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) studies. Methods: 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 throughout. Results: 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 population. Conclusions: 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 population. Clinical Trial Identifier NCT00856544 and NCT00413699.
Administration, Oral ; Adult ; Aged ; Arthritis, Rheumatoid ; drug therapy ; Asian Continental Ancestry Group ; Female ; Humans ; Male ; Middle Aged ; Piperidines ; adverse effects ; therapeutic use ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrimidines ; adverse effects ; therapeutic use ; Pyrroles ; adverse effects ; therapeutic use ; Surveys and Questionnaires ; Young Adult

Aged ; Delusional Parasitosis ; diagnosis ; drug therapy ; physiopathology ; psychology ; Diagnosis, Differential ; Female ; Humans ; Male ; Middle Aged ; Psychotropic Drugs ; administration & dosage ; Pyrimidines ; administration & dosage ; Retrospective Studies ; Risperidone ; administration & dosage ; Singapore ; epidemiology ; Symptom Assessment ; Treatment Outcome

OBJECTIVETo investigate the factors which may influence the imatinib plasma concentration in Chinese patients with gastrointestinal stromal tumor(GIST), and to illuminate the significance of monitoring imatinib plasma concentration in adjuvant therapy for patients with GIST.

METHODSA cross-sectional study with 60 GIST patients who accepted the imatinib therapy after surgery was conducted. They were respectively administrated in 10 domestic hospitals from December 2014 to April 2016, including The First Affiliated Hospital of Nanjing Medical University(n=28), The Affiliated Hospital of Nantong University(n=9), The Affiliated Hospital of Xuzhou Medical College(n=6), Nanjing Drum Tower Hospital(n=5), The Second Affiliated Hospital of Nanjing Medical University (n=2), Jingling Hospital (n=2), The Second People's Hospital of Lianyungang(n=2), Shandong Provincial Hospital(n=2), Jiangsu Province Tumor Hospital(n=2), and The First Affiliated Hospital of Zhejiang University(n=2). Some specific time points for collecting blood sample before and after taking imatinib were determined, then liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used for monitoring imatinib plasma concentration in patients with GIST. Linear regression analysis was used for the correlation analysis of imatinib plasma concentration with dosage, clinicopathologic feature and side effect.

RESULTSPatients who could not tolerate 400 mg imatinib per day(n=3) received 300 mg per day. There was no significant difference in imatinib plasma concentration between patients with 300 mg and those with 400 mg imatinib(n=53)(P=0.527). However, the imatinib plasma concentration in patients with 600 mg imatinib per day (n=4) was significantly higher as compared to those with 400 mg(P=0.000). Linear regression analysis indicated a negative correlation between the imatinib plasma concentration in patients with 400mg imatinib per day for 90 days continuously and body surface area(R=0.074, P=0.035), but no significant correlations of with age, creatinine clearance and serum albumin concentration were observed (all P>0.05). The differences in imatinib plasma concentration were not statistically significant between patients of different gender and those taking proton-pump inhibitor (PPI) or not (both P>0.05). Difference in imatinib plasma concentration between patients with different surgery was significant (P=0.026). Compared to patients who underwent wedge resection, enterectomy and other surgeries, the imatinib plasma concentration of patients with subtotal gastrectomy or total gastrectomy decreased significantly (all P<0.05). After 90 days of taking imatinib continuously, linear regression analysis revealed a negative correlation between imatinib plasma concentration in patients with 400 mg imatinib per day and white blood cell count (R=0.103, P=0.013), and a positive correlation with serum alanine aminotransferase (ALT) concentration (R=0.076, P=0.033).

CONCLUSIONSThe imatinib plasma concentration in patients with larger body surface area, subtotal gastrectomy or total gastrectomy may be lower. For these patients, dosage of imatinib should be considered to increase in order to achieve effective plasma concentration. Excessive imatinib plasma concentration can result in some side effects, such as decrease of white blood cells and liver damage. Therefore, it is significant for receiving optimal clinical therapeutic efficacy to monitor imatinib plasma concentration, adjust imatinib dosage timely and keep imatinib plasma concentration in effective and safe range.

Adult ; Antineoplastic Agents ; administration & dosage ; pharmacokinetics ; Benzamides ; Combined Modality Therapy ; Cross-Sectional Studies ; Female ; Gastrectomy ; Gastrointestinal Stromal Tumors ; drug therapy ; surgery ; Humans ; Imatinib Mesylate ; administration & dosage ; pharmacokinetics ; Male ; Middle Aged ; Piperazines ; Pyrimidines ; Tandem Mass Spectrometry

To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.
Animals ; Bee Venoms ; administration & dosage ; Benzamides ; pharmacology ; Epigenesis, Genetic ; Histone Deacetylase 1 ; genetics ; metabolism ; Histone Deacetylase 2 ; genetics ; metabolism ; Histone Deacetylase Inhibitors ; pharmacology ; Hot Temperature ; Hyperalgesia ; drug therapy ; Inflammation ; drug therapy ; Injections, Subcutaneous ; Nociception ; Pain ; chemically induced ; drug therapy ; Pain Measurement ; Pyridines ; pharmacology ; Pyrimidines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Up-Regulation

Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Child ; Dasatinib ; Female ; Humans ; Male ; Molecular Targeted Therapy ; Neoplasm, Residual ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; Protein Kinase Inhibitors ; administration & dosage ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; administration & dosage ; adverse effects ; Thiazoles ; administration & dosage ; adverse effects

BACKGROUND/AIMS: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP). Combination therapy w ith ora l udenafil and aceclofenac may reduce the occurrence of post-ERCP pancreatitis by targeting different pathophysiological mechanisms. We investigated whether combining udenafil and aceclofenac reduced the rates of post-ERCP pancreatitis. METHODS: A prospective, randomized, double-blind, placebo-controlled, multicenter study was conducted in four academic medical centers. Between January 2012 and June 2013, a total of 216 patients who underwent ERCP were analyzed for the occurrence of post-ERCP pancreatitis. Patients were determined to be at high risk for pancreatitis based on validated patient and procedure-related risk factors. RESULTS: Demographic features, indications for ERCP, and therapeutic procedures were similar in each group. There were no significant differences in the rate (15.8% [17/107] vs. 16.5% [18/109], p = 0.901) and severity of post-ERCP pancreatitis between the udenafil/aceclofenac and placebo groups. One patient in each group developed severe pancreatitis. Multivariate analyses indicated that suspected dysfunction of the sphincter of Oddi and endoscopic papillary balloon dilation without sphincterotomy were associated with post-ERCP pancreatitis. CONCLUSIONS: Combination therapy with udenafil and aceclofenac is not effective for the prevention of post-ERCP pancreatitis.
Acute Disease ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Anti-Inflammatory Agents, Non-Steroidal/*administration & dosage/adverse effects ; Cholangiopancreatography, Endoscopic Retrograde/*adverse effects ; Diclofenac/administration & dosage/adverse effects/*analogs & derivatives ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Pancreatitis/diagnosis/etiology/*prevention & control ; Phosphodiesterase 5 Inhibitors/*administration & dosage/adverse effects ; Prospective Studies ; Pyrimidines/*administration & dosage/adverse effects ; Republic of Korea ; Risk Factors ; Sulfonamides/*administration & dosage/adverse effects ; Treatment Outcome ; Young Adult

OBJECTIVETo evaluate the efficacy and safety of trastuzumab combined with chemotherapy in the treatment for HER-2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma.

METHODSTwenty consecutive cases of chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma treated in Peking University Cancer Hospital between 2009 June and 2013 August were included in this study. The patients with adenocarcinoma were previously confirmed and were eligible if their tumor showed overexpression of HER-2+++ by immunohistochemistry or HER-2 gene amplification-positive by FISH, and if they failed to at least one previous chemotherapy. Response and toxicities were evaluated with RECIST 1.0 and CTC AE 3.0 criteria.

RESULTSThe twenty patients received trastuzumab plus second- or later-line chemotherapy, consisting of nine platinum with fluoropyrimidines, five paclitaxel with fluoropyrimidines, three fluoropyrimidines monotherapy, two irinotecan monotherapy, and one docetaxel monotherapy. In these 20 cases, 3 PR (15.0%) and 10 SD (50.0%) were achieved, with a disease control rate of 65.0%. The median PFS was 6.1 months (95%CI 3.0-9.2) and median OS was 11.1 months (95%CI 8.4-13.7). The median cycle number of Trastuzumab administration was 6.5. The patients treated with Trastuzumab ≥ 6 times had a median OS of 13.8 months, significantly longer than that of 9.5 months in the patients treated <6 times (P < 0.001). The patients treated with Trastuzumab ≥ 6 times had a median PFS of 7.8 months, significantly longer than that of 3.7 months in patients treated <6 times (P = 0.029). Among the 20 cases, loss of appetite (13 cases of grade 1-2), neutropenia (12 cases of grade 1-2 and 3 cases of grade 3-4) and fatigue (9 cases of grade 1-2 and 3 cases of grade 3-4) were the most frequent adverse events. No cardiac events including asymptomatic decreases in LVEF ≥ 10% and no treatment-related death were recorded.

CONCLUSIONSCombination of trastuzumab with chemotherapy is effective and safe in patients with HER2-positive advanced chemo-refractory gastric or gastro-esophageal junction adenocarninoma. However, prospective studies are warranted to further confirm its efficacy and safety.

Adenocarcinoma ; drug therapy ; metabolism ; secondary ; surgery ; Adult ; Aged ; Anorexia ; chemically induced ; Antibodies, Monoclonal, Humanized ; administration & dosage ; adverse effects ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Camptothecin ; administration & dosage ; adverse effects ; analogs & derivatives ; Cisplatin ; administration & dosage ; adverse effects ; Disease Progression ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Esophagogastric Junction ; Fatigue ; chemically induced ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms ; drug therapy ; secondary ; Male ; Middle Aged ; Neutropenia ; chemically induced ; Paclitaxel ; administration & dosage ; adverse effects ; Pyrimidines ; administration & dosage ; adverse effects ; Receptor, ErbB-2 ; metabolism ; Remission Induction ; Retrospective Studies ; Stomach Neoplasms ; drug therapy ; metabolism ; secondary ; surgery ; Survival Rate ; Trastuzumab

OBJECTIVETo investigate the role of imatinib in induction therapy for newly diagnosed adult patients with Philadephia chromosome-positive acute lymphoblastic leukemia (Ph⁺ALL), as well as the status of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of adult Ph⁺ ALL in imatinib era.

METHODSRetrospectively analyzed 97 newly diagnosed adult Ph⁺ ALL patients from 2005 to 2013. According to whether administrated imatinib in the induction therapy and the administrating duration (≥3 d) , they were divided into imatinib (n=37) and non-imatinib group (n=60), and the former group was further divided into early-use (n=26) and late-use imatinib groups (n=11) (bounded by the fourteenth day of induction chemotherapy). We compared the overall response rate (ORR) and the negative rate of BCR-ABL fusion gene in patients who achieved complete remission (CR) or CR with incomplete recovery of blood cells (CRi) among the three groups at the end of the first induction therapy. There were 44 cases underwent allo-HSCT (transplant group) and 33 cases only adopted imatinib-based chemotherapy (non-transplant group) in 77 patients who administrated imatinib as a maintenance therapy, we further compared the incidences of overall survival (OS) , disease-free survival (DFS), relapse and nonrelapse mortality (NRM) between the two groups; and dynamically monitor polymerase chain reaction (PCR) negativity of patients who were in CR1 state before transplant (n=34) at the following timepoints of achieving CR or CRi, the first consolidation therapy, beginning the pretreatment of transplant and attaining hematopoietic reconstruction after transplant.

RESULTSAfter the first induction therapy, the ORR of imatinib group was significantly higher than of non-imatinib group (97.3%, 72.9% respectively, P=0.002), but early-use and late-use imatinib groups had no statistical significance in ORR (100% , 90.9% respectively, P=0.297); the rate of negativity of imatinib and non- imatinib groups were 20.0% and 0 respectively (P=0.041) in patients who achieved CR or CRi. The negative rate of patients in CR1 state before transplant attained 20.8%, 42.3%, 51.8%, 76.8%, respectively at the previously described 4 timepoints. And the differences between the fourth and the third, the third and the first timepiont all reached statistical significance (P=0.044, 0.022, respectively). The 5-year OS of transplant and non- transplant groups showed statistical difference (47.0%, 28.0% respectively, P=0.016), also for 5-year DFS (P=0.001) and the cumulative rate of relapse (P=0.000) of the former surpassing the latter; the cumulative rate of NRM between these two groups had no statistical significance (P=0.370).

CONCLUSIONConventional induction chemotherapy in combination with imatinib in the first induction therapy of adult Ph⁺ ALL, not only improved the rate of hematologic remission, also the rate of molecular response. Imatinib used as a consolidation and maintenance therapy after remission, and allo-HSCT scheduled as soon as possible improved the prognosis.

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Benzamides ; administration & dosage ; therapeutic use ; Disease-Free Survival ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Imatinib Mesylate ; Male ; Middle Aged ; Philadelphia Chromosome ; Piperazines ; administration & dosage ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; therapy ; Protein Kinase Inhibitors ; administration & dosage ; therapeutic use ; Pyrimidines ; administration & dosage ; therapeutic use ; Retrospective Studies ; Transplantation, Homologous ; Treatment Outcome ; Young Adult

BACKGROUND/AIMS: The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). METHODS: A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. RESULTS: Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. CONCLUSIONS: Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.
Antirheumatic Agents/administration & dosage/adverse effects/*therapeutic use ; Arthritis, Rheumatoid/*drug therapy ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Humans ; Janus Kinases/antagonists & inhibitors ; Methotrexate/therapeutic use ; Piperidines/administration & dosage/adverse effects/*therapeutic use ; Protein Kinase Inhibitors/administration & dosage/adverse effects/therapeutic use ; Pyrimidines/administration & dosage/adverse effects/*therapeutic use ; Pyrroles/administration & dosage/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome

No abstract available.
Adult ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Benzamides/therapeutic use ; Bone Marrow Examination ; Chemoradiotherapy ; Cyclophosphamide/administration & dosage ; Doxorubicin/administration & dosage ; Humans ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*diagnosis/drug therapy/genetics/pathology ; Lymphoma, Large B-Cell, Diffuse/*diagnosis/pathology/therapy ; Male ; *Neoplasms, Second Primary ; Piperazines/therapeutic use ; Positron-Emission Tomography ; Prednisolone/administration & dosage ; Protein Kinase Inhibitors/therapeutic use ; Pyrimidines/therapeutic use ; Time Factors ; Tomography, X-Ray Computed ; Treatment Outcome ; Vincristine/administration & dosage ; Whole Body Imaging/methods