究方向：卫生经济、卫生政策分析。

E-mail ：***************医保准入后德谷门冬双胰岛素对比甘精胰岛素治疗口服降糖药控制不佳的中国2型糖尿病患者的成本-效果陶立波1,2，王芳旭31.北京大学公共卫生学院卫生政策与管理学系，北京 100191；2. 北京大学医学部卫生政策与技术评估中心，北京 100191；3. 北京医药卫生经济研究会，北京 100012［摘要］目的：评价在德谷门冬双胰岛素医保谈判准入后，口服降糖药控制不佳的中国2型糖尿病患者应用德谷门冬双胰岛素治疗的长期成本-效果。

方法：基于IQVIA CORE 糖尿病模型，计算德谷门冬双胰岛素和甘精胰岛素治疗30年的成本和健康产出，并进行增量成本-效果分析。

研究采用卫生系统视角，成本包括降糖治疗、疾病管理及并发症治疗成本，健康产出指标采用质量调整生命年（QALYs ），贴现率使用5%。

通过概率敏感性分析评价结果的稳健性。

结果：与甘精胰岛素组比较，德谷门冬双胰岛素组的QALYs 增加了0.064年（8.285年vs 8.221年），直接总医疗成本减少77 567元（232 867元vs 310 434元）。