当前位置：文档库 › VEGF拮抗剂

VEGF拮抗剂

Vascular Endothelial Growth Factor-Trap Suppresses Tumorigenicity of Multiple Pancreatic

Cancer Cell Lines

Mitsuharu Fukasawa and Murray Korc Departments of Medicine,and Pharmacology and Toxicology, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon,New Hampshire

ABSTRACT

Purpose:Vascular endothelial growth factor A (VEGF-A)is a potent angiogenic agent that binds to two high affinity VEGF receptors(VEGFRs),a process facili-tated by the low affinity neuropilin receptors.Although VEGF-A is overexpressed in pancreatic ductal adenocarci-noma,it is not known whether the in vivo growth of multiple pancreatic cancer cells can be efficiently blocked by VEGF-A sequestration.

Experimental Design:Four human pancreatic cancer cell lines were grown s.c.in athymic nude mice.One cell line also was used to generate an orthotopic model of metastatic pancreatic cancer.The consequences of VEGF-A sequestra-tion on tumor growth and metastasis were examined by injecting the mice with a soluble VEGFR chimer(VEGF-Trap)that binds VEGF-A with high affinity.

Results:VEGF-Trap,initiated2days after tumor cell inoculation,suppressed the s.c.growth of four pancreatic cancer cell lines and markedly decreased tumor microvessel density.Analysis of RNA from tumors generated with T3M4 cells revealed that VEGF-Trap decreased the expression of VEGFR-1and neuropilin-1and-2.VEGF-Trap,initiated3 weeks after tumor implantation,also attenuated intrapan-creatic tumor growth and metastasis in an orthotopic model using PANC-1cells.

Conclusions:VEGF-Trap is a potent suppressor of pan-creatic tumor growth and metastasis and also may act to attenuate neuropilin-1and-2and VEGFR-1expression. Therefore,VEGF-Trap may represent an exceedingly useful therapeutic modality for pancreatic ductal adenocarcinoma.INTRODUCTION

Pancreatic ductal adenocarcinoma(PDAC)is responsible for?20%of deaths caused by gastrointestinal malignancies, making it the fourth most common cause of cancer-related mortality in the United States and other industrialized countries. The prognosis of patients with PDAC is extremely poor,with overall5-year survival rates?1%(1),1-year overall survival of 12%,and a median survival of6months(2).Survival often is limited to patients who had surgical resection at an early stage of the disease.However,the diagnosis of PDAC often is estab-lished at an advanced stage,precluding patients from undergo-ing tumor resection.Despite recent therapeutic advances(3), these statistics have remained dismal because of the tumor’s propensity to metastasize when small and undetectable,the advanced stage at which many patients first develop symptoms, and the intrinsic resistance of pancreatic cancer cells to cyto-toxic agents and/or radiotherapy(3–5).

Although PDAC is not a grossly vascular tumor,this ma-lignancy often exhibits enhanced foci of endothelial cell prolif-eration and frequently overexpresses vascular endothelial growth factor(VEGF),a potent angiogenic factor that is se-creted by many tumor cell lines(6).The principal form of VEGF is a homodimeric glycoprotein that has been renamed VEGF-A.It consists of five major isoforms with121,145,165, 189,and206amino acid residues,respectively,that originate as a result of alternative splicing from a single gene(7–10).All of the five isoforms are mitogenic toward vascular endothelial cells and act by binding to two related tyrosine kinase receptors, VEGFR-1and VEGFR-2,on the surface of endothelial cells (11–13).A third high affinity VEGF receptor,VEGFR-3,is expressed in lymphatic vessels(14–15).The three VEGFRs are transmembrane protein tyrosine kinases that possess seven immunoglobulin-like sequences in their extracellular domains and a kinase insert in their intracellular domains.

PDACs overexpress multiple additional angiogenic growth factors,including epidermal growth factor;transforming growth factor?;the three mammalian transforming growth factor?isoforms;hepatocyte growth factor;fibroblast growth factors (FGFs)such as FGF-1,FGF-2,and FGF-5;and platelet-derived growth factor(16).Therefore,it has not been firmly established that VEGF-A is of crucial importance in promoting the angio-genic process in PDAC.To address the potential role of VEGF-A in angiogenesis in PDAC,we used an s.c.nude mouse model of PDAC to assess the consequences of blocking VEGF-A action with VEGF-Trap,a modified soluble VEGFR that consists of the second immunoglobulin-like domain of VEGFR-1and the third immunoglobulin-like domain of VEGFR-2(17).We report that VEGF-Trap suppresses the s.c. growth of four distinct pancreatic cancer cell lines in athymic nude mice and that this effect is associated with a marked decrease in microvessel density.In addition,using an orthotopic

Received12/29/03;accepted2/10/04.

Grant support:United States Public Health Service grant CA-102687 awarded by the National Cancer Institute to M.Korc.

The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18U.S.C.Section1734solely to indicate this fact.

Requests for reprints:Murray Korc,Department of Medicine,One Medical Center Drive,Dartmouth-Hitchcock Medical Center,Lebanon, NH03756.Phone:603-650-7936;Fax:603-650-6122;E-mail:murray. korc@https://www.wendangku.net/doc/fa17222067.html,.3327

Vol.10,3327–3332,May15,2004Clinical Cancer Research

model,VEGF-Trap is shown to attenuate intrapancreatic tumor growth and regional and distant metastasis.These findings sup-port the hypothesis that VEGF-A has an important role in pancreatic cancer in vivo and raise the possibility that VEGF-Trap may ultimately provide a novel therapeutic option for management of this disease.

MATERIALS AND METHODS

Materials.The following were purchased:DMEM,RPMI 1640,fetal bovine serum,trypsin-EDTA,and glutamine-penicillin-streptomycin from Irvine Scientific(Santa Ana,CA);BxPC3and PANC-1human pancreatic cancer cell lines from American Type Culture Collection(Manassas,VA);and oligonucleotide primers for quantitative PCR from Applied Biosystems(Foster City,CA). The following were gifts:T3M4and COLO-357from Dr.R.S. Metzger at Duke University and Chimeric VEGF-Trap protein from Regeneron Pharmaceuticals(Tarrytown,NJ).

Cell Culture.Human pancreatic cancer cells were main-tained in monolayer culture at37°C in a humidified incubator with 5%CO

/95%air.BxPC3and T3M4cells were grown in RPMI 1640supplemented with10%heat-inactivated fetal bovine serum, 100units/ml penicillin,and100mg/ml streptomycin(complete RPMI),whereas COLO-357and PANC-1were grown in DMEM that was similarly supplemented(complete DMEM).These cell lines release variable levels of VEGF-A into conditioned medium, which range from intermediate(PANC-1)to relatively high (BxPC3)levels(18).They also harbor K-ras,p53,and/or Smad4 mutations or deletions and therefore are highly representative of cancer cells in PDAC(19–21).

In Vivo Tumorigenicity Assay.The effects of VEGF-Trap on tumor formation and growth were assessed for all of the four cell lines using an s.c.nude mouse model.One million cells per cell line were injected s.c.at one site in the flank region of female,athymic nu/nu nude mice(Harlan,Indianapolis,IN)that were6–8-weeks-old(18,22).Mice were housed in isolated con-ditions under pathogen-free conditions(18,22).Mice were injected s.c.in the nape of the neck(twice weekly)starting2days after tumor cell implantation and using either VEGF-Trap(25mg/kg)or control buffer containing an equal amount of human Fc protein (17).There were five mice/group/cell line and one tumor lesion per mouse to avoid any bystander effects.The tumors were measured externally once weekly,and tumor volume was calculated using the equation:vol?(l?h?w)??/4,where vol is the volume,l is the length,h is the height,and w is the width(18,22).Tumors were removed2–6weeks after injection,and portions were either im-mediately frozen in liquid nitrogen and stored at?80°C before RNA extraction or immediately embedded in OCT compound and stored at?80°C before histologic analysis.

The aforementioned s.c.mouse model is nonmetastatic(18, 22).Therefore,to determine whether VEGF-Trap could sup-press the metastatic potential of pancreatic cancer cells,we next used an orthotopic mouse model in which tumors derived from the s.c.model are aseptically resected and immediately minced into2-mm3pieces and implanted in the pancreas of nude mice via a surgical flap(23).PANC-1pancreatic cancer cells were tested in this metastatic model because we have determined previously that these cells express and release high levels of biologically active VEGF-A(18).Mice were randomized to a VEGF-Trap-treated group(n?6)or a control group(n?6) that received buffer containing an equal amount of human Fc protein(17).Injections of VEGF-Trap or control buffer were administered s.c.in the nape of the neck as described previously but were initiated3weeks after tumor fragment implantation using a dose of10mg/kg twice weekly.Injections were contin-ued for6weeks,at which time three of six control mice developed large abdominal masses and appeared cachectic,and all of the mice were killed.At autopsy,primary pancreatic tumors were excised and measured,and the number of metas-tases was determined.The University of California,Irvine and Dartmouth Medical School Institutional Animal Care and Use committees approved all of the studies with mice.According to their guidelines,whenever the tumors achieved a size?15mm and/or ulcerated,the mice were killed.

Immunohistochemistry.OCT-fixed sections were stained with an anti-CD31rat antimouse monoclonal antibody (Clone E13.1;PharMingen,San Diego,CA),counterstained with hematoxylin,and subjected to quantitative analysis of the blood vessel densities(18).Images(10random areas/slide)were captured by an Olympus DP70digital camera(Olympus,Tokyo, Japan)at100?magnification and were imported into an Image-Pro Plus version4.5.1(Media Cybernetics,Silver Spring,MD) image analysis program(18).The blood vessel densities then were calculated as the ratio of positively stained areas to the total area of the image or field.

Real-Time Quantitative PCR.RNA extraction,reverse transcription-PCR,and first-strand cDNA synthesis for quanti-tative real-time PCR analysis(Q-PCR)were carried out as described previously(24).Target gene sequences were from the National Center for Biotechnology Information GenBank data-bases as we reported previously(25).Q-PCR was performed using an ABI PRISM7700sequence detection system(Applied Biosystems;Ref.24).RNA expression was calculated based on a relative standard curve representing fivefold dilutions of hu-man cDNA.The parameter threshold cycle was defined as the fractional cycle number at which the fluorescence generated by cleavage of the probe passes the fixed threshold above baseline. The target gene copy number in unknown samples was quanti-fied by measuring the threshold cycle and by using a standard curve.Q-PCR data were expressed as a relative quantity based on the ratio of the fluorescent change observed with the target gene to the fluorescent change observed with rRNA.

Statistical analysis.Student’s t test was used for statis-tical analysis of the experiments.P?0.05was taken as the level of significance.

RESULTS

Effects of VEGF-Trap on Tumor Growth.The effects of VEGF-Trap on the tumorigenicity of four well-characterized human pancreatic cancer cell lines(BxPC3,COLO-357,PANC-1, and T3M4)were investigated.Two days following the s.c.injec-tion of cancer cells(1?106),the mice were initiated on twice-weekly injections of control buffer or VEGF-Trap(25mg/kg).At the end of the first week,there were no significant differences in tumor growth between control and VEGF-Trap-injected mice. However,by the second week,VEGF-Trap injections were asso-ciated with a marked inhibition of tumor growth in the case of

3328VEGF Sequestration Suppresses Pancreatic Cancer Growth

T3M4cells (Fig.1).By contrast,the T3M4-derived tumors from control animals were large and started to ulcerate,necessitating termination of these mice (Fig.1).By the third week,there was a significant difference in tumor growth with COLO-357cells.Thus,the growth of tumors in the VEGF-Trap group was markedly blunted,whereas tumors from control animals exhibited relatively rapid growth necessitating termination of the mice at week 5(Fig.1).Tumors formed by BxPC3and PANC-1cells exhibited a significant difference between control mice and VEGF-Trap mice by week 4,which persisted throughout the 6weeks of the experi-ments (Fig.1).Overall,by comparison of control mice with mice injected with vehicle only,there was 97%inhibition of tumor growth with COLO-357cells (5weeks)and PANC-1cells (6weeks),92%inhibition with BxPC-3cells (6weeks),and 89%inhibition with T3M4cells (2weeks).

Effects of VEGF-Trap on Tumor Angiogenesis.To evaluate the effects of VEGF-Trap on tumor-associated angio-genesis,the tumors from the aforementioned studies were im-munostained with anti-CD31antibodies to delineate the pres-ence of endothelial cells.The tumors from mice treated with control buffer exhibited numerous endothelial cells throughout the tumor mass (Fig.2A ).By contrast,tumors from mice treated with VEGF-Trap exhibited a marked decrease in CD31immu-noreactivity,and regions containing scant cellular material (Fig.2B ),suggesting that either necrosis or apoptosis of the cancer cells might have occurred in these areas.Moreover,quantitative morphometry with the Image-Pro Plus image analysis system revealed that the mean microvessel density (CD31-positive re-gions)was markedly decreased in tumors treated with VEGF-Trap compared with control tumors in all of the four cell lines (Fig.3).

Effects of VEGF-Trap on the Expression of VEGF Receptors and Ligands.In view of the marked decrease in microvessel density in the tumors of VEGF-Trap-treated mice,

we next sought to determine whether VEGF-Trap altered the expression of VEGF receptors or ligands in the tumors.Because of the limited amount of material (small tumor size)that was available for analysis in the VEGF-Trap-treated group,ligand and receptor expression was only examined in tumors from T3M4cells.Q-PCR of tumor RNA revealed that both groups of tumors expressed relatively high VEGF-A levels,moderate VEGF-B and VEGF-C levels,and relatively low VEGF-D lev-els (Fig.4A ).Moreover,VEGF-Trap treatment did not signifi-cantly alter the levels of any of these mRNA moieties (Fig.4A ).

Detectable levels of VEGFR-1and VEGFR-3also were present in tumors from both groups,whereas neuropilin-1and -2mRNA levels were relatively high in both groups,and VEGFR-2mRNA levels were below the level of detection (Fig.4B ).In contrast to the lack of an effect with respect to ligand expression,VEGF-Trap injections were associated with small but significant decreases in the expression of VEGFR-1and neuropilin-1and -2mRNA levels,whereas the levels of VEGFR-3were similar in both groups (Fig.4B

Fig.2CD31immunoreactivity in tumors formed by COLO-357cells.Immunohistochemical staining for CD31was performed as described in “Materials and Methods.”A,tumor from a control mouse.B,tumor from a mouse treated with vascular endothelial growth factor-Trap.Open arrows denote areas of scant cellular content in the central portion of the small tumor.Original magnification,?

100

Fig.1Effects of vascular endothelial growth factor (VEGF)-Trap on in vivo tumorigenicity of pancreatic cancer cells.BxPC3,COLO-357,PANC-1,and T3M4cells (1?106cells/site)were injected s.c.in athymic nude mice.Two days later,twice-weekly s.c.injections (nape of the neck)of VEGF-Trap protein (or control buffer)were initiated,using a dose of 25mg/kg,and continued for 2–6weeks.Tumor volumes (in mm 3)were calculated as described in “Materials and Methods ”and expressed as mean ?SE.?,P ?0.05;??,P ?0.01when compared with respective controls.

3329

Clinical Cancer Research

Effect of VEGF-Trap on Tumor Growth and Metasta-sis in an Orthotopic Model.The s.c.growing PANC-1-derived tumors were implanted into the pancreas of nude mice.Nine weeks following tumor implantation,six of six control mice had large intrapancreatic tumors with extensive local lymph node enlargement and mesenteric lymph node metastasis (Table 1).Five of these mice exhibited peritoneal dissemination,and two mice had ascites.By contrast,the intrapancreatic tu-mors in the six VEGF-Trap-treated mice were significantly smaller (Table 1).Moreover,one mouse did not exhibit any lymph node enlargement,and five mice exhibited local lymph node enlargement,but these nodes were significantly fewer in number (Table 1)and visibly smaller than in the control group.Only two of the VEGF-Trap-treated mice had mesenteric lymph node metastasis,and only one mouse had peritoneal dissemina-tion (Table 1).None of the VEGF-Trap-treated mice had ascites.

DISCUSSION

Angiogenesis is believed to be essential for growth and metastasis of solid malignancies,and most (26–28),but not all (29),of the studies have reported a positive correlation between tumor VEGF-A levels,blood vessel density,and disease pro-gression in PDAC.Moreover,VEGF-A expression in pancreatic PDAC may be associated with enhanced local spread and liver metastasis and decreased patient survival (26–28).Two addi-tional types of studies suggest that VEGF-A may have an important role in PDAC.In vitro ,pancreatic cancer cells secrete biologically active VEGF-A,which is the major angiogenic agent produced by these cells (18).In vivo ,antiangiogenic therapy is effective at suppressing tumor growth in animal models of pancreatic cancer.Thus,the antiangiogenic agent TNP-470reduces angiogenesis in tumors formed by pancreatic cancer cells,thereby decreasing their growth and metastasis (30);suppression of VEGF-A expression with a VEGF anti-

sense construct attenuates tumorigenicity in nude mice (18);and adenoviral vectors carrying sequences encoding soluble VEGFR-1and VEGFR-2(31–32)or the VEGFR tyrosine ki-nase inhibitor PTK 787(33)inhibit the growth and/or metastasis of pancreatic cancer cell tumors in mice.Together,these obser-vations suggest that VEGF-A may have an important role in PDAC.

Soluble forms of VEGFR-1generally exhibit nonspecific interactions with extracellular matrix and poor pharmacokinet-ics (17,34).By contrast,VEGF-Trap,which was created by fusing the second immunoglobulin domain of VEGFR-1with the third immunoglobulin domain of VEGFR-2,has minimal interactions with the extracellular matrix,an excellent pharma-cokinetic profile,and a high affinity for VEGF-A with a k d that is in the p M range (17).These are important characteristics in PDAC because this cancer often exhibits intense desmoplasia and the fibroblasts within this rich extracellular matrix also express high levels of VEGF-A (25).

In the present study we determined that administration of VEGF-Trap markedly suppressed the s.c.growth of four distinct human pancreatic cancer cell lines in athymic nude mice.More-over,this growth suppression was associated with a marked decrease in microvessel density.Inasmuch as VEGF-Trap did not alter the expression of either VEGF-A or related moieties,our findings indicate that VEGF-Trap interfered with

angiogen-

Fig.3Effects of vascular endothelial growth factor-Trap (VEGF-Trap )on microvessel density.Immunohistochemical staining for CD31was performed in the tumors from the indicated cell lines,as described in “Materials and Methods,”using an Olympus DP70digital camera and Image-Pro Plus version 4.5.1image analysis system.Data are the mean ?SE from three tumors/cell line/group.?,P ?0.01when compared with respective

controls.

Fig.4Effects of vascular endothelial growth factor (VEGF )-Trap on the expression of VEGF ligands and receptors in tumors formed by T3M4cells.Tumor-derived RNA was subjected to quantitative PCR.A,expression of VEGF ligands.B,expression of VEGF receptors.Relative expression levels were determined in duplicate.Data are the mean ?SE of three tumors/cell line/group.?,P ?0.01when compared with respective controls.

3330VEGF Sequestration Suppresses Pancreatic Cancer Growth

esis because it efficiently sequestered VEGF-A within the tumor microenvironment following its release from the cancer cells. Because injections of the decoy receptor were started2days after tumor inoculation in the s.c.model,it also is possible that VEGF-Trap interfered with co-option of host vasculature,which occurs early in tumor development,and this effect might rep-resent an additional advantage of VEGF-Trap compared with other forms of antiangiogenic therapies(35).

In the present study we also determined that VEGF-Trap administration was associated with decreased expression of VEGFR-1and neuropilin-1and-2.By contrast,VEGFR-2mRNA levels were below the level of detection,whereas VEGFR-3levels were not altered by VEGF-Trap.Decreased VEGFR-2expression following VEGF-Trap administration was reported previously with SK-NEP-1cultured human Wilms’tumor cell xenografts and was proposed to reflect a decrease in neovasculature(36).The de-creased expression of VEGFR-1and neuropilin-1and-2in the present study may reflect a similar phenomenon.

Neuropilin-1is a coreceptor for VEGF-A165and VEGF-B (37),whereas neuropilin-2binds VEGF-A165,VEGF-A145, and VEGF-C(38).Both coreceptors are nontyrosine kinase transmembrane proteins that are expressed in endothelial cells and that have been implicated in promoting angiogenesis.More-over,cultured human pancreatic cancer cell lines and PDAC-derived,laser-captured pancreatic cancer cells exhibit relatively high neuropilin-1and-2levels(34).Their ability to form complexes with VEGFR-1and VEGFR-2suggests that in ad-dition to promoting angiogenesis,neuropilins may allow for aberrant signaling in the cancer cells in PDAC(39–41).In this context,the observation that VEGF-Trap attenuated neuropilin expression in T3M4-derived tumor xenografts raises the possi-bility that,in addition to suppressing angiogenesis,VEGF-Trap also may act to abrogate VEGF-A-dependent aberrant autocrine/ paracrine loops that promote pancreatic cancer cell growth sur-vival in vivo.Three lines of evidence support this hypothesis.First,expression of neuropilin-1in Dunning rat prostate carci-noma AT2.1cells results in larger and more vascular tumors in rats(42).Second,neuropilin-1expression in breast cancer cells has been associated with a VEGF-A-induced survival signal that may enhance breast cancer metastasis(43).Third,VEGF is mitogenic in some pancreatic cancer cells in vitro(44–45).

VEGF-Trap induces the regression of SK-NEP-1cell-derived tumors in nude mice and decreases the size of lung micrometastases that were already established before VEGF-Trap therapy(36).In this model,in addition to endothelial cell apoptosis,there is apoptosis of the recruited perivascular cells within the tumors(36).VEGF-Trap also suppresses ascites formation in nude mice by ovarian cancer cells engineered to overexpress VEGF and inhibits the growth of metastatic lesions in this model(46).Moreover,in the present study we deter-mined that a relatively low dose of VEGF-Trap(10mg/kg) initiated3weeks following tumor implantation induced a sig-nificant reduction of the mean intrapancreatic tumor volume compared with the mean tumor volume in control mice,and a marked decrease in metastatic frequency.Together,these ob-servations suggest that VEGF-Trap may be useful to manage established tumors and their metastases.The present findings also are noteworthy in the context of the clinical course of PDAC,which is characterized by an early propensity to metas-tasize and a high risk for disease recurrence following resection. The marked overexpression of VEGF-A in PDAC(25),its ability to act as a survival factor for endothelial cells and perivascular cells and to render endothelial cells more radiore-sistant(47),and its capacity to promote cancer cell survival(43, 48–50)and suppress cancer-directed immune mechanisms(51) suggest that a VEGF-Trap-based strategy designed to sequester VEGF-A and block its actions in PDAC may have a unique therapeutic benefit for PDAC patients who have unresectable tumors and for patients who have undergone resection and who are at high risk for disease recurrence. ACKNOWLEDGMENTS

We thank Dr.Jocelyn Holash for helpful discussions in the course of this work.

REFERENCES

1.Warshaw AL,Fernandez-del Castillo C.Pancreatic carcinoma. N Engl J Med1992;326:455–65.

2.Greenlee RT,Murray T,Bolden S,Wingo PA.Cancer statistics, 2000.CA Cancer J Clin2000;50:7–3

3.Berlin JD,Rothenberg ML.Chemotherapeutic advances in pancre-atic cancer.Curr Oncol Rep2003;5:219–26.

4.Bodner WR,Hilaris BS,Mastoras DA.Radiation therapy in pancre-atic cancer:current practice and future trends.J Clin Gastroenterol 2000;30:230–3.

5.Pipas JM,Mitchell SE,Barth RJ Jr,et al.Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.Int J Radiat Oncol Biol Phys2001;50:1317–22.

6.Ferrara N.Molecular and biological properties of vascular endothe-lial growth factor.J Mol Med1999;77:527–43.

7.Poltorak Z,Cohen T,Sivan R,et al.VEGF145,a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem1997;272:7151–8.

8.Houck KA,Ferrara N,Winer J,Cachianes G,Li B,Leung DW.The vascular endothelial growth factor family:identification of a fourth

Table1Effects of VEGF-Trap in an orthotopic model a

Tissue fragments from PANC-1-derived s.c.tumors were im-planted into the pancreas of nude mice.VEGF-Trap(10mg/kg)or control buffer was injected s.c.in the nape of the neck twice weekly. Injections were initiated3weeks after tumor implantation and continued for6weeks.Data are the mean?SE from six mice per group.

Site Control

group

VEGF-Trap

group P

Primary tumor

Volume(mm3)4408?980646?2090.0038 Lymph nodes

Local

Number of affected mice65

Number of lymph nodes

(per mouse)

14.50?2.81 3.33?1.410.0052 Mesenteric region

Number of affected mice62

Number of lymph nodes

(per mouse)

13.67?3.13 1.17?0.980.0034 Peritoneum

Number of affected mice61

Number of affected sites

(per mouse)

7.17?2.150.67?0.670.0016

a VEGF,vascular endothelial growth factor.

3331 Clinical Cancer Research

molecular species and characterization of alternative splicing of RNA. Mol Endocrinol1999;5:1806–14.

9.Folkman J.Angiogenesis in cancer,vascular,rheumatoid and other disease.Nat Med1995;1:27–31.

10.Dvorak HF.VPF/VEGF and the angiogenic response.Semin Peri-natol2000;24:75–8.

11.Shibuya M.Structure and function of VEGF/VEGF-receptor system involved in angiogenesis.Cell Struct Funct2001;26:25–35.

12.Neufeld G,Cohen T,Gengrinovitch S,Poltorak Z.Vascular endo-thelial growth factor(VEGF)and its receptors.FASEB J1999;13:9–22.

13.Veikkola T,Karkkainen M,Claesson-Welsh L,Alitalo K.Regula-tion of angiogenesis via vascular endothelial growth factor receptors. Cancer Res2000;60:203–12.

14.Kukk E,Lymboussaki A,Taira S,et al.VEGF-C receptor binding and pattern of expression with VEGFR-3suggests a role in lymphatic vascular development.Development1996;122:3829–37.

15.Iljin K,Karkkainen MJ,Lawrence EC,et al.VEGFR3gene struc-ture,regulatory region,and sequence polymorphisms.FASEB J2001; 15:1028–36.

16.Korc M.Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer2003;2:1–8.

17.Holash J,Davis S,Papadopoulos N,et al.VEGF-Trap:a VEGF blocker with potent antitumor effects.Proc Natl Acad Sci USA2002; 99:11393–8.

18.Luo J,Guo P,Matsuda K,et al.Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo.Int J Cancer2001;92:361–9.

19.Hsiang D,Friess H,Bu¨chler MW,Ebert M,Butler J,Korc M. Absence of K-ras mutations in the pancreatic parenchyma of patients with chronic pancreatitis.Am J Surg1997;174:242–6.

20.Bartsch D,Barth P,Bastian D,et al.Higher frequency of DPC4/ Smad4alterations in pancreatic cancer cell lines than in primary pan-creatic adenocarcinomas.Cancer Lett1999;139:43–9.

21.Sun C,Yamato T,Furukawa T,Ohnishi Y,Kijima H,Horii A. Characterization of the mutations of the K-ras,p53,p16,and SMAD4genes in15human pancreatic cancer cell lines.Oncol Rep2001;8:89–92. 22.Kornmann M,Arber N,Korc M.Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum.J Clin Invest1998;101:344–52.

23.Rowland-Goldsmith MA,Maruyama H,Matsuda K,et al.Soluble type II transforming growth factor-a?receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell me-tastasis.Mol Cancer Ther2002;1:161–7.

24.Ketterer K,Rao S,Friess H,Weiss J,Bu¨chler MW,Korc M. Reverse transcription-PCR analysis of laser-captured cells points to potential paracrine and autocrine actions of neurotrophins in pancreatic cancer.Clin Cancer Res2003;9:5127–36.

25.Fukahi K,Fukasawa M,Neufeld G,Itakura J,Korc M.Aberrant expression of neuropilin-1and-2in human pancreatic cancer cells.Clin Cancer Res2004;10:581–90.

26.Itakura J,Ishiwata T,Friess H,et al.Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression.Clin Cancer Res1997;3:1309–16. 27.Seo YBH,Fukuda T,Takashima M,Sugimachi K.High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarci-noma.Cancer2000;88:2239–45.

28.Ikeda N,Adachi M,Taki T,et al.Prognostic significance of angio-genesis in human pancreatic cancer.Br J Cancer1999;79:1553–63. 29.Ellis LM,Takahashi Y,Fenoglio CJ,Cleary KR,Bucana CD,Evans DB.Vessel counts and vascular endothelial growth factor expression in pancreatic adenocarcinoma.Eur J Cancer1998;34:337–40.

30.Hotz HG,Reber HA,Hotz B,et al.Angiogenesis inhibitor TNP-470 reduces human pancreatic cancer growth.J Gastrointest Surg2001;2: 131–6.31.Hoshida T,Sunamura M,Duda DG,et al.Gene therapy for pan-creatic cancer using an adenovirus vector encoding soluble flt-1vascular endothelial growth factor receptor.Pancreas2002;25:111–21.

32.Ogawa T,Takayama K,Takakura N,Kitano S,Ueno H.Anti-tumor angiogenesis therapy using soluble receptors:enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1is used with soluble vascular endothelial growth factor receptor.Cancer Gene Ther2002;9:633–40.

33.Solorzano CC,Baker CH,Bruns CJ,et al.Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584,an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases.Cancer Biother Radiopharm2001;16:359–70.

34.Hood JD,Cheresh DA.Building a better Trap.Proc Natl Acad Sci USA2003;100:8624–5.

35.Kim ES,Serur A,Huang J,et al.Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma.Proc Natl Acad Sci USA2002;99:11399–404.

36.Huang J,Frischer JS,Serur A,et al.Regression of established tumors and metastases by potent vascular endothelial growth factor blockade.Proc Natl Acad Sci USA2003;100:7785–90.

37.Soker S,Takashima S,Miao HQ,Neufeld G,Klagsbrun M.Neu-ropilin-1is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.Cell1998;92: 735–45.

38.Gluzman-Poltorak Z,Cohen T,Herzog Y,Neufeld G.Neuropilin-2 is a receptor for the vascular endothelial growth factor(VEGF)forms VEGF-145and VEGF-165.J Biol Chem2000;275:18688–94.

39.Fuh G,Garcia KC,de Vos AM.The interaction of neuropilin-1with vascular endothelial growth factor and its receptor flt-1.J Biol Chem 2000;275:26690–5.

40.Whitaker GB,Limberg BJ,Rosenbaum JS.Vascular endothelial growth factor receptor-2and neuropilin-1form a receptor complex that is responsible for the differential signaling potency of VEGF(165)and VEGF(121).J Biol Chem2001;276:25520–31.

41.Gluzman-Poltorak Z,Cohen T,Shibuya M,Neufeld G.Vascular endothelial growth factor receptor-1and neuropilin-2form complexes. J Biol Chem2001;276:18688–94.

42.Miao HQ,Lee P,Lin H,Soker S,Klagsbrun M.Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progres-sion.FASEB J2000;14:2532–9.

43.Bachelder RE,Crago A,Chung J,et al.Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells.Cancer Res2001;61:5736–40.

44.von Marschall Z,Cramer T,Hocker M,et al.De novo expression of vascular endothelial growth factor in human pancreatic cancer:evidence for an autocrine mitogenic loop.Gastroenterology2000;119:1358–72.

45.Itakura J,Ishiwata T,Shen B,Kornmann M,Korc M.Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer.Int J Cancer2000;85:27–34.

46.Byrne AT,Ross L,Holash J,et al.Vascular endothelial growth factor-trap decreases tumor burden,inhibits ascites,and causes dramatic vascular remodeling in an ovarian cancer model.Clin Cancer Res 2003;9:5721–8.

47.Gupta VK,Jaskowiak NT,Beckett MA,et al.Vascular endothelial growth factor enhances endothelial cell survival and tumor radioresis-tance.Cancer J2002;8:47–54.

48.Harmey JH,Bouchier-Hayes D.Vascular endothelial growth factor (VEGF),a survival factor for tumour cells:implications for anti-angio-genic therapy.Bioessays2002;24:280–3.

49.Dias S,Shmelkov SV,Lam G,Rafii S.VEGF(165)promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2ex-pression and apoptosis inhibition.Blood2002;99:2532–40.

50.Gerber HP,Malik AK,Solar GP,et al.VEGF regulates haemato-poietic stem cell survival by an internal autocrine loop mechanism. Nature2002;417:954–8.

51.Ohm JE,Carbone DP.VEGF as a mediator of tumor-associated immunodeficiency.Immunol Res2001;23:263–72.

3332VEGF Sequestration Suppresses Pancreatic Cancer Growth

受体拮抗剂

受体拮抗剂Prepared on 21 November 2021

H2受体拮抗剂 [主要品种] H2受体拮抗剂包括西米替丁、雷尼替丁、法莫替丁等。 [适应症] 主要用于治疗胃和十二指肠溃疡。 [作用特点] H2受体拮抗剂能选择性地阻断壁细胞膜上的H2受体，使胃酸分泌减少。不仅抑制基础胃酸的分泌，而且能部分地阻断组胺、五肽胃泌素、拟胆碱药和刺激迷走神经等所致的胃酸分泌。 [药理作用] H2受体拮抗剂选择性地竞争结合壁细胞膜上的H2受体，使壁细胞内cAMP产生，胃酸分泌减少。H2受体拮抗剂不仅对组胺刺激的酸分泌有抑制作用，尚可部分地抑制胃泌素和乙酰胆碱刺激的酸分泌。常用的西咪替丁、雷尼替丁、法莫替丁等三种H2受体拮抗剂抑制胃酸分泌的相对能力相差20～50倍，以甲氰咪胍最弱，法莫替丁最强。相应地抑制50%五肽胃泌素刺激的酸分泌所需的有效血浓度(EC50)，以甲氰咪胍最高，法莫替丁最低。在常规剂量下，血浓度超过EC50的时间在甲氰咪胍约6小时，其他两种约10小时。

[不良反应] H2受体拮抗剂是相当安全的药物，严重不良反应的发生率很低。年龄大、伴肾功能和其他疾病时，易产生不良反应，常见腹泻、头痛、嗜睡、疲劳、肌痛、便秘等。[H2受体拮抗剂新用法] H2受体拮抗剂可高度选择性地与组胺H2受体结合，竞争性地拮抗组胺与H2受体结合后引起的胃酸分泌，产生抑酸作用，用于治疗消化性溃疡。传统的给药方法是一日剂量分次给药，如西咪替丁200毫克，每天四次或400毫克，每天二次；雷尼替丁150毫克，每天二次；法莫替丁20毫克，每天二次；尼扎替丁150毫克，每天二次；罗沙替丁75毫克，每天二次。近年来的研究结果表明，组胺的基础分泌以夜间为主，并且夜间胃液酸度在消化性溃疡，特别是十二指肠溃疡发病机制中起重要作用。白天的胃酸分泌与乙酰胆碱、胃泌素相关，且排出量不但与溃疡的形成无关，而且还具有以下显着的生理性作用：维持正常的消化过程，特别是蛋白质的消化，因为胃蛋白酶原转变为胃蛋白酶只有在足够酸的环境中才能实现；一定的胃酸酸度与钙和铁的吸收有重要关系；白天正常的胃酸分泌可保持胃内无菌环境，避免念珠菌使溃疡愈合延缓、幽门螺杆菌感染引起部分患者溃疡病的过早复发、胃酸持久抑制引起一些患者腹泻。因此，有学者认为，H2受体拮抗剂

试管婴儿周期长短与不同促排方案的关系

试管婴儿周期长短与不同促排方案的关系最近很多试管患者找我们泰嘉运抱怨，为什么我做试管婴儿要4个月，别人都才3个月。实际上试管婴儿周期的长短是因人而异的，每个人的不同情况，试管婴儿所需的时间也完全不一样，那么这里面的差异到底是怎么样的呢？今天泰嘉运给大家解疑试管婴儿周期长短。泰嘉运介绍，试管婴儿从前期的检查到移植后验孕，整个周期大约在2-3个月左右，时间的长短受女性月经周期以及试管婴儿促排方案的影响。试管婴儿促排方案分为长方案、短方案、拮抗剂方案、微刺激方案，还有自然周期。不同的方案有什么不同的特点呢？长方案是最常用的促排卵方案之一，也称之为黄体期长方案。从黄体中期开始，所需时间平均4周左右。主要适用于身体情况比较好的患者。长方案的优点是可控性强，失败风险较低，周期越长，就越有机会创造出更多优质卵子。短方案一般前后只要需要14-18天，适用于年龄大、卵巢储备功能下降、或卵巢反应差的女性。如果患者对长方案反应不良，医生很有可能建议做短方案。短方案优点是更加简单灵活，治疗周期短，药物少，副作用更少。拮抗剂方案很多人可能不熟悉。它的时长和短方案差不多，主要针对多囊卵巢综合征患者、卵巢功能低下、以及前次促排卵反应不良患者，是一种较灵活的方案。微刺激方案是在所有方案中用时最短的，一般只要8-12天。尤其适用于卵巢储备功能差的患者。用小剂量的促排卵药物进行促排卵，获卵数目一般不会太多，但同时对卵巢的刺激比较小，发生卵巢过度刺激综合征的风险也小。自然周期区别于人工周期，与女性自然生理周期相同，即不使用任何促排药物。适用于高龄卵巢储备低，促排也无法获得更多卵子的患者，不过自然周期每个月取到的卵子只有一两个，试管婴儿周期会比较长。

H受体拮抗剂

H受体拮抗剂文件排版存档编号：[UYTR-OUPT28-KBNTL98-UYNN208]

H2受体拮抗剂可高度选择性地与组胺H2受体结合，竞争性地拮抗组胺与H2受体结合后引起的胃酸分泌，产生抑酸作用，用于治疗消化性溃疡。传统的给药方法是一日剂量分次给药，如西咪替丁200毫克，每天四次或400毫克，每天二次；雷尼替丁150毫克，每天二次；法莫替丁20毫克，每天二次；尼扎替丁150毫克，每天二次；罗沙替丁75毫克，每天二次。近年来的研究结果表明，组胺的基础分泌以夜间为主，并且夜间胃液酸度在消化性溃疡，特别是十二指肠溃疡发病机制中起重要作用。白天的胃酸分泌与乙酰胆碱、胃泌素相关，且排出量不但与溃疡的形成无关，而且还具有以下显着的生理性作用：维持正常的消化过程，特别是蛋白质的消化，因为胃蛋白酶原转变为胃蛋白酶只有在足够酸的环境中才能实现；一定的胃酸酸度与钙和铁的吸收有重要关系；白天正常的胃酸分泌可保持胃内无菌环境，避免念珠菌使溃疡愈合延缓、幽门螺杆菌感染引起部分患者溃疡病的过早复发、胃酸持久抑制引起一些患者腹泻。因此，有学者认为，H2受体拮抗剂在白天的抑酸作用弱，而夜间给予此类药可以有效地抑制胃酸分泌，从而可以使溃疡快速愈合，症状缓解。临床观察也支持这一观点，即在睡前将H2受体拮抗剂一日剂量一次给药，在溃疡愈合速度、症状缓解和安全性上均与一日剂量分次给药法相同，并且这种给药法可以提高溃疡病患者的用药依从性。已经在临床应用的H2受体拮抗的一日剂量一次给药法为：睡前服，西咪替丁800毫克，雷尼替丁300毫克，法莫替丁40毫克，尼扎替丁300毫克，罗沙替丁150毫克。[H2受体拮抗剂市场分析]随着新药成果转化率的不断提高，国产药品价格连续下调，百姓得到了实惠的同时，消化类用药消费比值已呈现出下降的趋势。与此同时，在新药的推广应用下，产品的更新换代较快，用药金额仍呈现出增长势头，2003年国内16个典型城市样本医院中，消化系统及代谢药物用药金额已达亿元，同比上一年增长了%。

7 阿片样镇痛药

第七章阿片样镇痛药 *阿片（opium）即鸦片的简介（来源、用途）阿片是罂粟科植物罂粟的未成熟蒴果被划破后流出的白色液汁，干燥后呈棕黑色膏状物。→阿片内含多种复杂成分，其中的生物碱具有药理活性。阿片中分离到20多种生物碱，其中的主要成分是吗啡，其它成分尚有可待因（Codeine）、蒂巴因(Thebaine)等。吗啡是用于临床的镇痛药；可待因镇痛作用为Morphine的1/10，主要用作镇咳药；蒂巴因为半合成镇痛药（阿片样激动剂埃托啡（eterphine）、阿片样拮抗剂纳络酮（nalotone）等）的合成原料。吗啡于1806年从阿片中分离提取出来，1923年确定了化学结构，1952年完成了合成工作。 *吗啡的药理活性：吗啡除具有强镇痛活性（显著减轻或消除疼痛）、镇静和欣快作用外，还有严重的副作用。例如治疗剂量时呼吸抑制、血压降低、恶心呕吐、大小便困难、嗜睡等，最为严重的不良反应是吗啡反复使用，易产生耐受性、成瘾性，一旦停药即出现戒断症状，危害极大。寻找成瘾性小、不良反应少的理想镇痛药成为研发新镇痛药的目标。 *在研究构效关系、开发新镇痛药方面所做的工作： 1、对吗啡进行结构修饰——半合成镇痛药。 2、简化吗啡结构——合成镇痛药和吗啡拮抗剂； ——具有阿片样激动/拮抗作用成瘾小的镇痛药、高效镇痛药。（近年的发展）*阿片受体的外源性配体、内源性镇痛物质、阿片受体阿片样镇痛药作用机理的研究认为：阿片样镇痛药（Opioid Agents）通过与体内高度特异性受体部位结合后产生药理活性。阿片样镇痛药是阿片受体的外源性配体，与阿片受体相互作用产生减轻剧烈锐痛或钝痛等药理活性。阿片受体的外源性配体及内源性镇痛物质阿片样镇痛药（阿片样激动剂、拮抗剂和激动/拮抗剂）是阿片受体的外源性配体；脑啡肽、内啡肽、强啡肽等是内源性镇痛物质。阿片受体与其内源性配体相互作用，除调节疼痛感觉外，还有重要的生理功能。（继1975年发现内源性具有吗啡样镇痛活性的脑啡肽之后，又发现了内啡肽、强啡肽等内源性镇痛物质。）

血管加压素受体拮抗剂(VRAs)

血管加压素受体拮抗剂（VRAs）传统治疗等容性或高容量性低钠血症的方法包括限水、应用高渗盐水及去甲金霉素等，但均有明显的副作用，导致其临床应用受限。血管加压素受体拮抗剂（VRAs）主要通过阻断过度产生的（精氨酸加压素）AVP，使净水（非溶质水）排出增加，达到升高血浆渗透压的作用已被美国食品药品管理局（FDA）批准用于治疗等容性低钠血症。对此类药物的进一步研究发现VRAs还可用于治疗由于AVP受体变异导致的肾源性糖尿病（NDI），甚至可能延缓多囊肾的进展。本文对于目前国内外非肽类VRAs药物的研究情况进行综述，并进一步探讨其潜在的临床使用价值。 1 AVP及其受体 AVP又被称为抗利尿激素(ADH),是下丘脑垂体分泌的一种肽类激素,还有文献报道外周组织如心脏也可分泌AVP〔1〕。AVP在体内主要负责调节水的重吸收，维持体液渗透压、血容量、血压等，还在细胞收缩、增殖和肾上腺皮质激素的分泌等方面扮演重要角色，这些生理作用都是通过与其受体结合而产生的〔1〕。AVP受体属于G蛋白耦联受体，有3种亚型：V1a受体（V1aR）、V1b受体（V1bR）和V2受体（V2R），它们在体内的分布和信号传导的机制均不同。V1aR位于血管平滑肌、血小板、肝细胞和子宫肌层，通过激活磷脂酶C增加细胞内钙离子浓度，分别介导血管收缩、血小板聚集、肝糖原分解及子宫收缩；V1bR位于垂体前叶，介导促肾上腺皮质激素（ACTH）释放；V2受体（V2R）位于肾脏集合管细胞的基底侧膜，通过激活蛋白激酶A使位于细胞内囊泡中已形成的水孔蛋白（AQP2）磷酸化并使其插入集合管细胞顶膜，从而调节集合管对水的通透性。V2R还在血管内皮及血管平滑肌细胞表达，可诱导血管性血友病因子第8因子(vWF)及Ⅷ因子释放及介导血管扩张效应。正常情况下，当体液渗透压降低至一定水平，血浆AVP水平也相应下调，同时产生利尿效应。在抗利尿激素分泌异常综合征(SIADH)患者，虽然存在低渗，但AVP释放却不完全受抑制。而在肝硬化及慢性充血性心力衰竭(CHF)患者，由于肾小球滤过率降低导致水排泄受限，同时非渗透压刺激下的AVP释放或与受体结合也可能参与了体液潴留的发生机制。正常生理环境下，心室、颈动脉窦和主动脉弓的压力感受器通过输出的迷走神经张力抑制AVP、肾素、儿茶酚胺释放。CHF时动脉扩张异常和压力感受器受抑制导致迷走神经张力下降，上述激素分泌增加〔2，3〕。而在肝硬化时，脾血管的持续扩张导致了动脉充盈不足，AVP释放增加。肝硬化伴有腹水及浮肿的患者，其AVP、肾素及醛固酮水平较水排泄正常的肝硬化患者明显升高。给予肝硬化动物模型行垂体切除或应用去甲金霉素发现体液潴留减轻，提示SIADH、CHF及肝硬化导致的低钠血症均是由AVP介导的。 2 非肽类VRAs 20世纪70年代，第一个肽类V2R拮抗剂在动物实验中被证实有效，而在人体却产生弱的V2R激动作用〔4〕，且口服生物利用度差，限制了其应用。1993年，Ohnishi等〔5〕首先报道了口服非肽类选择性V2R拮抗剂，并在健康人体内产生了水排泄作用。

兴奋性氨基酸受体拮抗剂

兴奋性氨基酸受体拮抗剂发明背景在哺乳动物的中枢神经系统(CNS)中，神经冲动的传递受传送神经元释放的神经递质与接受神经元上表面受体之间的相互作用调控，这种相互作用导致这种接受神经元兴奋。L-谷氨酸是CNS中最丰富的神经递质，介导哺乳动物体内主要的兴奋途径，因此被称为兴奋性氨基酸(EAA)。应答于谷氨酸的受体称为兴奋性氨基酸受体(EAA受体)。兴奋性氨基酸受体分为两大类。直接与神经元细胞膜中的开放性阳离子通道结合的受体称为“离子型”。这种类型受体至少已分为三种亚型，它们根据对选择性激动剂N-甲基-D-天冬氨酸(NMDA)、α-氨基-3-羟基-5-甲基异噁唑-4-丙酸(AMPA)和红藻氨酸的去极化作用而定义。分子生物学研究已经确认AMPA受体是由亚单位(GluR1-GluR4)组成，它们可以组装形成功能性离子通道。已经鉴定出五中红藻氨酸受体，它们被分为高亲和性(KA1和KA2)或低亲和性(由GluR5，GluR6，和/或GluR7亚单位组成)两类。第二大类受体是G-蛋白偶联或第二信使连接的“代谢型”兴奋性氨基酸受体。该第二大类受体与多个第二信使系统结合，从而能够增强磷酸肌醇的水解、激活磷脂酶D、增加或降低cAMP的形成以及改变离子通道的功能。这两类兴奋性氨基酸受体可能不仅介导正常突触沿兴奋性途径的传递，而且还参与发育和整个生命过程的突触连接的改变。过度或不适当地刺激兴奋性氨基酸受体会以称为兴奋性毒性的机制方式导致神经元细胞损伤或损失。已经有人提出，该过程在许多神经性疾病或病症中介导神经元变性。这种神经元变性的医学后果对这些变性神经病变过程的缓解具有重要的治疗意义。例如，兴奋性氨基酸受体的兴奋性毒性与多种神经性疾病的病理生理学有关，包括心脏旁路手术和移植后大脑功能性缺氧或缺血(cerebral deficit)、中风、脑缺血、创伤或炎症引起的脊髓损伤、产期缺氧、心博停止和低血糖性神经损伤的病因学。此外，兴奋性毒性还与慢性神经变性疾病包括阿耳茨海默氏病、杭廷顿氏舞蹈病、遗传性共济失调、艾滋病诱发的痴呆、肌萎缩性侧索硬化、特发性和药物引发的帕金森病以及眼部损伤和视网膜病有关。与兴奋性毒性和/或谷氨酸功能异常有关的其它神经性疾病包括肌痉挛(包括震颤)、药物耐受性和戒断、脑水肿、惊厥症(包括癫痫)、抑郁症、焦虑症和焦虑症有关的病症(例如创伤后紧张综合症)、迟发性运动障碍、与抑郁症有关的精神病、精神分裂症、双相障碍、躁狂症以及药物中毒或成瘾。兴奋性氨基酸受体拮抗剂还可用作镇痛剂，用于治疗或预防各种不同形式的头痛，包括偏头神经痛、紧张性头痛和慢性每日头痛。此外，已公开的欧洲专利申请WO 98/45720报道了兴奋性氨基酸受体的兴奋性毒性与急性和慢性疼痛状态包括严重疼痛、顽固性疼痛、神经病性疼痛、创伤后疼痛的病因有关。人们还知道，三叉神经节及其相关的神经途径与头和面部的疼痛感觉如头痛，尤其是偏头痛有关。Moskowitz(Cephalalgia，12，5-7，(1992))提出未知原因的触发能刺激三叉神经的神经节(这种神经节能使神经分布于头部组织的脉管系统中)，引发脉管系统中的轴突释放出血管活性神经肽。这些释放的神经肽随后能激活一系列活动，引发脑脊膜的神经性炎症，结果产生疼痛。在治疗急性人偏头痛所需的相似剂量下，这种神经性炎症能够被舒马坦(sumatriptan)阻滞。然而，由于舒马坦伴有血管收缩特性，因而这种剂量的舒马坦因会并发禁忌证。最近已经报道了离子型谷氨酸受体的所有五种红藻氨酸亚型都在大鼠的三叉神经节神经元上表达，尤其是观测到了高水平的GluR5和KA2.(Sahara等，The Journal of Neuroscience，17(17)，6611(1997))。因而，偏头痛仍然是另一种可能与谷氨酸受体兴奋毒性有关的神经性疾病。

H受体拮抗剂

H2受体拮抗剂 [主要品种] H2受体拮抗剂包括西米替丁、雷尼替丁、法莫替丁等。 [适应症] 主要用于治疗胃和十二指肠溃疡。 [作用特点] H2受体拮抗剂能选择性地阻断壁细胞膜上的H2受体，使胃酸分泌减少。不仅抑制基础胃酸的分泌，而且能部分地阻断组胺、五肽胃泌素、拟胆碱药和刺激迷走神经等所致的胃酸分泌。 [药理作用] H2受体拮抗剂选择性地竞争结合壁细胞膜上的H2受体，使壁细胞内cAMP产生，胃酸分泌减少。H2受体拮抗剂不仅对组胺刺激的酸分泌有抑制作用，尚可部分地抑制胃泌素和乙酰胆碱刺激的酸分泌。常用的西咪替丁、雷尼替丁、法莫替丁等三种H2 受体拮抗剂抑制胃酸分泌的相对能力相差20～50倍，以甲氰咪胍最弱，法莫替丁最强。相应地抑制50%五肽胃泌素刺激的酸分泌所需的有效血浓度(EC50)，以甲氰咪胍最高，法莫替丁最低。在常规剂量下，血浓度超过EC50的时间在甲氰咪胍约6小时，其他两种约10小时。 [不良反应] H2受体拮抗剂是相当安全的药物，严重不良反应的发生率很低。年龄大、伴肾功能和其他疾病时，易产生不良反应，常见腹泻、头痛、嗜睡、疲劳、肌痛、便秘等。[H2受体拮抗剂新用法]

GnRH拮抗剂配伍HMG方案对卵巢低反应患者IVF-ET治疗结局分析

GnRH拮抗剂配伍HMG方案对卵巢低反应患者IVF-ET治疗结局分析发表时间：2016-03-02T16:07:41.320Z 来源：《航空军医》2015年19期作者：许慧黄向红谭小军 [导读] 湘潭市中心医院生殖中心针对卵巢低反应患者，GnRH拮抗剂配伍HMG方案能够有效提高IVF-ET的妊娠率，并且价格低廉. 湘潭市中心医院生殖中心湖南湘潭 411100 【摘要】目的：研究GnRH拮抗剂配伍HMG方案对卵巢低反应患者IVF-ET的结局。方法：选择我院2012年6月至2015年6月收治的经IVF-ET失败、卵巢低反应患者71例，将患者分为治疗组和对照组，治疗组36例采用GnRH拮抗剂配伍HMG方案；对照组35例患者仅接受GnRH 激动剂方案。比较两组患者年龄、FSH水平、Gn情况、获卵数、胚胎种植率、妊娠率等情况。结果：两组患者年龄、基础FSH水平、IVF-ET治疗间隔时间、Gn使用天数、获卵数、胚胎种植率无明显差异（p＞0.05）；但两组患者Gn用量、临床妊娠率、受精率比较差异有统计学意义（p＜0.05）。结论：针对卵巢低反应患者，GnRH拮抗剂配伍HMG方案能够有效提高IVF-ET的妊娠率，并且价格低廉，值得临床推广。【关键词】GnRH拮抗剂；HMG；卵巢低反应；体外受精-胚胎移植体外受精-胚胎移植（IVF-ET）是指从男性和女性体内分别取出精子和卵子进行体外受精，发育成胚胎后，再移植回母体子宫内的一种受孕技术。在控制性超排卵的过程中，卵巢低反应的发生率大约在9%-24%，卵巢低反应患者的IVF-ET妊娠率较低，也是IVF-ET不成功的一大问题[1]。本次研究针对经IVF-ET失败卵巢低反应行GnRH拮抗剂配伍HMG方案，就其临床效果和价值进行探讨。 1 资料与方法 1.1 一般资料选择我院2012年6月至2015年6月收治的经IVF-ET失败确诊为卵巢低反应患者71例，所有患者均符合卵巢低反应表现，前次IVF-ET周期获卵数≤3个，要求再次进行IVF-ET助孕。卵巢低反应的标准按照2011年博洛尼亚卵巢低反应共识：1）高龄（≥40岁）或存在卵巢低反应的其他危险因素；2）前次周期卵巢低反应（常规刺激方案获卵数≤3个）；3）卵巢储备下降（AFC<5-7个或AMH<0.5~1.1ng/ml）。以上三条满足两条。 1.2 治疗方案治疗组：根据年龄、基础卵泡数、基础FSH水平在患者月经第三天起给予HMG（上海丽珠制药有限公司，国药准字H20023863）按照3-4支/d进行肌肉注射，并根据患者阴道超声监测卵泡发育情况对HMG用量进行调整。当监测到优势卵泡直径13-14mm时，给予 0.25mgGnRH拮抗剂西曲瑞克（德国 Serono Europe Limited，注册证号：H20100368）皮下注射至绒毛膜促性腺激素使用日（HCG日）[2]。对照组：在患者月经来潮第2天行皮下注射GnRH激动剂0.1mg曲普瑞林（法国 IPSEN PHARMA，注册证号：H20110290），第3天根据患者年龄、基础卵泡数、基础FSH水平选择使用促性腺激素（Gn），按照4-5支/d行皮下注射至HCG日，同样根据患者阴道超声监测卵泡发育情况对Gn用量进行调整。两组患者均当发现有1-2个卵泡直径达到18mm时，给予10000 IU HCG（Merck Serono S.p.A.，批准文号：S2*******）肌注，并在36h后进行超声引导取卵和常规IVF受精。取卵3天后行腹部超声引导胚胎移植，并给予肌注60mg/d的黄体酮支持[3]。 1.3 统计学方法对本组所收集的数据结果通过统计学软件SPSS 19.0处理，计量资料用均数±标准差（x±s）表示，并采用 t 检验，计数资料采用（n，%）表示，采用卡方检验，以p＜0.05为差异有统计学意义。 2 结果治疗组中2例取卵失败，2例因卵泡生长不良取消，对照组中4例因卵泡生长不良取消，3例取卵失败。两组患者年龄、基础FSH水平、IVF-ET治疗间隔时间、Gn使用天数、获卵数、胚胎种植率无明显差异（p＞0.05）；但患者Gn用量、临床妊娠率、受精率比较差异有统计学意义（p＜0.05），详见表1。 3 讨论卵巢低反应是卵巢对促性腺激素刺激反应不良的病理状态，主要表现为卵巢刺激周期发育的卵泡少，血雌激素峰值低，Gn用量多，周期取消率高、获卵少和很低的临床妊娠率。GnRH拮抗剂竞争性地阻断了下丘脑垂体GnRH受体，与垂体细胞膜上的受体相结合后迅速抑制内源性促性腺激素的分泌。GnRH拮抗剂的抑制效果呈剂量依赖性，避免了flare-up效应，缩短了刺激周期和减少了Gn的用量。GnRH拮抗剂在卵泡中晚期使用，可避免激动剂对卵巢的过度抑制，有利于卵巢反应不良患者卵泡的募集。但GnRH拮抗剂会引起内源性LH迅速下降从而影响卵泡的发育，使用含有LH的HMG与拮抗剂进行配伍，弥补了内源性LH不足对卵泡发育造成的影响。同时，相对低剂量的Gn能够提高患者卵巢反应，最终提高种植率[4]。除此之外，使用GnRH拮抗剂配伍HMG成本低廉，在拮抗剂方案中，开始前仅接受HMG，而GnRH拮抗剂则作为中期药物，如果发现患者卵泡发育不满意，则可不使用GnRH拮抗剂，因此也降低了成本。本次研究中，治疗组中2例取卵失败，2例因卵泡生长不良取消，对照组中4例卵泡生长不良取消，3例取卵失败。两组患者年龄、基础

P2Y12受体拮抗剂

P2Y12受体拮抗剂 P2Y12受体拮抗剂是一类作用于血小板P2Y12受体，对二磷酸腺苷引起的血小板聚集起抑制作用的药物，临床上主要用于预防和治疗心血管疾病的血栓事件。P2Y12受体拮抗剂与阿司匹林联用的双重抗血小板治疗方案，是各种指南推荐、临床上常用的心血管病抗栓治疗方案。目前，临床上可供选用的P2Y12受体拮抗剂有氯吡格雷、普拉格雷和替格瑞洛，这些药物各自有哪些作用特点，疗效和安全性又有何差异？氯吡格雷氯吡格雷是第二代P2Y12受体拮抗剂（注：第一代P2Y12受体拮抗剂为1979年上市的噻氯匹定，其副作用较多，在临床应用中逐渐被氯吡格雷所取代），其在化学结构上属噻吩并吡啶类化合物，是前体药物，需要在肝脏中通过细胞色素 P450（CYP 450）酶代谢成为活性代谢物后，才会不可逆地抑制P2Y12受体，抑制血小板的聚集反应。因此，氯吡格雷抗血小板活性的发挥存在延迟现象，即起效时间比较长。氯吡格雷在临床应用中存在一些缺陷，包括：消除半衰期较长，个体差异较大，部分患者服用该药后未产生抗血小板效果即“氯吡格雷抵抗”, 与质子泵抑制剂（PPI）合用时可能会升高不良反应的发生率。目前，已经明确CYP 2C19是与氯吡格雷抵抗相关的代谢酶之一，美国食品与药物管理局（FDA ）已增加了氯吡格雷的黑框警告，建议临床医生选用氯吡格雷前对患者进行基因检测，对弱代谢患者应增加剂量。普拉格雷普拉格雷是第三代P2Y12受体拮抗剂，同氯吡格雷相同，此药也是噻吩并吡啶类化合物和前体药物，需要在体内转化为其活性代谢产物后，才会不可逆地抑制P2Y12受体从而发挥作用。研究显示，与氯吡格雷的标准剂量或更大剂量相比，普拉格雷对血小板的抑制作用更快、更持续、更强。同时，由于普拉格雷的强抑制血小板聚集的作用，也增加了其出血风险。替格瑞洛与噻吩并吡啶类药物（氯吡格雷和普拉格雷）的化学结构分类不同，替格瑞洛是一种环戊烷三唑并吡啶类的新型抗血小板药物，故之前的中文名“替卡格雷”现已更换为“替格瑞洛”。与氯吡格雷和普拉格雷相比，替格瑞洛是第一个可以口服却不需要生物转化就可直接发挥药效且可与P2Y12受体可逆结合的抗血小板药物。因其与受体的结合是可逆性的，故一天须服药2 次。替格瑞洛具有快速起效、非前体药物可直接作用、不受个体基因差异影响等优势，且与血小板可逆结合，停药后血小板功能迅速恢复。与普拉格雷类似，替格瑞洛对P2Y12受体的抑制效果也要强于氯吡格雷。替格瑞洛的疗效已经PLATO研究证实，被国内外多部指南列于一线推荐地位，欧洲指南更是在2011年将替格瑞洛的推荐级别列于氯吡格雷之前，在替格瑞洛或普拉格雷不能使用的患者中才推荐使用氯吡格雷。上述三种药物主要药理学性质和药代动力学参数比较见表。

药理学—肾上腺素受体拮抗剂

药理学—肾上腺素受体拮抗剂交感神经兴奋时，效应器的表现？——应急反应 β-受体拮抗剂

注：A类药物均无内在拟交感活性（ISA） B类药物均有内在拟交感活性（ISA） β受体阻断药---洛尔 β-受体阻断药，普萘洛尔是代表，临床治疗高血压，心律失常心绞痛。三条禁忌记心间，哮喘心衰心动缓。 β1-长在心脏上，阻断效果是四降；降率降传降耗氧，降低输出降血压； β2-长在气管上，还有冠脉和腿上；阻断无益反不良，哮喘急冠和肢凉。【普萘洛尔（心得安）的药理作用、临床应用和不良反应】

【例题】 β肾上腺素受体阻断药能引起 A.脂肪分解增加 B.肾素释放增加 C.心排出量增加 D.支气管平滑肌收缩 E.房室传导加快『正确答案』D 『答案解析』β肾上腺素受体阻断剂可以收缩支气管平滑肌。 β肾上腺素受体阻断药禁用于 A.糖尿病 B.支气管哮喘 C.窦性心动过速 D.心绞痛 E.甲状腺功能亢进『正确答案』B 『答案解析』β肾上腺素受体阻断剂可以收缩支气管平滑肌，因此禁用于支气管哮喘。以下不可用β受体阻断药治疗的是 A.过速型心律失常 B.感染性休克 C.心绞痛 D.高血压

E.甲状腺功能亢进『正确答案』B 『答案解析』β受体阻断药不治疗感染性休克。下列哪项不属于β受体阻断药的不良反应 A.诱发或者加剧哮喘 B.掩盖低血糖的症状 C.引起末梢循环不良 D.心动过缓 E.诱发或加剧溃疡穿孔『正确答案』E 『答案解析』ABCD是β受体阻断药的不良反应。【多选题】用β受体阻断药时要注意 A.用药剂量要个体化，长期用药不能突然停药 B.重度房室传导阻滞病人禁用 C.严重左室心功能不全的患者禁用 D.支气管哮喘及窦性心动过缓者禁用 E.肝功能不良及心肌梗死者应慎用『正确答案』ABCDE 『答案解析』本题五个选项都正确，注意掌握。【其他药物】 1.有内在拟交感活性的β1.β2受体阻断药 ——吲哚洛尔（吲哚心安，心得静） □对β1、β2受体无选择性 □作用强度为普萘洛尔的6～15倍 □有膜稳定作用，较弱 □其特点是内在拟交感活性最强 2.无内在活性的β1受体阻断药 □阿替洛尔（氨酰心安）、美托洛尔（美多心安，倍他乐克）□选择性阻断β1受体，无ISA； □一般不诱发或加重支气管哮喘； □对血糖影响少（糖尿病患者宜选用）； □主要用于治疗高血压、心律失常和心绞痛、甲亢、偏头痛等。 3.有内在活性的β1受体阻断药 □醋丁洛尔（醋丁酰心安） □选择性阻断β1受体，有ISA，有膜稳定作用 □首过效应较明显 □用于高血压，心绞痛及心律失常，一般不良反应同普萘洛尔。 α-受体阻断药 1.非选择性α受体拮抗剂——酚妥拉明 2.选择性α1-受体拮抗剂——妥拉唑林、特拉唑嗪

H受体拮抗剂

H2受体拮抗剂 [主要品种] H2受体拮抗剂包括西米替丁、雷尼替丁、法莫替丁等。[适应症] 主要用于治疗胃和十二指肠溃疡。 [作用特点] H2受体拮抗剂能选择性地阻断壁细胞膜上的H2受体，使胃酸分泌减少。不仅抑制基础胃酸的分泌，而且能部分地阻断组胺、五肽胃泌素、拟胆碱药和刺激迷走神经等所致的胃酸分泌。 [药理作用] H2受体拮抗剂选择性地竞争结合壁细胞膜上的H2受体，使壁细胞内cAMP产生，胃酸分泌减少。H2受体拮抗剂不仅对组胺刺激的酸分泌有抑制作用，尚可部分地抑制胃泌素和乙酰胆碱刺激的酸分泌。常用的西咪替丁、雷尼替丁、法莫替丁等三种H2受体拮抗剂抑制胃酸分泌的相对能力相差20～50倍，以甲氰咪胍最弱，法莫替丁最强。相应地抑制50%五肽胃泌素刺激的酸分泌所需的有效血浓度(EC50)，以甲氰咪胍最高，法莫替丁最低。在常规剂量下，血浓度超过EC50的时间在甲氰咪胍约6小时，其他两种约10小时。[不良反应] H2受体拮抗剂是相当安全的药物，严重不良反应的发生

率很低。年龄大、伴肾功能和其他疾病时，易产生不良反应，常见腹泻、头痛、嗜睡、疲劳、肌痛、便秘等。[H2受体拮抗剂新用法] H2受体拮抗剂可高度选择性地与组胺H2受体结合，竞争性地拮抗组胺与H2受体结合后引起的胃酸分泌，产生抑酸作用，用于治疗消化性溃疡。传统的给药方法是一日剂量分次给药，如西咪替丁200毫克，每天四次或400毫克，每天二次；雷尼替丁150毫克，每天二次；法莫替丁20毫克，每天二次；尼扎替丁150毫克，每天二次；罗沙替丁75毫克，每天二次。近年来的研究结果表明，组胺的基础分泌以夜间为主，并且夜间胃液酸度在消化性溃疡，特别是十二指肠溃疡发病机制中起重要作用。白天的胃酸分泌与乙酰胆碱、胃泌素相关，且排出量不但与溃疡的形成无关，而且还具有以下显著的生理性作用：维持正常的消化过程，特别是蛋白质的消化，因为胃蛋白酶原转变为胃蛋白酶只有在足够酸的环境中才能实现；一定的胃酸酸度与钙和铁的吸收有重要关系；白天正常的胃酸分泌可保持胃内无菌环境，避免念珠菌使溃疡愈合延缓、幽门螺杆菌感染引起部分患者溃疡病的过早复发、胃酸持久抑制引起一些患者腹泻。因此，有学者认为，H2受体拮抗剂在白天的抑酸作用弱，而夜间给予此类药可以有效地抑制胃酸分泌，从而可以使溃疡快速愈合，症状缓解。临床观察也支持这一观点，即在睡前将H2

阿片受体研究进展

阿片受体研究进展上海第二医科大学附属瑞金医院麻醉科彭章龙罂粟用于减轻疼痛已有近千年的历史。1803年由罂粟生物碱分离物质出的晶体，被证实是天然阿片的镇痛活性成份，称为吗啡。吗啡的立体化学结构是其与机休特异部位相互作用产生镇痛所必须。通过吗啡、酮唑辛和SKF-10047等一组激动药所产不同药理活性，确定了三种阿片类药物综合征，分别命名为μ, κ和σ原型，由此导致了μ, κ和σ三种阿片受体的发现。后来发现与SKF-10047相关的σ型综合征不能被普通阿片拮抗剂纳洛酮(naloxone)所阻断，因此σ型受体不再被认为是阿片受体家族的成员。δ型受体是由kosterlitz小组在研究内源性阿片肽和内啡肽的效应时发现的。经过近30年的实验室研究，对μ、κ和δ型受体的认识已较清楚，其基因编码已被克隆，这3种受体称为“经典型阿片受体”。最近cDNA 编码一种称之为“孤立阿片”受体，经签定与经典阿片受体有高度同源性，它的结构基团是阿片受体，因此称其为阿片样受体(opioid receptor-like，ORL1)。有药理学迹象表明每种阿片受体存在亚型，以及其他新型、较少了解的阿片受体ε、λ、ι和ζ。本文着重介绍阿片受体研究进展。一．经典阿片受体三种经典μ、κ和δ阿片受体被确认后，发现在脑内分布广泛但不均匀。这些受体分布在痛觉传导区以及与情绪和行为有关的区域，集中分布在导水管周围灰质、内侧丘脑、杏仁核和脊髓胶质区。这些复杂的受体可以被不同的激动剂激活，产生不同的生物效应。例如主要分布于脑干的μ受体被吗啡激活后，可产生镇痛和呼吸抑制等作用，而主要分布于大脑皮质的κ受体只产生镇痛作用而不抑制呼吸。然而不同阿片受体在中枢神经系统的分布，以及对不同阿片配体结合能力存在差异。阿片受体的内源性配体为脑啡肽、内啡肽和强啡肽，它们分别由不同的基因编码。这些五肽对阿片受体的亲和力不同，但三者均可与一种以上的阿片受体结合。其中脑啡肽对δ型受体有较强的选择性，被认为是其内源性配体。强啡肽对κ 型受体选择性较强，是其内源性配体。μ型受体的内源性配体直到1997年才被发现，称为内啡肽或内源性吗啡(endomorphine)。内源性吗啡在中枢神经系统与μ-阿片受体呈镜像分布，对μ受体的结合力比对δ和κ受体的结合力高100倍。

试管婴儿的详细流程步骤

试管婴儿的详细流程步骤试管婴儿过程是怎么样的?试管婴儿需要通过检查排卵、取卵取精、体外受精、受精卵移植、补充激素和后续观察受精卵是否着床等过程，其中每一步都要经过严格的操作，一旦出错，整个试管婴儿手术都会失败。试管婴儿的具体流程步骤如下：促排卵治疗由于不是每个卵子都能受精，不是每个受精卵都能发育成有活力的胚胎，因此要从女性体内获得多个卵子，才能保证有可以移植的胚胎，这就需要对女性进行促排卵治疗。促排卵的方案有很多种，如标准长方案、短方案、拮抗剂方案等。长方案是指在前一周期的黄体期开始应用GnRH激动剂，短方案是指在月经周期的第2天开始应用GnRH激动剂，而拮抗剂方案是在先应用促性腺激素、卵泡长到一定程度后开始应用GnRH拮抗剂。应用GnRH激动剂或拮抗剂的目的都是为了防止卵子在取卵前自发排掉。总的来讲，长方案的成功率最高，但并不是所用的妇女都适合用长方案。促排卵方案一定要根据每个人的具体情况来制定，既所谓的“个体化”治疗。在进入IVF周期前，多数情况下会让妇女在前一个周期服用避孕药，目的是抑制排卵，这样可以避免自然周期万一妊娠，在月经前应用GnRH激动剂对胎儿造成影响(有造成流产的可能)。另外，对于月经不规律的人，应用避孕药便于确定促排卵的时间。此外，应用避孕药还可以防止卵巢生理性囊肿的形成，利于促排卵治疗。在月经周期的第2天，或GnRH激动剂压抑满意后(生殖激素和子宫卵巢超声检查结果达到要求)，妇女开始应用促排卵药物。医生根据超声监测和血清激素测定的结果判断卵泡生长的情况，决定是否需要调整促排卵药物的用量。当卵泡成熟后，给予hCG注射，以促进卵子最后成熟。通常在注射hCG后36-38小时取卵。泰国一般促排7-8天时间，视个人情况来决定。取卵医生在B超引导下应用特殊的取卵针经阴道穿刺成熟的卵泡，吸出卵子。取卵通常是在静脉麻醉下进行的，因此妇女并不会感到穿刺过程导致的痛苦。体外受精精子的获取当女性取卵时，男性进行取精。精液经过特殊的洗涤过程后，将精卵放在特殊的培养基中，以期自然结合。这就是所谓的常规受精方式。

H1受体拮抗剂

H1受体拮抗剂 1.第一代H1受体拮抗剂 ①苯海拉明（可太敏、苯那君）：是最早的抗组胺药，镇静作用明显，亦有抗胆碱、止吐和局麻作用，是治疗婴儿特应性皮炎和湿疹的首选药。口服，成人剂量为25～50mg/次，体重＞9kg的儿童为12.5～25mg/次，每日2～3次。小儿用0.2%糖浆1～2mg/(kg.d)，分3～4次口服。苯海拉明糖浆，患儿＜6个月，苯海拉明糖浆每次lml，每日3次；＞6个月，每次1.5ml，每日3次；1岁，每次2m1，每日3次；2岁，每次3ml，每日3次；3岁，每次4m1，每日3次。6岁以上儿童及成人苯海拉明注射液肌注用量为20mg/次，每日1～2次。偶可引起皮疹及粒细胞减少，长期应用6个月以上可引起贫血。 ②氯马斯汀（吡咯醇胺）：口服后30分钟起效，抗组胺作用强而持久，可维持药效12小时。口服，成人及12岁以上儿童，1.34mg/次，每日2次。可配成0.25%～0.5%糖浆供儿童服用。3～6岁，每次2.5～5ml；6～12岁，每次5m1，均为每日2次。常见头昏、嗜睡，尚有轻度抗胆碱作用，新生儿和早产儿禁用。 ③氯苯那敏（扑尔敏）：抗组胺作用强，有镇静及抗胆碱作用。口服，成人剂量为4～8mg/次，每日3次；小儿0.35mg/(kg.d)，分3～4次服。忌用于1岁以下的儿童，孕妇慎用。肌注，成人10mg/次，每日1次；儿童皮下注射0.35mg/(kg.d),分4次给药。肝功能不全者不宜长期使用本药。 ④赛庚啶(安替根）：抗组胺作用较扑尔敏强，且具有轻、中度的抗5-羟色胺作用及抗胆碱作用，是治疗急性荨麻疹的有效药物，尤其对寒冷性荨麻疹有较好的疗效。口服，成人2～4mg/次，每日3～4次；儿童每日0.15～0.25mg/kg，分3次服。2～6岁儿童单次剂量不超过lmg, 2岁以下儿童不宜使用本药，孕妇及哺乳期妇女慎用。副作用多以嗜睡为主。 ⑤异丙嗪(非那根）：为氯丙嗪的衍生物，抗组胺作用强，兼有显著的中枢抑制作用和抗胆碱作用，其作用时间较苯海拉明长。口服，成人12.5～25mg/次，

临床用阿片受体拮抗剂研究进展

Journal of Organic Chemistry Research 有机化学研究, 2015, 3, 9-15 Published Online March 2015 in Hans. https://www.wendangku.net/doc/fa17222067.html,/journal/jocr https://www.wendangku.net/doc/fa17222067.html,/10.12677/jocr.2015.31002 Research Progress of Opioid Receptor Antagonist Used in Clinic Qiao Wang1,2, Lang Shu1,2, Ming Liu3, Kaiyuan Shao2, Wenxiang Hu1,2,3* 1School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan Hubei 2Beijing Excalibur Space Military Academy of Medical Sciences, Beijing 3School of Life Sciences, Capital Normal University, Beijing Email: *huwx66@https://www.wendangku.net/doc/fa17222067.html, Received: Jan. 23rd, 2015; accepted: Feb. 4th, 2015; published: Feb. 10th, 2015 Copyright ? 2015 by authors and Hans Publishers Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). https://www.wendangku.net/doc/fa17222067.html,/licenses/by/4.0/ Abstract Opioid receptor antagonists are a class of specifically drugs for antagonizing the opioid on opioid receptors, thereby reducing or reversing the analgesic activity of narcotic agonists. Antagonists can also eliminate breathing suppression, gastrointestinal disorders and other side effects caused by the use of the agonist. Antagonists are used in clinic as side effects and coma antidote arising from excessive usage of analgesic. This paper summarizes several common clinical types of opioid receptor antagonists and clinical applications. In recent years, antagonists have achieved greater development, but there are still some deficiencies; further research of opioid receptor antagonists is needed to get more competitive, safer and simpler novel μ opioid receptor-specific antagonist, for better use in clinical treatment. Keywords Opioid Receptor, General Opioid Receptor Antagonist, Peripheral Opioid Receptor Antagonist 临床用阿片受体拮抗剂研究进展王乔1,2，舒浪1,2，刘明3，邵开元2，胡文祥1,2,3* 1武汉工程大学化工与制药学院，湖北武汉 2北京神剑天军医学科学院，北京 3首都师范大学生命科学学院，北京 *通讯作者。