治疗血小板减少症新药——马来酸阿凡泊帕(avatrombopag maleate)

马来酸阿凡泊帕(avatrombopag maleate)是血小板生成素受体激动药,最早由日本安斯泰来制药集团研制,几经授权,最后由美国Dova制药公司的子公司AkaRx制药公司完成新药研制,向美国食品药品管理局(FDA)提出新药上市申请,于2018年5月21日获准上市,商品名为Doptelet,用于患有血小板减少症并拟接受医疗或牙科手术的成人慢性肝病(CLD)患者。该文对马来酸阿凡泊帕的非临床和临床药理毒理学、临床研究、不良反应、适应证、剂量与用法、用药注意事项及知识产权状态和国内外研究进展等进行介绍。

Irsogladine maleate and rabeprazole in non-erosive reflux disease: A double-blind, placebo-controlled study

AIM:To evaluate the efficacy of adding irsogladine maleate(IM) to proton-pump inhibitor(PPI) therapy in non-erosive reflux disease(NERD) treatment.METHODS:One hundred patients with NERD were recruited and randomized to receive rabeprazole plus IM(group I) or rabeprazole plus placebo(group P).The efficacy of the treatment was assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease(FSSG) and the short form(SF)-36 quality of life questionnaires after four weeks of treatment.We also assessed whether patients with NERD with minimal changes(grade M) had different responses to the therapies compared with patients who did not have minimal changes(grade N).RESULTS:Group I and group P showed significant improvements in their FSSG scores after the treatment(from 17.9 ± 7.9 to 9.0 ± 7.6, and from 17.7 ± 7.3 to 11.2 ± 7.9, respectively, P = 0.0001), but there was no statistically significant difference between the FSSG scores in group I and those in group P.Subgroup analysis showed that significant improvements in the FSSG scores occurred in the patients in group I who had NERD grade N(modified Los Angeles classification)(7.8 ± 7.4 vs 12.5 ± 9.8, P = 0.041).The SF-36 scores for patients with NERD grade N who had received IM and rabeprazole were significantly improved in relation to their vitality and mental health scores.CONCLUSION:The addition of IM to rabeprazole significantly improves gastroesophageal reflux diseasesymptoms and the quality of the lives of patients with NERD grade N.

Effects of tanshinone Ⅱ sodium sulfonate plus cinepazide maleate on the hemorrheologic indexes and blood lipids in patients with acute cerebral infarction

BACKGROUND： The severity of cerebral infarction is associated with the increase of blood viscosity caused by hyperfibrinogenemia and hyperlipidemia, etc. Thus it has become one of the target for treating cerebral infarction to decrease blood viscosity by integrated Chinese and western medicine. OBJECTIVE： To investigate the influence and clinical therapeutic effects of cinepazide maleate combined with tanshinone Ⅱ A sodium sulfonate on the hemorrheologic indexes and blood lipids of patients with acute cerebral infarction, and compare the results with those of simple cinepazide maleate treatment. DESIGN： A non-randomized case-controlled observation. SETTINGS： Hebei North University; the Second Affiliated Hospitals of Hebei North University; the Third Affiliated Hospitals of Hebei North University, PARTICIPANTS： Eighty-six inpatients with cerebral infarction were selected from the infirmary, the Second and Third Affiliated Hospitals of Hebei North University from September 2004 to October 2006. They were all diagnosed to have acute cerebral infarction by CT or MRI, and accorded with the diagnostic standards for acute cerebral infarction set by the Fourth National Academic Meeting for Cerebrovascular Disease in 1995. Meanwhile, 40 teachers and medical staff of voluntary physical examinees were selected as the control group. Informed contents were obtained from all the patients and their relatives. METHODS： The patients were divided into combined treatment group （n=43） and simple treatment group （n=3）. In the combined treatment group, the patients were administrated with 160 mg cinepazide maleate injection （Beijing Four-ring Pharmaceutical, Co.,Ltd, No. H200220125; 80 mg/2 mL） added in 5% glucose, and 40 mg tanshinone Ⅱ sodium sulfonate （Shanghai No.1 Biochemical ＆ Pharmaceutical Co.,Ltd., No. H31022558, 10 mg/2 mL） added in 250 mL normal saline. In the simple treatment group, the patients were only administrated with cinepazide maleate 320 mg added in 5% glucose or 250 mL normal saline. They were treated for 1 or 2 courses, once a day, and 14 days as a course. The patients were detected before treatment and at 14 and 28 days after treatment respectively. ① Determination of hemorrheologic indexes： Whole blood viscosity was determined with LBY-N6B automatic hemorrheologic meter; Plasma viscosity with LBY-F200B automatic plasma viscosity meter; Volume of fibrinogen was determined by the method of 12.5% sodium nitrate depositing biuret reaction. ② Determination of blood lipids： The serum levels of total cholesterol （TC）, triglyceride （TG）, low density lipoprotein cholesterol （LDL-C） and high density lipoprotein cholesterol （HDL-C） were determined. ③ Severity of neurological deficit： The total score of neurological deficit score （NDS） ranged from 0 to 45 points, 0 - 15 points was taken as mild, 16 - 30 points as moderate and 31 - 45 points as severe.④ Evaluation of curative effects： Generally cured： NDS decreased by 91% - 100%, and disabled severity of grade 0; Significantly improved： NDS decreased by 46% - 90%, and disabled severity of grades 1 - 3; Improved： NDS decreased by 18% - 45%; No change： NDS decreased by less than 18%; Aggravated： NDS increased by more than 18%. Generally cured and significant improved were taken as significant effect. ⑤ The adverse events and side effects after medication were observed. MAIN OUTCOME MEASURES： ① Results of hemorrheologic indexes and blood lipids; ② NDS results in the combined treatment group and simple treatment group; ③ Therapeutic effects and adverse events. RESULTS： All the 86 patients with cerebral infarction and 40 healthy controls were involved in the analysis of results. ① Results of hemorrheologic indexes and blood lipids： The hemorrheologic indexes and blood lipids before treatment were manifested as abnormalities to different extents in both the combined treatment group and simple treatment group; The hemorrheologic indexes after treatment were obviously improved in both groups. But the hemorrheologic indexes were improved more obviously in the combined treatment group as compared with those in the simple treatment group （P 〈 0.05）; The levels of TC, TG and LDL-C after treatment in the combined treatment group were obviously lowered （P 〈 0.05）, whereas those in the simple treatment group were not significantly changed （P 〉 0.05）. ② NDS results： The NDS scores at 14 and 28 days after treatment in the combined treatment group [（6.23±2.34）, （4.27± 1.83） points] were obviously lower than those in the simple treatment group [（8.76±3.41）, （6.65±2.49） points, P 〈 0.05]. ③ Therapeutic effects and side effects： The total significant effective rates in the combined treatment group and simple treatment group were 93% and 81% respectively. In the combined treatment group, 1 case suffered from palpitation, dizziness and agrypnia. In the simple treatment group, 1 case suffered from palpitation, dizziness and agrypnia, 1 case had itch of skin. All the above symptoms disappeared gradually after the transfusing speed was adjusted to be slower. No drug withdrawal occurred in the patients due to the adverse events. CONCLUSION： Cinepazide maleate combined with tanshinon can obviously improve the abnormalities of hemorrheologic indexes and blood lipids and nerve function in patients with acute cerebral infarction, and its curative effect is faster than that of simple cinepazide maleate treatment.

Effect of Rosiglitazone Maleate on Inflammation Following Cerebral Ischemia/Reperfusion in Rats

In order to evaluate the neuroprotective effect of Rosiglitazone Maleate (RSG) against brain ischemic injury, the effects of Rosiglitazone Maleate on the inflammation following cerebral ischemia/reperfusion were investigated. Focal cerebral ischemia was induced by the intraluminal thread for cerebral middle artery (MCA) occlusion. Rosiglitazone Maleate at concentrations of 0.5, 2 and 5 mg/kg was infused by intragastric gavage twice immediately and 2 h after MCA occlusion, respectively. The effects of Rosiglitazone Maleate on brain swelling, myeloperoxidase and inter- leukin-6 mRNA level in brain tissue after MCA occlusion and reperfusion were evaluated. The results showed that as compared with the model control group, RSG (0.5 mg/kg) had no significant influence on brain swelling (P>0.05), but 2 mg/kg and 5 mg/kg RSG could significantly alleviate brain swell- ing (P<0.05). All different doses of RSG could obviously reduce MPO activity in brain tissue after MCA occlusion and reperfusion in a dose-dependent manner. RSG (0.5 and 2 mg/kg) could decrease the expression levels of IL-6 mRNA in brain tissue after MCA occlusion and reperfusion to varying degrees (P<0.05) with the difference being significant between them. It was concluded that RSG could effectively ameliorate brain ischemic injury after 24 h MCA occlusion and inhibit the inflam- matory response after ischemia-reperfusion in this model.

Avatrombopag maleate(Doptelet)

2018年5月21日,Dova制药子公司AkaRx公司研发的avatrombopag maleate片剂经美国FDA批准上市(商品名为Doptelet),用于治疗成人慢性肝病(CLD)导致的血小板减少症,这是FDA批准用于此用途的第一款药物[1]。血小板减少症(thrombocytopenia)是血液中的循环血小板数低于正常数量的一种病症,当患者的血小板数有中度或重度减少时,可能会发生严重甚至危及生命的出血,Doptelet被证明可以安全地增加血小板数量。

Near-infrared chemical imaging for quantitative analysis of chlorpheniramine maleate and distribution homogeneity assessment in pharmaceutical formulations

Near infrared chemical imaging(NIR-CI)combines conventional near infrared(NIR)spectros-copy with chemical imaging,thus provides spectral and spatial information simult aneously.It could be utilized to visualize the spatial distribution of the ingredients in a sample.The data acquired using NIR CI instrument are hyperspectral data cube(hypercube)containing thousands of spectra.Chemometric methodologies are necessary to transform spectral information into chemical information.Partial least squares(PLS)method was performed to extract chemical information of chlorpheniramine maleate in pharmaceutical formulations.A series of samples which consisted of different CPM concentrations(w/w)were compressed and hypercube data were measured.The spectra extracted from the hypercube were used to establish the PLS model of CPM.The results of the model were R^(2)_(val)0.981,RMSEC 0.384%,RMSECV 0.483%,RMSEP 0.631%,indicating that this model was reliable.

Synthesis and Characterization of a Cobalt Complex with Maleate and Pyridine

A new polymeric cobalt complex [Co(-male)(py)(H2O)]n (male = maleate; py = pyridine) 1 was prepared by cobalt chloride hexahydrate with disodium maleate and pyridine in an alcohol-aqueous solution. Single-crystal X-ray analysis has revealed that 1 crystallizes in the orthor- hombic system, space group Pnma with a = 18.001(1), b = 7.6001(6), c = 7.4731(6) ? V = 1022.4(1) 3, Z = 4, C9H9CoNO5, Mr = 270.10, Dc = 1.755 g/cm3, F(000) = 548, m(MoK? = 1.683 mm-1, S = 1.002, the final R = 0.0280 and wR = 0.0746 for 883 observed reflections with I > 2s(I). The structure analysis shows an approximate octahedral coordination environment of metal center. The Co(II) ions are bridged by maleic anions in a rare tetradentate coordination fashion with a syn-anti coplanar con- formation of the carboxyl group, forming a two-dimensional corrugated 2-D structure which is further attached into a three-dimensional framework via non-classical CH…O interactions between adjacent layers.

Study on Synthesis and Polymerization of Mono (isopropylmaleate oyloxyl) Diisopropoxyl Dysprosium

Mono(isopropyl maleate-oyloxyl) diisopropoxyl dysprosium(DM) was synthesized by the reaction of dysprosium isopropoxide with maleic anhydride. Dy-containing polymer(PDM) was obtained by the solution polymerization of DM using 2, 2'-azobisisobutyronitrile (AIBN) as an initiator. The kinetic study on the polymerization shows that the polymerization of DM exhibits high apparent activation energy(96.3 kJ.mol(-1)), indicating that the activity of DM is low for polymerization. The kinetic equation of polymerization can be expressed as R-P = k(P)C(DM)(1.23)c(AIBN)(0.82). The polymeric solid material shows excellent heat-stability and strong characteristic fluorescence of Dy3+, (4)Fg(9/2) --> H-6(15/2) and F-4(9/2) --> H-6(13/2).

Aqueous Diels-Alder Reactions of Cyclopentadicnc with Symmetric Diester of Fumarate or Maleate

Symmetric, diesters of cis- or trans- bicyclo[2,2,1]hept-5-ene-2,3-dicarboxylate were prepared by aqueous Diels-Alder reaction of cyclopentadiene with symmetric diester of fumarate or maleate.

Validation of a Capillary Electrophoresis Method for Analyzing Chlorphenamine Maleate-Based Drugs Using the Accuracy Profile Approach

This study aimed at validating an analytical method, using the accuracy profile approach, for the assay of chlorphenamine maleate by capillary electrophoresis. The validation was done using concentrations ranging between 75% and 125% of the target concentration of 600 mg/ml. Validation standards were prepared separately in triplicate for each series. Studied validation criteria were selectivity, linearity, trueness, precision (repeatability and intermediate precision), accuracy and limits of detection and quantification. The method was selective, with recoveries ranging between 99.55% and 99.84%. The relative standard deviations of repeatability and intermediate precision were <5%. The accuracy profile confirmed the performance of the assay method between 75% and 100% of the target concentration of 600 mg/ml. The detection and quantification limits were 5 mg/l and 15 mg/l respectively. This ecological and economical method was applied to identify and quantify chlorphenamine maleate in 3 samples of chlorphenamine maleate-based drugs provided by the Senegalese National Medicines Control Laboratory. All analyzed samples were in accordance with official standards.

One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C

BACKGROUND Entecavir(ETV)is a potent and selective nucleotide analog with significant activity against hepatitis B virus(HBV).ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV(Baraclude)when used in Chinese patients with chronic hepatitis B(CHB)in phase III clinical trials(Clinical Trials.gov number,NCT-01926288)at weeks 48,96,and 144.AIM To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C.METHODS In this double-blind study,we randomly assigned patients to receive 0.5 mg/d ETV(Group A)or ETV maleate(Group B)(ratio,1:1),each with a placebo tablet for 48 wk.Then,all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49.The primary efficacy endpoint was the reduction in HBV DNA levels from baseline.Secondary endpoints included the proportion of patients with undetectable HBV DNA(<20 IU/m L),serologic response,serum alanine aminotransferase(ALT)normalization and development of resistance mutations.RESULTS Two hundred eighteen patients who were hepatitis B e antigen(HBe Ag)positive and 57 who were HBe Ag negative were analyzed and predominantly presented with genotype B(49.82%)or C(48.73%).For the HBe Ag-positive CHB patients,the mean HBV DNA level decrease(6.61 Log10 IU/m L vs 6.69 Log10 IU/m L,P>0.05),viral suppression with HBV DNA<20 IU/m L(83.33%vs 79.17%,P>0.05)and HBe Ag seroconversion(28.77%vs 20.00%,P>0.05)occurred similarly between Groups A and B at week 192.However,there was a significant difference in the proportion of patients with normal ALT levels(91.14%vs 78.38%,P<0.05).For the HBe Ag-negative CHB patients,no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline(6.05 Log10 IU/m L vs 6.03 Log10 IU/m L,P>0.05),percentages of patients who achieved undetectable HBV DNA(100%vs 100%,P>0.05)and rates of ALT normalization(95.65%vs 100.00%,P>0.05).Safety and adverse event profiles were similar between Groups A and B.Two HBe Ag-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV.CONCLUSION Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

新型胃溃疡治疗药IsogladineMaleate的合成

以2，5-二氯苯甲腈为原料合成了一种新型胃溃疡治疗药物IsogladineMaleate，经红外光谱鉴定，符合结构特征。

Effect of Cinepazide Maleate Combined with Promethazine Hydrochloride in the Treatment of Emergency Vertigo

Objective:To explore the effect of cinepazide maleate combined with promethazine hydrochloride in the treatment of emergency vertigo.Methods:48 cases of emergency vertigo patients in our hospital from November 2017 to November 2019 were divided into experimental group(24 cases,treated with cinepazide maleate combined with promethazine hydrochloride)and control group (24 cases,treated with cinepazide maleate).The clinical efficacy,symptom relief time,adverse reactions and quality of life were compared.Results:The total effective rate of the experimental group(95.83%,23/24)was higher than that of the control group(75.00%),The remission time of nausea and vomiting(1.75±0.22)d,vertigo(3.54±0.63)d,deafiiess and tinnitus(3.47±0.58)d,night sweats(3.05±0.33)d in the experimental group were shorter than those in the control group,P<0.05;the incidence of adverse reactions in the experimental group(8.33%,2/24)was lower than that in the control group(33.33%),The scores of social function,material life attitude,physical health and psychological function in the experimental group were 59.14±7.23,54.05±8.04,53.58±0.86 and 60.11±8.44 respectively,P<0.05.Conclusion:In the process of clinical treatment of emergency vertigo patients,the combined application of cinepazide maleate and promethazine hydrochloride has definite curative effect,can relieve clinical symptoms in a short time,has less adverse reactions,and improves the quality of life of patients to a certain extent,which is worthy of promotion.

Sonochemical Synthesis of Maleated Rosin

松香的出租机动三轮车加成反应并且缩苹果酸在超声的照耀下面的酐被调查了。结果证明异构化和一天一夜桤木的出租机动三轮车加成反应显著地被加速。sonochemical 反应在 5 ~ 到达了平衡在 110 ° C 的 10 min，在 180 ° C 上与 4-5 h 的常规合成作比较。

Conventional Radical and RAFT Alternating Copolymerizations of Hydroxyalkyl Vinyl Ethers and Dialkyl Maleates

The alternating copolymerization of hydroxyalkyl vinyl ethers and dialkyl maleates is investigated by conventional radical polymerization and reversible addition-fragmentation chain transfer polymerization(RAFT).The influence of comonomer structure,comonomer feeding ratios,and monomer concentrations on the copolymerization and the copolymer structure have been investigated systematically.With 2-hydroxyethyl vinyl ether(HEVE)and dimethyl maleates(DMM)as comonomers,a well-defined alternating copolymer is prepared with M_(n)=3400 and M_(w)/M_(n)=1.93 up to 71.6% monomer.The alternating sequential chain structure of the copolymers has been proved by both NMR and matrixassisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS).The experimental reactivity ratios and theoretical calculated highest occupied molecular orbital and the lowest unoccupied molecular orbital of vinyl ethers and alkyl maleates support that these monomer pairs have tendency to form alternating copolymers.With 2-cyanopropan-2-yl N-methyl-N-(pyridin-4-yl)carbamodithioate as the RAFT agent,the molecular weight of HEVE and DMM copolymer increases with the monomer conversion,demonstrating a controlled radical polymerization feature with well-controlled molecular weight and relatively narrower molecular weight distribution.With alternating copolymer of HEVE and DMM as macro-CTA(M_(n)=5200 and M_(w)/M_(n)=1.46),both the chain extension with HEVE and DMM(M_(n)=10400 and M_(w)/M_(n)=1.72)and block copolymerization with vinyl acetate have been successfully achieved(M_(n)=8500 and M_(w)/M_(n)=1.52).

阿伐曲泊帕联合他克莫司治疗老年难治性重型再生障碍性贫血1例报告

目的 总结阿伐曲泊帕联合他克莫司治疗老年难治性重型再生障碍性贫血的临床疗效和不良反应。方法 报道1例阿伐曲泊帕联合他克莫司治疗老年难治性重型再生障碍性贫血患者,并针对阿伐曲泊帕、他克莫司作用机制及安全性进行文献复习。结果 患者经环孢素、十一酸睾酮、艾曲泊帕联合治疗6个月无效,并出现肝肾功能损伤,停药并予以阿伐曲泊帕(20 mg,每日1次)联合他克莫司(1 mg,每日2次)治疗9个月后,患者血小板升至54×10^(9)/L,血红蛋白升至124 g/L,白细胞升至8.23×10^(9)/L,肝肾功能也均恢复到正常,未观察到血栓事件等其他不良反应,且治疗后CD4/CD8下降,CD8^(+)T细胞增多,Treg细胞比例增多。结论 阿伐曲泊帕联合他克莫司治疗老年难治性再生障碍性贫血有效且耐受性良好,今后仍需长期追踪观察及继续积累病例。

血小板生成素受体激动剂治疗化疗相关性血小板减少症的研究现状

化疗相关性血小板减少症(chemotherapy-induced thrombocytopenia, CIT)仍是目前肿瘤治疗的严重并发症,既往针对CIT的处理主要为输注血小板、使用重组人白介素-11(recombinanthumaninterleukin-11,rhIL-11)及重组人血小板生成素(recombinanthuman thrombopoietin, rhTPO)等,但对一些难治性CIT,效果有限。近年来,新型血小板生成素受体激动剂(thrombopoietin receptor agonists, TPO-RAs)已上市并用于血小板减少症,但尚未批准用于CIT治疗。本文对TPO-RAs类药物在CIT方面已开展的临床研究进行汇总,结果显示罗米司亭、艾曲泊帕、阿伐曲泊帕研究相对较多,但多为小样本或单中心回顾性分析,而芦曲泊帕和海曲泊帕尚缺乏治疗CIT的临床研究。

血小板生成素受体激动剂avatrombopag的药理作用及临床评价

avatrombopag是第2代口服生物可利用小分子血小板生成素受体激动剂,可以模拟血小板生成素的作用,增加血小板的产生。2018年5月FDA批准avatrombopag上市,用于成人慢性肝病患者血小板减少症的治疗。临床试验表明其具有良好的安全性和有效性,主要不良反应有发热、腹痛、恶心、头痛、疲倦和手足水肿等。本文对其药理作用、药动学、临床研究及不良反应等做一综述。