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Modified docetaxel, cisplatin and capecitabine for stage Ⅳ gastric cancer in Japanese patients: A feasibility study

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World Journal of Gastroenterology 2017年第6期23卷 1090-1097页

作者： Osamu Maeda Ayumu Matsuoka Ryoji Miyahara Kohei Funasaka Yoshiki Hirooka Masahide Fukaya Masato Nagino Yasuhiro Kodera Hidemi Goto Yuichi Ando Department of Clinical oncology and Chemotherapy Nagoya University Hospital Department of Gastroenterology and Hepatology Nagoya University Graduate School of Medicine Department of Endoscopy Nagoya University Hospital Department of Surgery Nagoya University Graduate School of Medicine Department of Gastroenterological Surgery(Surgery II)Nagoya University Graduate School of Medicine

AIM To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese *** We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage Ⅳ gastric cancer. In particular, 30 or 40 mg/m^2 of docetaxel on day 1, 60 mg/m^2 of cisplatin on day 1, and 2000 mg/m^2 of capecitabine for 2 wk were administered every three *** Three patients were treated with modified DCX(m DCX) with 30 mg/m^2 docetaxel, and five patients were treated with this regimen with 40 mg/m^2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph *** m DCX was well tolerated by Japanese patients with stage Ⅳ gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.

关键词： Docetaxel Cisplatin Capecitabine Gastric cancer

基于形成复合物的中性分子LC-ESI-MS-MS方法发展

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生命科学仪器 2007年第5期5卷 6-11页

作者： Geralyn Kocan Daniel Tang Douglas M.Fast Steven M.Michael Dynamics & Metabolism Pfizer Global Research and Development Michigan Laboratories Pfizer Inc. 2008 Plymouth Rd. Ann Arbor MI 48105 U.S.A.

对于极性与可带电分子而言,电喷雾离子化(ESI)是一种合适的质谱离子化模式,但由于非极性与中性分子的离子化效率低,一般不能直接采用ESI的离子化模式。为了克服电喷雾离子化的这种限制,已经发展了多种相应的策略,本文介绍的方法便是其... 详细信息

对于极性与可带电分子而言,电喷雾离子化(ESI)是一种合适的质谱离子化模式,但由于非极性与中性分子的离子化效率低,一般不能直接采用ESI的离子化模式。为了克服电喷雾离子化的这种限制,已经发展了多种相应的策略,本文介绍的方法便是其中一种。这种方法采用一个小的阴离子与中性分子形成复合物,可以有效提高中性分子的电喷雾离子化能力。

关键词：中性分子复合物 S方法电喷雾离子化质谱离子化非极性 ESI 阴离子

Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

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Cancer Drug Resistance 2019年第3期2卷 568-579页

作者： David K.Lau Laura Jenkins Andrew Weickhardt Olivia Newton John Cancer Research Institute HeidelbergVictoria 3084Australia School of Cancer Medicine La Trobe UniversityHeidelbergVictoria 3084Australia Department of Medical oncology Austin HealthHeidelbergVictoria 3084Australia.

Oncogenic activation of the fibroblast growth factor receptor(FGFR)through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and *** of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are *** resistance to FGFR inhibition using a variety of mechanisms that includes,activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR *** review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance.

关键词： Fibroblast growth factor receptor targeted therapy acquired resistance

Population pharmacokinetic/pharmacodynamic analysis for Pegylated Recombinant Human Growth Hormone(PHA-794428) in male healthy volunteers

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Population pharmacokinetic/pharmacodynamic analysis for Pegy...

IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion

中国药理学会临床药理学专业委员会会议暨第十次全国临床药理学学术会议

作者： Didier Eric Harris Philip Milligan Peter A Karlsson Mats O PGRD Sandwich UK Clinical Pharmacometrics pfizer Global Research & Development(PGRD) SandwichUK Department of Pharmaceutical Biosciences Uppsala University Sweden

AIM:The purpose of this analysis was to construct approp- riate models to characterise population pharmacokinetics (PK)for PHA-794428 and PK/pharmacodynamics(PD) for the efficacy biomarker Insulin-like Growth factor-1 (IGF-1). METHODS:Fifty-six male healthy volunteers were en- rolled into a clinical *** received in a random- ised manner 3 subcutaneous injections over 3 periods:i) 3.6 mg recombinant human growth hormone(rhGH),ii) PHA-794428 0,3,10,30,60,100,300 or 500μg/kg, and iii)PHA-794428 0,10,or 30μg/*** PK and IGF-1 data were collected up to 336 h *** PK and PK/PD models were constructed in 3 stages:i)the PK model was developed,ii)the PK parameters were fixed during IGF-1 model building,iii)PK and IGF-1 da- ta were analysed simultaneously. RESULTS:PHA-794428 exhibited non-linearity with re- spect to dose.A one-compartment disposition model with parallel linear and non-linear elimination most appropriate- ly described the PHA-794428 serum concentrations versus time *** absorption of PHA-794428 was character- ised as a first-order process involving two absorption rate *** nonlinear elimination,characterised in terms of the maximal elimination capacity(V=91.5 μg/h for 70 kg)and Michaelis-Menten constant(K= 73.9μg/L)describing the concentration at which elimina- tion is at half *** non-linear elimination pathway is approximately 10 times higher than the linear route(0.129 L/h).PHA-794428 has a limited distribution in the blood (V=4.4 L),due to its large molecular *** IGF-1 concentrations versus time data were best described by an indirect response model with PEG-hGH stimulating IGF-1 production *** effect was appropriately char- acterised by a maximum effect(E)*** maxi- mal IGF-1 production rate could increase up to 8-fold across the dose range *** PHA-794428 concen- tration at half Emax(EC)is 56.5 ng/mL.A negative feedback loop was incorporated into the PK/IGF-1 model. The maximal inhibition(I)

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Cellular & Molecular Immunology 2021年第9期18卷 2199-2210页

作者： Sadiq Umar Karol Palasiewicz Katrien Van Raemdonck Michael V.Volin Bianca Romay MAsif Amin Ryan K.Zomorrodi Shiva Arami Mark Gonzalez Vikram Rao Brian Zanotti David A.Fox Nadera Sweiss Shiva Shahrara Jesse Brown VA Medical Center ChicagoIL60612USA Department of Medicine Division of RheumatologyUniversity of Illinois at ChicagoChicagoIL60612USA Department of Microbiology and Immunology Midwestern UniversityDowners GroveIL60515USA Division of Rheumatology and Clinical Autoimmunity Center of Excellence University of MichiganAnn ArborMI481096USA Department of Orthopedic Surgery University of Illinois at ChicagoChicagoIL60612USA pfizer Research CambridgeMA02139USA

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis(RA)patients could reflect activation of innate immune ***,we show that a TLR7 GU-rich endogenous ligand,miR-Let7b,potentiates synovitis by amplifying RA monocyte and fibroblast(FLS)***-Let7b ligation to TLR7 in macrophages(MΦs)and FLSs expanded the synovial inflammatory ***,secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell *** showed that IRAK4 inhibitor(i)therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦor FLS activation,as well as monokine-modulated Th1/Th17 cell ***4i therapy also disrupted RA osteoclastogenesis,which was amplified by miR-Let7b ligation to joint myeloid ***,the effectiveness of IRAK4i was compared with that of a TNF inhibitor(i)or anti-IL-6R treatment in collagen-induced arthritis(CIA)and miR-Let7b-mediated *** found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480+iNOS+MΦs,the expression of certain monokines,and Th1 cell ***,these biologic therapies were unable to alleviate miR-Let7b-induced *** superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480+iNOS+MΦs,vimentin+fibroblasts,and CD3+T cells,in addition to negating the expression of a wide range of monokines,including IL-12,MIP2,and IRF5 and Th1/Th17 *** conclusion,IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.

关键词： TLR7 MΦs RA FLSs osteoclasts T cells IRAK4

Efficacy and Safety of Tofacitinib in Chinese Patients with Rheumatoid Arthritis

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Chinese Medical Journal 2018年第22期131卷 2683-2692页

作者： Zhan-Guo Li Yi Liu Hu-Ji Xu Zhi-Wei Chen Chun-De Bao Jie-Ruo Gu Dong-Bao Zhao Yuan An Lie-Ju Hwang Lisy Wang Joel Kremer Qi-Zhe Wu Department of Rheumatology and Immunology Peking University People's HospitalBeijing 100044China Center for Rheumatology Albany Medical CollegeAlbanyNY 12208USA Medical Pfizer IncBeijing 100010China Department of Rheumatology and Immunology West China Hospital of Sichuan UniversityChengduSichuan 610041China Department of Rheumatology and Immunology Shanghai Changzheng HospitalThe Second Military Medical UniversityShanghai 200003China Department of Rheumatology First Affiliated Hospital of Soochow UniversitySuzhouJiangsu 215006China Department of Rheumatology Shanghai Renji HospitalShanghai 200000China Department of Rheumatology The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouGuangdong 510630China Department of Rheumatology and Immunology Changhai Hospital of ShanghaiShanghai 200433China Statistician Pfizer IncNew YorkNY 10017USA(at the time of analysis) Clinician Pfizer IncCrotonCT 06340USA

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis(RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long?term extension(LTE) ***: ORAL Sync was a 1?year, randomized, placebo?controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily(BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease?modifying antirheumatic drug. ORAL Sequel is an open?label LTE study(data?cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology(ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate(DAS28?4 [ESR]). Patient? and physician?reported outcomes: Health Assessment Questionnaire?Disability Index(HAQ?DI), Patient and Physician Global Assessment of Arthritis, and pain(visual analog scale). Safety was assessed ***: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20(tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28?4(ESR) <2.6(tofacitinib 5 mg BID, 7.1%;10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ?DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib?treated patients were similar to the global ***: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate?to?severely active RA up to Month 48. The safety profile was consistent with the global *** Trial Identifie

关键词： Clinical Efficacy Patient-Reported Outcomes Rheumatoid Arthritis Safety Tofacitinib

A combination of density-based clustering method and DEM to numerically investigate the breakage of bonded pharmaceutical granules in the ball milling process

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Particuology 2021年第5期19卷 153-168页

作者： Alexander Krok Peter Peciar Kieran Coffey Keith Bryan Sandra Lenihan Department of Process Energy and Transport EngineeringMunster Technological UniversityBishopstownCork T12 P928Ireland Department of Mechanical Biomedical and Manufacturing EngineeringMunster Technological UniversityBishopstownCork T12 P928Ireland pfizer Newbridge LittleconnellNewbridgeCo.Kildare W12 HX57Ireland Institute of Process Engineering Faculty of Mechanical EngineeringSlovak University of TechnologyNam.Slobody 1781231 BratislavaSlovakia

Ball milling is widely used in industry to mill particulate *** primary purpose of this process is to attain an appropriate product size with the least possible energy *** process is also extensively utilised in pharmaceuticals for the comminution of the excipients or ***,for ball mill,little is known concerning the mechanism of size *** prediction approaches are not deemed useful to provide significant insights into the operation or facilitate radical step changes in ***,the discrete element method(DEM)as a computational modelling approach has been used in this *** previous research,DEM has been applied to simulate breaking behaviour through the impact energy of all ball collisions as the driving force for ***,the nature of pharmaceutical material fragmentation during ball milling is more *** functional equations which link broken media and applied energy do not consider the collision of particulate media of different shapes or collisions of particulate media(such as granules)with balls and rotating mill *** could have a significant impact on ***,this paper aimed to investigate the fragmentation of bounded particles into DEM granules of different shape/size during the ball milling process.A systematic study was undertaken to explore the effect of milling speed on breakage ***,in this study,a combination of a density-based clustering method and discrete element method was employed to numerically investigate the number and size of the fragments generated during the ball milling process over *** was discovered that the collisions of the ball increased proportionally with rotation speed until reaching the critical rotation ***,results illustrate that with an increase of rotation speed,the mill power increased *** caratacting motion of mill material together with balls was identified as the most

关键词： Ball milling Granular pharmaceutical lactose Density-based clustering Discrete element method Breakage Mill rotation speed ABAQUS

Applications of multi-nuclear magnetic resonance spectroscopy at 7T

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World Journal of Radiology 2011年第4期3卷 105-113页

作者： Mary C Stephenson Frances Gunner Antonio Napolitano Paul L Greenhaff Ian A MacDonald Nadeem Saeed William Vennart Susan T Francis Peter G Morris The Sir Peter Mansfield Magnetic Resonance Centre School of Physics and AstronomyUniversity of Nottingham School of Biomedical Sciences University of Nottingham Medical School Academic Radiology University of Nottingham Molecular Medicine PfizerSandwich

AIM: To discuss the advantages of ultra-high field (7T) for 1H and 13C magnetic resonance spectroscopy (MRS) studies of ***: Measurements of brain metabolites were made at both 3 and 7T using 1H MRS. Measurements of glycogen and lipids in muscle were measured using 13C and 1H MRS ***: In the brain, increased signal-to-noise ratio (SNR) and dispersion allows spectral separation of the amino-acids glutamate, glutamine and γ-aminobutyric acid (GABA), without the need for sophisticated editing sequences. Improved quantification of these metabolites is demonstrated at 7T relative to 3T. SNR was 36% higher, and measurement repeatability (% coefficients of variation) was 4%, 10% and 10% at 7T, vs 8%, 29% and 21% at 3T for glutamate, glutamine and GABA respectively. Measurements at 7T were used to compare metabolite levels in the anterior cingulate cortex (ACC) and insula. Creatine and glutamate levels were found to be significantly higher in the insula compared to the ACC (P < 0.05). In muscle, the increased SNR and spectral resolution at 7T enables interleaved studies of glycogen (13C) and intra-myocellular lipid (IMCL) and extra-myocellular lipid (EMCL) (1H) following exercise and re-feeding. Glycogen levels were significantly decreased following exercise (-28% at 50% VO2 max; -58% at 75% VO2 max). Interestingly, levels of glycogen in the hamstrings followed those in the quadriceps, despite reduce exercise loading. No changes in IMCL and EMCL were found in the ***: The demonstrated improvements in brain and muscle MRS measurements at 7T will increase the potential for use in investigating human metabolism and changes due to pathologies.

关键词： Magnetic resonance spectroscopy 13C 1H 7 Tesla Glutamate Glutamine γ-aminobutyric acid

Targeting HER2 genomic alterations in non-small cell lung cancer

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Journal of the National Cancer Center 2021年第2期1卷 58-73页

作者： Jie Zeng Weijie Ma Richard Benjamin Young Tianhong Li Division of Hematology/oncology Department of Internal MedicineUniversity of California Davis School of MedicineUniversity of California Davis Comprehensive Cancer CenterSacramentoCAUSA Department of Respiratory Medicine Shanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina

Oncogenic mutations and amplifications in the erythroblastic oncogene B(ERBB2),or human epidermal growth factor receptor 2(HER2),have emerged as distinct oncogenic drivers and drug targets in non-small cell lung cancer(NSCLC).Each genomic alteration occurs in 2-4%of NSCLC by next generation sequencing and is asso-ciated with constitutive HER2 *** most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA mutation in the kinase domain and S310F mutation in the extracellular *** in breast and gastric cancer,HER2 protein overexpression in NSCLC is not validated to be a biomarker predictive of clinical response to HER2-targeted *** HER2 protein overexpression by immunohistochemistry(3+)only occurs in 2-4%of *** now HER2-targeted agents(such as afatinib and ado-trastuzumab emtansine)only demonstrate modest clinical activity in patients with HER2-mutant *** studies show concern for inferior clinical benefit of immune checkpoint inhibitors in HER2-mutated ***,platinum-based chemotherapy with or without an anti-angiogenesis inhibitor remains the first line standard treatment for this pa-tient *** May 2020 trastuzumab deruxtecan(T-DXd)received the *** and Drug Administration breakthrough therapy designation for HER2-mutant metastatic NSCLC,and was added as an option for HER2-mutant NSCLC to the NCCN guidelines V1.2021.A global phase III study of pyrotinib compared to docetaxel as a second line therapy for advanced NSCLC harboring HER2 exon 20 mutations was just opened for enrollment in September *** this review,we highlight the current knowledge and perspectives on targeting-HER2 genomic alterations in NSCLC.

关键词： HER2 ERBB2 Genomic alterations Biomarkers Non-small cell lung cancer