Leuprolide_Acetate_HNMR_13282_MedChemExpress
端粒酶抑制剂伊美司他治疗血小板增多IF56
T h e ne w engl a nd jour na l o f medicineFrom the Department of Hematology, University Hospital of B ern and Univer-sity of B ern, B ern, Switzerland (G.M.B., E.O.L., M.D.); the Department of Hema-tology, School of Medicine, Cardiff Uni-versity, Cardiff, United Kingdom (O.G.O.); Upstate Oncology Associates, Greenville, SC (G.S.); the Section of Hematology and Oncology, University of Chicago, Chica-go (O.O.); the Divisions of Hematologic Malignancies and Hematology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Med-icine, B altimore (M.A.M.); the Depart-ment of Hematology, University Hospital Essen, Essen, Germany (A.R.); and Geron, Menlo Park (B.B., M.S.), and the Depart-ment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Gehr Family Center for Leukemia Research, Duarte (D.S.S.) — both in California. Ad-dress reprint requests to Dr. Baerlocher at the Department of Hematology, Stem Cell and Molecular Diagnostics Labora-tory, Freiburgstr. 4, Inselspital, University Hospital of Bern, CH-3010 Bern, Switzer-land,or at g abriela.b aerlocher@i nsel.c h. N Engl J Med 2015;373:920-8.DOI: 10.1056/NEJMoa1503479Copyright © 2015 Massachusetts Medical Society.BACKGROUNDImetelstat, a 13-mer oligonucleotide that is covalently modified with lipid exten-sions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether ime-telstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies.METHODSA total of 18 patients in two sequential cohorts received an initial dose of 7.5 or9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic milli-meter. The primary end point was the best hematologic response.RESULTSImetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 pa-tients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neu-tropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity.CONCLUSIONSRapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; number, NCT01243073.)ABSTR ACTTelomerase Inhibitor Imetelstat in Patients with Essential ThrombocythemiaGabriela M. Baerlocher, M.D., Elisabeth Oppliger Leibundgut, Pharm.D.,Oliver G. Ottmann, M.D., Gary Spitzer, M.D., Olatoyosi Odenike, M.D., Michael A. McDevitt, M.D., Ph.D., Alexander Röth, M.D., Michael Daskalakis, M.D., Bart Burington, Ph.D., Monic Stuart, M.D.,and David S. Snyder, M.D.Imetelstat in Essential ThrombocythemiaE ssential thrombocythemia, a myelo-proliferative neoplasm, is a clonal disorderof a multipotent hematopoietic progenitor cell.1,2 The disease is associated with an in-creased risk of thrombotic complications, hemor-rhagic complications, or both, and can evolve into myelofibrosis or, in rare cases, can trans-form to acute leukemia.3 Common mutations associated with essential thrombocythemia are found in the Janus kinase 2 (JAK2) gene, the gene encoding the thrombopoietin receptor (MPL), and the calreticulin (CALR) gene.4-8 Cur-rent standard therapies for high-risk patients with essential thrombocythemia induce nonspe-cific reductions in platelet counts but do not typically eliminate or alter the biologic charac-teristics of the disease.9-12We have reported that telomerase activity in malignant cells obtained from patients with es-sential thrombocythemia and induced telomerase activity in cells isolated from healthy donors were inhibited by the telomerase inhibitor imetelstat.13 However, imetelstat inhibited spontaneous pro-liferation of megakaryocytic colonies obtained from patients with essential thrombocythemia but did not inhibit cytokine-induced megakaryo-cytic colonies from healthy donors. These find-ings suggest an intrinsic sensitivity of essential-thrombocythemia megakaryocytes to telomerase inhibition.13Imetelstat, a 13-mer thiophosphoramidate oli-gonucleotide that is covalently modified with lipid extensions, inhibits telomerase enzymatic activity14 (see the Supplementary Background sec-tion in the Supplementary Appendix, available with the full text of this article at ). In this phase 2 study, we investigated whether im-etelstat could elicit hematologic and molecular responses in patients with essential thrombocy-themia who had disease that was refractory to prior therapies or who had had unacceptable side-effects from previous therapies.MethodsEligibility CriteriaPatients who were 18 years of age or older and had received a diagnosis of essential thrombocy-themia defined according to World Health Orga-nization criteria15 (Table S1 in the Supplemen-tary Appendix) were eligible for enrollment if they required cytoreduction because of a platelet count higher than 600,000 per cubic millimeter and if they had not had a response to or had had unacceptable side effects from at least one prior therapy or if they declined to receive standard therapy. Additional inclusion and exclusion cri-teria are described in the Supplementary Ap-pendix.Study DesignThis was a phase 2, open-label study that was conducted at seven sites in the United States, Germany, and Switzerland; enrollment occurred during the period from January 2010 through January 2013. Patients were enrolled into se-quential cohorts that received weekly doses of 7.5 or 9.4 mg of imetelstat per kilogram of body weight, intravenously, until a platelet count of approximately 250,000 to 300,000 per cubic milli-meter was achieved or toxic effects occurred. Maintenance dosing at a reduced frequency be-gan after a patient had a complete or partial hematologic response (Table S2 in the Supple-mentary Appendix), with doses (7.5 to 11.7 mg per kilogram) adjusted according to the patient’s response and the side-effect profile of the drug. Additional details regarding the study design are provided in the Supplementary Appendix.The primary end point of the study was the best overall hematologic response, which was defined according to the platelet response com-ponent of the 2009 European LeukemiaNet (ELN) response criteria16 (Table S2 in the Supplemen-tary Appendix). Secondary end points included the frequency and severity of adverse events, the duration of hematologic response, the ELN “clin-icohematologic” response, and the molecular response in patients with JAK2 V617F mutations (Table S2 in the Supplementary Appendix), MPL W515L or MPL W515K mutations, or CALR mu-tations.All patients were assessed for JAK2 V617F, MPL W515L, MPL W515K, and CALR mutations at baseline and were reassessed every 12 weeks (±4 weeks) (see the Supplementary Methods sec-tion in the Supplementary Appendix). Patients who were enrolled in Europe underwent testing of spontaneous growth inhibition of mega-karyocyte colony-forming units (CFUs) (see the Supplementary Methods section in the Supple-mentary Appendix).T h e ne w engl a nd jour na l o f medicineSafety AssessmentData were collected on the extent of imetelstat exposure and on all adverse events. Adverse events were summarized according to terms used in the Medical Dictionary for Regulatory Activities, and severity was assessed with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE),17 version 4.03. For events with varying severity, the maxi-mum reported grade was used in summaries. Laboratory abnormalities were defined accord-ing to normal laboratory ranges from each insti-tution and converted to CTCAE grades.Study OversightThis phase 2 study was approved by the institu-tional review board at each participating site. The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines. All patients provid-ed written informed consent.The sponsor, Geron, provided the study drug and in collaboration with the authors designed the study and analyzed the data. The first author wrote the initial draft, and subsequent drafts were written by all authors with assistance from medical writers paid by Janssen Research and Development. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and analyses and for adherence to the study protocol, which is available at . Clini-cal-trial agreements between the sponsor and the authors’ institutions included confidentiality provisions.Statistical AnalysisThe analysis of the primary end point of hema-tologic response included all patients who re-ceived at least one dose of imetelstat. The analy-sis of the duration of response included all patients who had a response. The analysis of molecular response included patients who re-ceived at least one dose of imetelstat and who had a JAK2 V617F, MPL W515L, MPL W515K, or CALR mutant allele burden at baseline. For re-sponse end points, exact 95% confidence inter-vals were calculated. The duration of hemato-logic response was estimated with the use of the Kaplan–Meier method. Patients who were lost to follow-up, discontinued the study, or began to receive other essential thrombocythemia–directed therapy before a hematologic response was documented and confirmed were counted as not having had a response. Safety analyses included all patients who received at least one dose of imetelstat.R esultsPatientsA total of 18 patients were enrolled in the study, and all had received one or more previous treat-ments; 17 had received hydroxyurea (94%), 13 had received anagrelide (72%), and 4 had received interferon (22%) (Table 1). Nine of the 18 pa-tients (50%) had disease that was resistant to at least one prior therapy, and 14 (78%) had had unacceptable side effects from prior therapy. The median time from the initial diagnosis ofe ssential thrombocythemia to enrollment was7.2 years (range, 0.3 to 24.9), and the median baseline platelet count was 788,000 per cubic millimeter (range, 521,000 to 1,359,000). Fifteen patients had baseline mutant allele burdens (8 with JAK2 V617F mutations, 2 with MPL W515L or MPL W515K mutations, and 5 with CALR mu-tations) (Table 1). Table S3 in the Supplementary Appendix describes additional baseline charac-teristics of the patients.Primary Efficacy End Point and Key Secondary Efficacy End PointOf the 18 patients who received imetelstat, 7 re-ceived an initial dose of 7.5 mg per kilogram and 11 received 9.4 mg per kilogram intravenously. The overall rate of hematologic response was 100% (95% confidence interval [CI], 83 to 100), and 16 of the 18 patients (89%) had a complete hematologic response (95% CI, 65 to 99) (Fig. 1A). In the 2 patients with a partial hematologic re-sponse, the lowest platelet counts were 261,000 per cubic millimeter at 23 weeks and 56,000 per cubic millimeter at 18 weeks, but neither response was sustained. Among the 16 patients who had a complete hematologic response, the median time to a complete response was 6.1 weeks (range, 5.1 to 12.1); the median time to a com-plete response was similar in JAK2 V617F–posi-tive and JAK2 V617F–negative patients. A trend was observed toward a more rapid response in patients in whom the initial dose was 9.4 mg per kilogram than in those in whom the initial dose was 7.5 mg per kilogram (median, 6.1 vs. 12.1Imetelstat in Essential Thrombocythemia weeks), although the difference was not signifi-cant (P = 0.71).During maintenance dosing, intermittent dos-ing was attempted in most patients and thefrequency of dosing generally decreased withtime; all the patients who had a complete hema-tologic response received a dose every 2 weeksor less frequently. At the time of the primaryanalysis, with a median follow-up of 17 months,10 of the 16 patients with a complete hemato-logic response (62%) were still receiving treat-ment, and the median duration of responsehad not been reached (follow-up range, 5 to 30months).While receiving the study treatment, one pa-tient had grade 2 bilateral retinal ischemia andwas recovering, and another had grade 2 lefthemiparesis and recovered; these thromboem-bolic events were assessed by the study investi-gators as being potentially related to underlyingessential thrombocythemia. The durations ofresponse ended at the reported onset of theseconditions, no further clinical follow-up infor-mation was obtained, and neither patient dis-continued imetelstat. Three patients had diseaseprogression from essential thrombocythemia tosecondary myelofibrosis, either during the studytreatment period or during the safety follow-upperiod.Other Secondary Efficacy End PointsMolecular ResponseA partial molecular response was detected inseven of eight patients with JAK2 V617F mutationsat baseline (88%; 95% CI, 47 to 100) (Fig. S1 inthe Supplementary Appendix). The median JAK2V617F mutant allele burden was reduced by 71%at month 3 after the initiation of treatment andremained reduced by 59% at month 12 despiteless frequent maintenance dosing (Fig. 1B).MPL W515L, MPL W515K, and CALR mutantallele burdens were also reduced, by 15 to 66%. Further information is provided in Table S4 in the Supplementary Appendix.Inhibition of ProliferationA megakaryocyte CFU assay was performed in five patients. It showed substantial inhibition of spontaneous proliferation at 1 month after ini-tiation of imetelstat treatment, with a median 92% reduction from baseline (Table S5 in the Supplementary Appendix).ELN “Clinicohematologic” ResponseResults with respect to the secondary end pointof a “clinicohematologic” response according toELN criteria16 (see Table S2 of the Supplementary Appendix) were similar to those of the primaryend point. A complete ELN clinicohematologic response was observed in 17 of the 18 patients (94%), and a partial response was observed in1 patient (6%). In 1 patient, splenomegaly thatwas palpable at 3 cm at baseline became nonpal-pable after the first cycle of treatment. None of* O ne patient did not meet the inclusion criteria for the minimum baseline platelet count, but the investigator thought that cytoreductive therapy was clinically indicated.† T hree patients had no mutation.T h e ne w engl a nd jour na l o f medicinethe 18 patients had constitutional symptoms at baseline.Telomerase Activity, Telomere Length, and Bone Marrow ResponseFigure S3 in the Supplementary Appendix shows telomerase activity. Assessments of telomere length and bone marrow response are described in the text of the Supplementary Appendix.S afetyThe most frequent adverse events that occurred during treatment (those that occurred in 50% or more of the patients and selected clinically sig-nificant adverse events) are listed in Table 2. All adverse events are listed in Table S6 in the Sup-plementary Appendix. Adverse events were re-ported in all patients, and 15 of the 18 patients (83%) reported at least one event of grade 3 or higher. Eighteen events of grade 3 or higher were attributed to imetelstat by the investigators, including neutropenia, headache, anemia, and a syncopal episode due to an infusion reaction (a second syncopal episode in the same patient was deemed to be unrelated to imetelstat). One grade 4 adverse event (a femoral-neck fracture) was reported by the treating clinician as being unrelated to imetelstat (Table S6 in the Supple-mentary Appendix). Eight of the 18 patients (44%) discontinued the study (Table S7 in the Supplementary Appendix).The most common nonlaboratory adverse events attributed to imetelstat were fatigue (in 15 of the 18 patients), nausea (in 12), diarrhea (in 11), and headache (in 8) (Table S8 in the Supplemen-tary Appendix). Infections occurred during treat-ment in 17 of the 18 patients (94%); 15 of these 17 patients (88%) had infections of grade 2 or lower. The most common infections were upper respiratory infections (in 39% of the patients), urinary tract infections (in 22%), and influenza (diagnosed on the basis of clinical and labora-tory findings), nasopharyngitis, and rash (each in 17%). The infections lasted less than 3 weeks in 81% of the patients and were not typically as-sociated with cumulative imetelstat exposure or with concurrent neutropenia or lymphopenia.At least one increase in grade, from baseline, in a liver-function value was observed in all 18 patients (Table 3). The majority of patients had grade 1 increases in alanine aminotransferase levels, with accompanying grade 1 increases in aspartate aminotransferase levels (the latter per-Figure 1. Hematologic and Molecular Responses in Patients Who Received Imetelstat.Panel A shows the hematologic response according to mutation status (cal-reticulin [CALR ], Janus kinase 2 [JAK2] V617F, MPL W515L or MPL W515K mutations, or no mutation). A complete hematologic response was observed in 16 of the 18 patients in the study (89%), and a partial hematologic response (“no complete response”) was observed in 2 patients (11%). The median time to a complete hematologic response was 1.4 months. Percentages shown are the best percent change in the mutant allele burden from base-line. Panel B shows the molecular response in JAK2 V617F–positive patients after treatment with imetelstat. The median JAK2 V617F mutant allele bur-den was reduced by 71% at month 3 and by 59% at month 12 despite less frequent maintenance dosing. I bars indicate 95% confidence intervals. The percent change shown is the median percent change in the JAK2 V617F mutant allele burden from baseline.CALR−31−36−48−55−15JAK2 V617FNo mutation04628121026181614282220243230MonthsB Molecular ResponseA Hematologic ResponseTime to first platelet count of 400×103/mm 3Time to complete responseNocomplete responseTreatment continuedM e d i a n J A K 2 V 617F (p e r c e n t c h a n g e f r o m b a s e l i n e )C h a n g e f r o m B a s e l i n e (%)−40−20−60−80−100Baseline 3691215MonthsP=0.001No. at Risk Percent Change88−718−688−727−595−52Discontinuation of treatment−96−82MPL−93−24−90−72−96−82−66−16−50−25Imetelstat in Essential Thrombocythemia sisted with ongoing imetelstat treatment). With-in 4 weeks after the initiation of imetelstat treat-aminotransferase level of 5 to 7 times the stan-dard upper limit of the normal range (grade 3)and concurrent increases in the aspartate ami-notransferase level of 2 to 6 times the standardupper limit of the normal range (grades 1 to 3)with dose reduction and did not recur with con-tinued treatment. With a longer duration oftreatment, persistent (≥6 weeks) grade 1 in-creases in alkaline phosphatase levels were ob-served in 14 of the 18 patients; these increaseswere associated with grade 1 or 2 unconjugated hyperbilirubinemia in 4 patients (Table 3).In post-study follow-up safety assessments,among the 14 patients who had persistent (≥6weeks) abnormalities in liver-function values, 11(79%) had values that reversed to normal orbaseline values. In 3 patients, the liver-functionvalues did not return to the upper limit of thenormal range; all hepatic biochemical abnor-malities in 2 of these patients improved, withcomplete resolution of the abnormal values, andthe 1 remaining patient whose condition wasnot improving at the end of follow-up had pro-patients who underwent extended follow-up forpersistent (≥6 weeks) abnormalities on liver-function tests, the median time to resolutionafter discontinuation of treatment was 12 weeks.The observed resolutions of these abnormalitiesfollowed permanent discontinuation of ime-telstat in all patients as the result of a full clini-cal hold issued by the Food and Drug Adminis-tration (FDA) (see the Discussion section).After the primary analysis was performed inOctober 2013, one patient who had received im-etelstat for approximately 3 years died frommonths after discontinuation of treatment. Cir-rhosis, secondary to hepatic steatosis, was thesuspected underlying disease. Although the pa-tient’s age (83 years), multiple coexisting condi-tions (including a history of exposure to hepati-tis B), and concomitant medications confoundedassessment, imetelstat could not be conclusivelyexcluded as a contributory agent.Hematologic toxic effects, defined according to changes in laboratory results from baseline values, are listed in Table 4. Thrombocytopenia of less than grade 3 was seen in 9 of the 18 pa-tients (50%). Neutropenia was observed in 15 pa-tients (83%), including 7 with grade 3 neutrope-nia (39%) and 3 with grade 4 neutropenia (17%).* I ncluded are the adverse events that occurred in 50% or more of the patients and selected clinically significant adverse events, regardless of whether they were deemed to be related to the study drug. The grade of adverse event was defined on the basis of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).* L aboratory abnormalities were defined on the basis of normal laboratory rang-es at each institution and were graded according to the CTCAE. The maximum grade was calculated for patients who had an increase in grade, as compared with the baseline grade. There were no grade 4 increases.na l o f medicineNo cases of febrile neutropenia were reported,and no patients with grade 4 neutropenia had a concurrent infection. Lymphopenia was reported in 6 patients (33%), with one grade 3 event. Fif-teen patients (83%) had anemia, and 3 (17%) had grade 3 anemia. Three patients required red-cell transfusions, including a patient who had a postsurgical hemorrhage. Three reported cases of cytopenia led to dose reductions: one for grade 1 thrombocytopenia, one for grade 3 ane-mia in a patient who required a red-cell transfu-sion, and one for grade 3 neutropenia; all three cases resolved.DiscussionIn this study, imetelstat rapidly induced hemato-logic responses in patients with essential throm-bocythemia who had disease that was refractory to conventional therapies or who had had unac-ceptable side effects from conventional therapies. All the patients had a hematologic response, and 89% had a complete hematologic response, a rate that exceeded rates observed with hydroxyurea, anagrelide, and interferon treatment.12,18-21 Else-where in this issue of the Journal , Tefferi et al. report the results of a pilot study of imetelstat therapy showing the induction of complete or partial remissions, as well as molecular remis-sions, in a subgroup of patients with myelofi-brosis.22JAK2 V617F may provide a useful marker of neoplastic proliferation, and current therapies elicit molecular responses in only a minority of patients with this mutation.12,20,23,24 In contrast,a rapid, substantial reduction in mutant allele burden was observed in all JAK2 V617F–positive patients in this study; 88% of patients had a partial molecular response. Attenuation and loss of a molecular response later during therapy may be due in part to reduced-frequency maintenance dosing; this suggests that the duration of ime-telstat treatment was insufficient to eliminate all mutated committed and clonal primitive hema-topoietic progenitors. The decrease in the CALR and MPL mutant allele burdens provides support for the hypothesis that imetelstat can reduce the various malignant clones observed in myelopro-liferative neoplasms. The decrease in the mutant allele burden appeared to be more pronounced for the JAK2 V617F mutations than for the CALR mutations, possibly because of activation of telomerase reverse transcriptase by the Janus kinase–signal transducer and activator of tran-scription (JAK-STAT) signaling pathway in pa-tients with essential thrombocythemia who had JAK2 V617F mutations.25,26Megakaryocyte CFU assays that were used to more directly measure inhibition of proliferation showed more than 90% inhibition of baseline proliferation activity within 1 month after the initiation of treatment in four of the five patients tested. These data suggest that imetelstat may have a selective inhibitory effect on the growth of the neoplastic clone or clones that drive es-sential thrombocythemia.Although all the patients had hematologic responses, there were subsequent fluctuations above normal platelet levels in all patients. Re-sponses were considered to be durable if inter-mittent dosing restored and maintained the platelet count (≤600,000 per cubic millimeter for a partial response or ≤400,000 per cubic milli-meter for a complete response). Once an initial response was achieved, patients with platelet counts that were not controlled by maintenance dosing (i.e., platelet counts that were >600,000 per cubic millimeter in patients with a partial response or >400,000 per cubic millimeter in patients with a complete response) for at least 8 weeks were considered to have a loss of re-sponse. The reported complete hematologic re-sponses were durable but required ongoing ime-telstat therapy; interpatient variability was noted in the frequency of dosing required to manage platelet levels (every 2 weeks to every 4 weeks or more) (Fig. S2 in the Supplementary Appendix).* L aboratory abnormalities were defined on the basis of normal laboratory rang-es at each institution and were graded according to the CTCAE. The maxi-mum grade was calculated for patients who had an increase in grade, as com-pared with the baseline grade.Imetelstat in Essential ThrombocythemiaAfter discontinuation of treatment, increases in platelet counts were consistent with the main-tenance interval during treatment. Patients with longer treatment intervals had more gradual increases after discontinuation of treatment, whereas patients who required more frequent dosing had more rapid increases.At the time of the primary analysis, 10 pa-tients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Of the adverse events attributed to imetelstat, most were mild to moderate; 18 events were of grade 3 or higher (Table S8 in the Sup-plementary Appendix). Upper respiratory infec-tions, which were reported in 6 of 18 patients (33%), were mostly mild to moderate and were not associated with myelosuppression or disease progression. Three patients had disease progres-sion from essential thrombocythemia to second-ary myelofibrosis, either during the study treat-ment period or during the safety follow-up period, and JAK inhibitor therapies were initiat-ed. Among these 3 patients, one had an unrelated grade 2 upper respiratory tract infection and grade 3 osteomyelitis and another had grade 2 influenza.In a study involving 1104 patients, the rates of progression from essential thrombocythemia and from early or prefibrotic primary myelofi-brosis to overt myelofibrosis were 0.8% and 12.3%, respectively, at 10 years and 9.3% and 16.9%, respectively, at 15 years.26 The prognostic variables associated with death or progression to leukemia or myelofibrosis were bone marrow histologic features (early or prefibrotic primary myelofibrosis vs. essential thrombocythemia), age (>60 years), history of thrombosis, leukocy-tosis, and anemia.27 The 3 patients in our study who had disease that progressed to myelofibro-sis had essential thrombocythemia for 12, 13, and 21 years and were 67, 61, and 56 years old, respectively, when myelofibrosis was diagnosed. Two of the 3 patients received the diagnosis near the date of their last dose of imetelstat, and 1 received the diagnosis 6 months after the last dose, during extended follow-up of liver func-tion. At baseline, 2 of the 3 patients had 1+ and 2+ reticulin fibrosis in the bone marrow, and the hemoglobin level in all 3 patients was lower than 12 g per deciliter. The rate of progression to myelofibrosis in the current study (17%; 3 of 18 patients) is higher than historical estimates; however, the small number of patients in this study and the presence of prognostic factors make cross comparisons difficult.Abnormal results of liver-function tests were observed frequently but were mostly mild in grade; one fatal event of bleeding esophageal varices occurred after the primary-analysis time point. On March 11, 2014, the FDA issued a full clinical hold on imetelstat, citing a lack of evi-dence of reversibility of hepatotoxicity, concern regarding a risk of chronic liver injury, and a lack of adequate follow-up in patients who had hepatotoxic effects. All the patients who were still receiving the study medication permanently discontinued active treatment and were observed for safety. Follow-up safety data showed that treatment-related abnormalities on liver-function tests resolved in most patients (Table S9 in the Supplementary Appendix), and the FDA lifted the clinical hold on October 31, 2014.In conclusion, imetelstat, a telomerase inhibi-tor, had a clinically significant effect on disease burden in patients with essential thrombocythe-mia who had not had a response to previous treatment or who had had unacceptable side ef-fects from conventional therapies. Neutropenia and abnormal liver-function tests were the main adverse events. Furthermore, molecular respons-es were observed in patients with mutated JAK2 and CALR molecular signatures; this finding suggests therapeutic activity in the malignant clones that are the underlying source of essential thrombocythemia.Supported by Geron.Disclosure forms provided by the authors are available with the full text of this article at .We thank the patients who volunteered to participate in this study and the study site staff who cared for them: Renata Bünter, Ursina Sager, Regula Jäggi, and Dr. Stephan Reichenbach at the Clinical Trials Unit of the University of Bern, Switzerland; Drs. Alexandre Theocharides, Gabi Vetsch, Giuseppe Colucci, and other members of the Clinical Hematology Team of the Univer-sity Hospital of Bern; Dr. Monika Haubitz, Dr. Meike Dahlhaus, Ingrid Helsen, Barbara Hügli, Elisabeth Ischi, and other mem-bers of the Experimental Hematology, Molecular Diagnostics, and Stem Cell Laboratory of Hematology teams of the University of Bern and University Hospital of Bern; the staff of Geron who were involved in data collection and analyses, including Dr. Joi Ninomoto for contributions to study design, and Ted Shih, Neeru Batra, Dianne Morfeld, and Raheela Kauser Steiner of Geron for their contributions to data acquisition, review, and interpreta-tion in previous studies and throughout the span of the trial; and Dr. Tracy T. Cao of Source One Technical Solutions and Dr. Namit Ghildyal of Janssen Research and Development, for edi-torial assistance with an earlier version of the manuscript.。
碘乙酰胺溶液(IAM,10mgml)
北京雷根生物技术有限公司
碘乙酰胺溶液(IAM,10mg/ml)
简介：
蛋白酶抑制剂(Protease Inhibitor)是指与蛋白酶分子活性中心上的一些基团结合，使蛋白酶活力下降甚至消失但不使蛋白变性的物质。
蛋白酶抑制剂有很多种，包括EDTA、E-64、NaVO 3、Bestatin、Leupetin、Pepstatin A、Aprotinin 等均可有效抑制蛋白的降解，并维持原有的蛋白间相互作用。
Leagene 碘乙酰胺溶液(IAM,10mg/ml)主要由碘乙酰胺iodacetamide 等组成，不含EDTA。
该碘乙酰胺溶液适用于从哺乳动物组织、细胞中提取蛋白质，能够更有效的获得目的蛋白质。
提取出来的蛋白可以用于Western Blot、免疫共沉淀等试验。
组成：
操作步骤(仅供参考)：
1、开盖前请低速离心一下，以便将黏附于管壁的液体甩至管底。
2、使用时，根据裂解液的用量加入碘乙酰胺溶液(IAM,10mg/ml)，使其终浓度达到恰当浓度。
注意事项：
1、碘乙酰胺溶液(IAM,10mg/ml)有轻微刺激性，小心操作，同时应避免反复冻融。
2、为了您的安全和健康，请穿实验服并戴一次性手套操作。
有效期：12个月有效。
相关：编号
名称PI0018
Storage 碘乙酰胺溶液(IAM,10mg/ml)
10ml -20℃避光使用说明书1份编号
名称DC0032
Masson 三色染色液DF0135
多聚甲醛溶液(4%PFA)TC0699葡植物总糖和还原糖检测试剂盒(硝基水杨酸法)。
枸橼酸爱地那非片
研发背景
国内抗ED类药物市场，一直以来，仿制药生产一直被“只仿药，不仿工艺、流程及晶型”难题所困扰，使用 原研药又有中西方体质不同导致用药差异的担忧。随着国家药监部门对创新药的持续和支持，为满足国人的用药 需求，新药研发已成为药企间竞争的关键点。
据统计，2021年我国创新药获批数量创历史新高，达68个，较2020年增长50%。且本土创新力量不断壮大， 从获批占比看，2021年国产创新药获批占达42.6%，中国创新显现硬核实力。悦康爱力士®枸橼酸爱地那非与此同 时经国家药监局批准成功上市，成为了2021年唯一获批的全球首个针对中国男性生理特征研发的抗ED1.1类创新 药。
禁止PDE5抑制剂（包括本品）与鸟苷酸环化酶激动剂（例如：利奥西呱）合用，因为这样可能会引起症状性 低血压。
临床实验
本品III期临床试验采用随机、双盲、多中心、安慰剂对照设计，比较口服枸橼酸爱地那非片与安慰剂治疗 ED的安全性和有效性。受试者随机进入爱地那非60mg组或安慰剂组，治疗期为12周。患者于性活动前1小时服用 规定剂量的试验药物或安慰剂，服药后应有性刺激。每位受试者每周内必须至少服药2次，但24小时内最多只能 服药1次。共入选470例（试验组352例、安慰剂组118例），FAS集460例（试验组343例、安慰剂组117例）。组 间人口学特征、ED病史、基线指标无统计学差异。患者年龄22～65岁，其中轻度（17～25分）、中度（11～16分） 和重度（1～10分）ED患者分别有99例（21.52%）、217例（47.17%）、144例（31.30%）。
佐匹克隆快速检验
佐匹克隆快速检验赵海雨;阚旭升【摘要】利用电喷雾液质联用法快速检验血中佐匹克隆。
少量血液样品采用乙腈沉淀蛋白后直接取上清液进样，使用 Allure PFP Propyl（5μm，100mm×2.1mm）柱，流动相：乙腈：10mmol/L 乙酸铵-0.1%甲酸缓冲液=70：30进行分离，经电喷雾离子源正离子化后通过三重四级杆质谱多反应监测（MRM）对佐匹克隆（m/z 389.3/345.4和 m/z 389.3/245.2）进行定性分析。
被害人血中检出佐匹克隆成分。
液质联用法检验血中佐匹克隆快速、准确、简单，可用于案件中检测血中佐匹克隆成分。
%Zopiclone, one kind of new generation of sedative-hypnotic of the cyclopyrrolone compounds, has different chemical structures and different pharmacological function from that of the first and second generations of the hypnagogue like barbitals and benzodiazepines. Recently, in a robbery case, the suspects utilized the zopiclone to anesthetize the victims. In our laboratory, the blood sample of the victim was treated with acetonitrile to precipitate the proteins and the supernatant was separated through an Allure PFP Propyl column (5μm,100mm×2.1mm) with the mobile phase containing acetonitrile (diluted to 70% by the buffer of 10mmol/L ammonium acetate mixed with 0.1% formic acid). The AB Sciex 4000Qtrap mass spectrometer equipped with an electro-spraying ionization source was used to detect two ion combinations of m/z 389.3/345.4 and m/z 389.3/245.2 by multiple reaction monitoring (MRM) for qualitative analysis of zopiclone. Finally, zopiclone was detected in the blood of the victims.【期刊名称】《刑事技术》【年(卷),期】2015(000)002【总页数】2页(P164-165)【关键词】法医毒物分析;LC/MS/MS;快速检验;佐匹克隆【作者】赵海雨;阚旭升【作者单位】辽宁省刑事科学技术研究所，沈阳 110032;辽宁省刑事科学技术研究所，沈阳 110032【正文语种】中文【中图分类】DF794.1DOΙ: 10.16467/j.1008-3650.2015.02.021佐匹克隆（zopiclone）是新一代环吡咯酮类镇静催眠药，纯品佐匹克隆是白色至淡黄色结晶或结晶性粉末，无臭，味苦，易溶于二甲亚砜或氯仿，较易溶于醋酸，较难溶于甲醇、丙酮或乙腈，极难溶于乙醚或异丙醇，几乎不溶于水，熔点178℃。
应用ELISA检测注射用重组人促血小板生成素模拟肽-Fc融合蛋白中卡那霉素残留量
药 物 分 析 杂 志 Chin J Pharm Anal 20人促血小板生成素 模拟肽 -Fc 融合蛋白中卡那霉素残留量
常翠云，崔颖，李晓然，齐连权 *
（北京泰德制药股份有限公司生物制品部，北京 100176）
摘要 目的：建立灵敏度更高的 ELISA 方法检测卡那霉素残留量并进行方法学验证，用于重组生物制品的 质量控制。方法：采用直接竞争 ELISA 方法，样品中残留的卡那霉素将和酶标抗原竞争酶标板上预包被的 卡那霉素抗体，用 3，3，5，5- 四甲基联苯胺（TMB）底物显色，样品吸光值与残留卡那霉素的含量成负相关， 用酶标仪进行检测并用 Ridasoft Win 分析软件进行分析。结果：此方法灵敏度高，在 0.2~3.0 ng·mL-1 范围 内 spline 拟合良好，且平行复孔 RSD 小于 10%；方法精密度良好，加标回收率在 80%~120% 之间。应用该 方法对 1 批注射用重组人促血小板生成素模拟肽 -Fc 融合蛋白（简称 TMP-Fc）成品的卡那霉素残留量进 行测定，结果表明，每瓶 TMP-Fc（250 μg）卡那霉素残留量小于 0.2 ng。结论：该方法具有灵敏度高、操作 便捷、检测迅速等特点，可以用于重组生物制品中卡那霉素残留量的质量控制。 关键词：ELISA；卡那霉素；残留量；重组生物制品；质量控制；TMP-Fc
* 通信作者 Tel：13911264110；E-mail：qilianquan@ 第一作者 常翠云 Tel：13717780827；E-mail：changcy2008@ 崔 颖 Tel：13522266832；E-mail：cuiying119@
药物分析杂志
Chinese Journal of Pharmaceutical Analysis
Leuprolide_Acetate_DataSheet_MedChemExpress
Inhibitors, Agonists, Screening Libraries Data SheetBIOLOGICAL ACTIVITY:Leuprolide acetate (Leuprorelin) is a GnRH analog; leuprolide acetate acts as an agonist at pituitary GnRH receptors.IC50 Value:Target: GnRH receptorBy interrupting the normal pulsatile stimulation of, and thus desensitizing, the GnRH receptors, it indirectly downregulates the secretion of gonadotropins luteinizing hormone (LH) and follicle–stimulating hormone (FSH), leading to hypogonadism and thus a dramatic reduction in estradiol andtestosterone levels in both sexes.in vitro: The number of DNA 3'–end–labeled cells/cm2 in leiomyomas of control patients and in leiomyomas at the 2nd, 8th, 12th,and 16th weeks of Leuprolide Acetate treatment were at low levels [1]. Testosterone, estradiol and progesterone were also reduced by LA, even though this reduction occurred for progesterone only at the highest LA dosage (10(–6)M; 606.0+/–114.3 ng/ml versus 1524.0+/–246.5 ng/ml; p=0.02) [2].in vivo: Leuprolide acetate treatment decreases the severity of clinical signs of locomotion, induces a significantly greater body weight gain, increases the MBP and NFs expression, axonal area and cell infiltration in EAE animals [3]. Leuprolide (200 and 300 microg kg(–1)s.c.) per se showed anti–compulsive effect, causing statistically significant inhibition of marble–burying behavior of mice [4].Clinical trial: Neoadjuvant Abiraterone Acetate Plus Leuprolide Acetate in Men With Localized High Risk Prostate Cancer . Phase 2References:[1]. Mizutani T, Sugihara A, Nakamuro K, Suppression of cell proliferation and induction of apoptosis in uterine leiomyoma by gonadotropin–releasing hormone agonist (leuprolide acetate). J Clin Endocrinol Metab. 1998 Apr;83(4):1253–5.[2]. Silva AL, Abreu LG, Rosa–e–Silva AC, Leuprolide acetate reduces both in vivo and in vitro ovarian steroidogenesis in infertile women undergoing assisted reproduction. Steroids. 2008 Dec 22;73(14):1475–84.[3]. Guzmán–Soto I, Salinas E, Hernández–Jasso I, Leuprolide acetate, a GnRH agonist, improves experimental autoimmune encephalomyelitis: a possible therapy for multiple sclerosis. Neurochem Res. 2012 Oct;37(10):2190–7.[4]. Gaikwad U, Parle M, Kumar A, Effect of ritanserin and leuprolide alone and combined on marble–burying behavior of mice. Acta Pol Pharm. 2010Sep–Oct;67(5):523–7.Product Name:Leuprolide (Acetate)Cat. No.:HY-13665CAS No.:74381-53-6Molecular Formula:C 61H 88N 16O 14Molecular Weight:1269.45Target:GNRH Receptor Pathway:GPCR/G Protein Solubility:DMSO: ≥ 43.4 mg/mLCaution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@ Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。
超高效液相色谱-串联质谱法测定人血浆中精氨酸及衍生物含量
超高效液相色谱-串联质谱法测定人血浆中精氨酸及衍生物含量田晔;江骥;胡蓓;薛金萍;王洪允【摘要】建立了超高效液相色谱-串联质谱(UPLC-MS/MS)法同时测定使用艾普拉唑后人血浆中二甲基精氨酸(ADMA)、对称二甲基精氨酸(SDMA)、单甲基精氨酸(NMMA)、瓜氨酸(Cit)和L-精氨酸(L-Arg)的浓度.采用HILIC亲水相互作用色谱和非衍生化的蛋白沉淀法进行分离分析,色谱柱选取Waters Atlantic HILIC柱(2.1 mm×50 mm×3μm),流动相由乙腈(含0.5％乙酸和0.025％三氟乙酸)-水(含0.5％乙酸和0.025％三氟乙酸)(85:15,v/V)组成,流速0.25 mL/min.采用多反应离子监测(MRM)模式,以电喷雾离子源(ESI)正离子方式检测.结果显示,ADMA、SDMA、NMMA、L-Arg和Cit的线性关系良好,相关系数r均大于0.994 0;ADMA、SDMA和NMMA的线性范围为0.1～5 mmol/L,L-Arg和Cit的线性范围为10～250 mmol/L;5种氨基酸的日内、日间精密度均小于15％,准确度在85％～115％之间.该方法快速、简便、灵敏,可为相关疾病的临床诊断提供一种高效的检测手段.【期刊名称】《质谱学报》【年(卷),期】2016(037)005【总页数】7页(P446-452)【关键词】超高效液相色谱-串联质谱(UPLC-MS/MS);艾普拉唑;蛋白沉淀法;亲水性色谱【作者】田晔;江骥;胡蓓;薛金萍;王洪允【作者单位】福州大学化学学院,福建省功能材料工程研究中心,福建省光动力治疗药物与诊疗工程技术研究中心,福建福州350108;中国医学科学院北京协和医院临床药理中心,北京100730;中国医学科学院北京协和医院临床药理中心,北京100730;中国医学科学院北京协和医院临床药理中心,北京100730;福州大学化学学院,福建省功能材料工程研究中心,福建省光动力治疗药物与诊疗工程技术研究中心,福建福州350108;中国医学科学院北京协和医院临床药理中心,北京100730【正文语种】中文【中图分类】O657.63一氧化氮是人体重要的信使分子，L-精氨酸(L-Arg)在一氧化氮全酶(NOS)的催化下，产生一氧化氮(NO)和瓜氨酸(Cit)[1-2]。
常用蛋白酶切割位点
4.溴化氰处理，专一性的切割甲硫氨酸羧基端的肽键。
SIGMA, Roche
Benzamidine-Agarose
Factor Xa
Ile-Glu/Asp-Gly-Arg▼?
I-E/D-G-R▼
Amersham-Biosciences,
New England Biolabs,
Roche
Benzamidine-Agarose
Enterokinase
Asp-Asp-Asp-Asp-Lys▼
羧肽酶
羧肽酶B可以切割C端的Lys或Arg；羧肽酶A可以切割C端除了Lys、Arg、Pro的氨基酸，但如果倒数第二个氨基酸为Pro两种羧肽酶均不能作用
1.胰蛋白酶属肽链内切酶，能把多肽链中Lys和Arg残基中的羧基侧切断。
2.胰凝乳蛋白酶（亦称糜蛋白酶）属肽链内切酶，主要切断多肽链中的芳香族氨基酸（Phe、Trp、Tyr）残基的羧基一侧。
LifeSensors
Ni-NTA (6His recomb. enzyme)
Kex-2
-Arg-X-Lys/Arg-Arg▼
Invitrogen – Life Technologies,
Ni-NTA (6His recomb. enzyme)
KEX2对arg的专一性高，要求最重要。
Arg前为lys效率最高，不切-Arg-lys，Pro影响KEX2切割
Ni-NTA (6His recomb. TEV)
PreScission
Leu-Glu-Val-Leu-Phe-Gln▼Gly-Pro
一甲基澳瑞他汀 e 化学结构-概述说明以及解释
一甲基澳瑞他汀e 化学结构-概述说明以及解释1. 引言1.1 概述一甲基澳瑞他汀（Simvastatin）是一种广泛应用于临床治疗高胆固醇血症和心血管疾病的药物。
它属于被称为他汀类药物的一员，是一种竞争性抑制HMG-CoA还原酶的药物，通过降低胆固醇的合成来达到降低血浆胆固醇的效果。
随着现代生活方式的改变和不良饮食习惯的普遍存在，高胆固醇血症在全球范围内变得越来越普遍。
该疾病不仅与心血管疾病的发展密切相关，还可能导致其他严重的健康问题，如动脉粥样硬化和心肌梗死等。
一甲基澳瑞他汀由黄曲霉属真菌产生，即通过天然发酵法生产得到。
然而，为了提高其药代动力学性质和治疗效果，科学家们通过改进和优化合成方法，合成了合成一甲基澳瑞他汀。
现在，一甲基澳瑞他汀已经成为一种被广泛研究和临床使用的药物。
在本篇文章中，我们将介绍一甲基澳瑞他汀的化学结构、合成方法、性质与用途等方面的内容。
通过深入了解一甲基澳瑞他汀，我们可以更好地理解它在治疗高胆固醇血症和心血管疾病方面的作用机制，并有望对该药物的未来发展提供一定的启示。
在接下来的章节中，我们将详细介绍一甲基澳瑞他汀的化学结构、合成方法以及它在临床上的广泛用途。
最后，我们将总结这篇文章的主要观点，并对一甲基澳瑞他汀的未来进行展望。
通过本文的阅读，读者将能够全面了解一甲基澳瑞他汀，为今后的相关研究和临床实践提供有益的指导与参考。
文章结构部分的内容如下：1.2 文章结构本文主要包含以下几个部分：引言、正文和结论。
引言部分通过概述一甲基澳瑞他汀的化学结构和合成方法，介绍背景知识和研究意义。
此外，本部分还会明确文章的目的，即对一甲基澳瑞他汀进行全面的分析和探讨。
正文部分将围绕一甲基澳瑞他汀展开讨论。
首先，我们将介绍一甲基澳瑞他汀的化学结构，包括其分子式、分子量等信息，并通过图表等形式直观地展示其结构。
其次，我们将详细介绍一甲基澳瑞他汀的合成方法，包括起始原料的选择、反应步骤和条件等。
HPLC法测定拉呋替丁胶囊含量及有关物质
HPLC法测定拉呋替丁胶囊含量及有关物质孙莉;张萍;金建平【摘要】Objective To establish a method for determination of lafutiding capsules and its related substances. Method The column was Agilent ZORAX Eclipse XDB C18 column( 150 mm x4. 6 mm,5 μm ). The mobile phase was methanol-1% ammonium acetate solution ( pH adjusted to 5. 7 with glacial acetic acid )( 40:60 ). The flow-rate was 1.0 ml · Min-1 , and the detection wavelength was 279 nm. Results The calibration curves of lafutiding was 10. 12 ~ 506 mg · L-1 ( r =0. 999 9 ),the average recovery rate was 100. 75 % and RSD was 0. 67% . Conclusion The method is sensitive,accurate and rapid, which can be used to determine the content of lafutiding capsules and its related substances.%目的建立HPLC法测定拉呋替丁胶囊含量及有关物质.方法用Agilent ZORAX Eclipse XDB C18 (150 mm×4.6 mm,5 μm),以甲醇-1%醋酸铵溶液(冰醋酸调节pH为5.7)(40:60)为流动相,流速为1.0 ml·min-1,检测波长为279 nm.结果拉呋替丁线性范围为10.12～506 mg·L-1(r=0.999 9);平均回收率为100.75 %,RSD为0.67 %.结论该方法灵敏,快速,结果准确,可用于拉呋替丁胶囊的质量控制.【期刊名称】《安徽医药》【年(卷),期】2012(016)004【总页数】3页(P452-454)【关键词】HPLC;拉呋替丁胶囊;含量;有关物质【作者】孙莉;张萍;金建平【作者单位】安徽省芜湖市药品检验所,安徽,芜湖,241001;安徽省芜湖市药品检验所,安徽,芜湖,241001;安徽省芜湖市药品检验所,安徽,芜湖,241001【正文语种】中文拉呋替丁是一种第二代组胺H2受体拮抗剂，具有持续的抗分泌作用和潜在的胃黏膜保护作用，主要用于消化性溃疡、胃炎、反流性食管炎、胃溃疡、十二指肠溃疡及其它相关症状的治疗［1］。
谷美替尼 结构
谷美替尼结构
谷美替尼是一种靶向治疗癌症的药物，它属于酪氨酸激酶抑制剂的一类。
谷美替尼的化学名称为（R）-3-（4-氨基-3-（4-氨基苯基）-1H-吡唑-5-基）-1-（1-氧代-2-丙基）-1,4-二氢基-9H-吡喃并[3，4-d]吡咯-9-酮。
谷美替尼的分子式为C22H26N6O2，分子量为406.48 g/mol。
它是一种白色或类白色的结晶粉末，可以在水和乙醇中溶解。
谷美替尼的化学结构中含有许多重要的功能基团，如苯环、吡唑环、吡咯环和吡咯烷酮环等。
这些基团为谷美替尼的靶向作用提供了必要的化学结构基础。
谷美替尼作为一种酪氨酸激酶抑制剂，主要通过抑制细胞内的酪氨酸激酶（c-Met）的活性，从而阻止肿瘤细胞的生长和扩散。
它被广泛应用于多种实体瘤的治疗，如肺癌、胃癌、乳腺癌等。
总之，谷美替尼是一种具有重要生物医学意义的化合物，它的化学结构为其在癌症治疗中的靶向作用提供了基础。
- 1 -。
血管紧张素
可被其他杂环取代， 但咪唑环活性最佳
N NR
5位可变范围大， 以可形成氢键的小 基团为好
酸性基团
2位可引入2~6个碳的直链 烷基、烯基和芳基，以正丙 基和正丁基活性最好
对位取代有利活性
氯沙坦 Losartan
5、构效关系
H3C
Cl N
N
邻位酸性取代基有利，四氮唑增强 活性；若为三氮唑则需在苯环上引 入吸电子基团
含羧基的 ACEI
螺普利 spirapril
H3CH2CO
O CH3
S S
N
N
H O
COOH
1995年在荷兰上市 最大降压作用出现在口服后4-8h 作用维持24h
赖诺普利Lisinopril
依那普利的赖氨酸衍生物， 降压作用缓慢而长效
含磷酸基的 ACEI 福辛普利 fosinopril
0.5h起效，酯键在体内易水解， 水解后产物仍具药理活性
血管紧张素I Angiotensin I
血管紧张素转化酶 ACE
ACEI ARB
Asp-Arg-Val-Tyr-Ile-His-Pro-
Phe 血管紧张素II Angiotensin II
Angiotensin II受体
血管收缩
醛固酮 Aldosterone
血容量增加
血压升高
卡托普利 与 ACE 的相互作用
氯沙坦 Losartan
2、药理作用
Cl
N
H3C
OH
N
NN
N NH
药理作用： 强力和持久性地降低血压， 收缩压和舒张压均下降。
对各种组织中的AT1受体有较高的亲和力和选择性， 直接阻断AⅡ分子与相应受体的结合， 阻断所有已知AII效应。
基于miR-139
郭瑾,王梓仪,张倩,孟骊冲,胡志希*湖南中医药大学,湖南长沙410208〔收稿日期〕2023-07-12〔基金项目〕国家自然科学基金项目(82274412);广东省重点领域研发项目(2020B1111100001);湖南省教育厅项目(21A0230,21B0361)。
〔通信作者〕*胡志希,男,医学博士,教授,博士研究生导师,E-mail:****************。
〔摘要〕目的探讨参附注射液对盐酸异丙肾上腺素(isoprenaline hydrochloride ,ISO )诱导的慢性心力衰竭(chronic heart fail⁃ure ,CHF )大鼠心肌纤维化的作用与机制。
方法采用随机数字表法将45只SD 大鼠随机分为正常组9只,造模组36只,采用ISO 背部皮下多点注射14天制备CHF 大鼠模型,再正常饲养14d 通过模型验证和评价,期间死亡大鼠5只,未成模大鼠4只。
将造模成功的27只大鼠按随机数字表法分为3组:模型组(腹腔注射6mL ·kg -1氯化钠注射液+灌胃10mL ·kg -1蒸馏水)、参附注射液组(腹腔注射6mL ·kg -1参附注射液+灌胃10mL ·kg -1蒸馏水)、卡托普利组(腹腔注射6mL ·kg -1生理盐水+灌胃10mL ·kg -1蒸馏水,蒸馏水含8.8mg ·kg -1卡托普利,相当于临床等效量)。
药物干预15d 后,检测各组大鼠心功能及心肌纤维化的相关指标:超声心动图、体质量、心脏质量指数及左心室质量指数;ELISA 法检测氨基末端脑钠肽前体(N-terminal pro brain natriuretic peptide ,NT-proBNP );HE 染色、Masson 染色检测心肌组织病理形态及纤维化状态;RT-qPCR 检测心肌组织中miR-139、Wnt 家族成员3a (Wnt family member 3a ,Wnt3a )、β-连环蛋白(β-catenin )、糖原合成酶激酶3β(glycogen synthase kinase 3β,GSK3β)、Ⅰ型胶原蛋白(typeⅠcollagen ,Col-Ⅰ)、Ⅲ型胶原蛋白(typeⅢcollagen ,Col-Ⅲ)及α-平滑肌肌动蛋白(α-smooth muscle actin ,α-SMA)、基质金属蛋白酶-2(matrix metalloproteinase-2,MMP-2)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)mRNA 的表达;Western blot 检测心肌组织中Wnt3a 、β-catenin 、GSK3β、Col-Ⅰ、Col-Ⅲ、α-SMA 、MMP-2、MMP-9蛋白表达。
伊立替康分子量
伊立替康分子量
伊立替康分子量是多少？这是很多人关心的问题。
作为一款常被用于治疗糖尿病的口服药物，伊立替康的分子量对药物的疗效和副作用产生重要影响。
1. 什么是伊立替康？
伊立替康（Empagliflozin）是一种双吡嗪类抑制剂，用于治疗2型糖尿病。
它起到促进肾脏排泄过多的糖分，从而降低血糖水平的作用。
2. 伊立替康的分子结构
伊立替康的化学名为（编号：761423-87-4）-（S）-1，5-二羟甲基-4-（4-甲基苯基）-2- [4-（三氟甲基）苯氧]吡咯烷-3-羧酸二乙酯。
其分子式为C23H27F3O7，分子量为僅僅450.46。
3. 伊立替康分子量和药效的关系
伊立替康分子量较小，因此可以更容易地进入肾脏和其他器官。
这种小分子量也是许多糖尿病患者更喜欢选择口服药物的原因之一。
由于其分子量越小，越容易口服，被吸收和运输到靶细胞位置。
4. 小结
伊立替康分子量为僅僅450.46，这使得它能够更容易地进入肾脏和其他器官，发挥其治疗糖尿病的作用。
因此，掌握伊立替康分子量是非常重要的，关于伊立替康的更多知识应该通过各种途径，包括药品说明书和医疗专业人员来获取。
司美格鲁肽结构式
司美格鲁肽结构式司美格鲁肽也被称为双相肽1（Liraglutide），是一种用于治疗2型糖尿病和肥胖症的生长激素类似物。
它是一种人工合成的肽，在化学结构上与天然激素胰高血糖素(GLP-1)相似。
司美格鲁肽的分子式为C172H265N43O51司美格鲁肽的结构特点是它具有一种15个氨基酸的多肽，以特殊的方式组装在一起。
在这个多肽结构中，司美格鲁肽的氨基酸序列为H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH2在司美格鲁肽的氨基酸序列中，有几个关键的氨基酸决定了其药理活性。
例如，Gly2使司美格鲁肽稳定，并提高了其活性；Glu9通过与胰岛素受体结合，激活了细胞内信号转导途径；Thr34在结构上类似于胰高血糖素(GLP-1)的Thr34，具有减少肝葡萄糖生成和提高胰岛素分泌的作用。
司美格鲁肽的结构在一定程度上类似于人体内的GLP-1激素。
GLP-1是一种由肠道L细胞分泌的激素，在食物摄入后会增加胰岛素分泌，并抑制胰高血糖素(glucagon)的分泌。
它还减缓胃排空速度和降低食欲，有助于体重控制。
GLP-1具有显著的抗糖尿病作用，但其半衰期短，易被酶降解，因此无法作为治疗剂。
相比之下，司美格鲁肽具有更长的半衰期和更强的药理活性，因此更适合用于治疗2型糖尿病和肥胖症。
在临床上，司美格鲁肽以注射剂的形式供应，以确保精确的剂量和吸收。
其剂量和使用频率根据患者的具体情况和治疗目标而定。
司美格鲁肽通过与细胞表面的GLP-1受体相互作用，激活细胞内的信号转导途径，从而增加胰岛素分泌，抑制肝糖生成，并延缓胃排空速度。
这些作用有助于降低血糖水平，控制体重和改善胰岛功能。
总体来说，司美格鲁肽是一种结构独特的肽类药物，具有与天然胰高血糖素(GLP-1)相似的药理活性。