OBJECTIVE: To retrospectively analyze the efficacy and safety of ruxolitinib therapy for children with thalassemia after unrelated or haploidentical stem cell transplantation. METHODS: From March 2020 to March 2021, 22 patients received successfully allogeneic hematopoietic stem cell transplantation in the Zhongshan Hospital of Xiamen University, from +30 to 100 days,those patients received ruxolitinib therapy (2.5 mg, twice daily) and all adverse reactions were observed, include aGVHD, cGVHD, CMV and EBV infection. RESULTS: 22 patients underwent allogeneic stem cell transplantation, 5 patients were diagnosed as aGVHD, 3 patients had grade I－II skin GVHD and 2 patients had grade II intestinal GVHD, those patients were cured. All patients were followed up for more than 21 weeks, 4 cases developed cGVHD, including 3 cases of localized liver GVHD and 1 case of pulmonary GVHD, those were relieved after active treatment. 8 patients had elevated EBV copies (>3×10³/ml), and 3 patients had increased CMV copies, the patients recovered after immunosuppressant and antiviral treatment. There was no CMV infection and EBV related post-transplantant lymphoproliferative disorders(PTLD), and no transplant related deaths. CONCLUSION Ruxolitinib can effectively reduce the incidence and severity of GVHD without affecting the hematopoietic recovery, and improve the survival status of thalassemia children after transplantation.
Antiviral Agents/therapeutic use* ; Child ; Graft vs Host Disease/prevention & control* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Humans ; Immunosuppressive Agents/therapeutic use* ; Nitriles ; Pyrazoles ; Pyrimidines ; Retrospective Studies ; Thalassemia

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
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Aminopyridines ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Consensus ; Drug Resistance, Neoplasm/genetics* ; Drug-Related Side Effects and Adverse Reactions/drug therapy* ; Humans ; Lactams ; Lactams, Macrocyclic/adverse effects* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/adverse effects* ; Protein-Tyrosine Kinases/genetics* ; Pyrazoles

OBJECTIVEThis study aims to evaluate the efficacy and safety of crizotinib for advanced ALK-positive non-small cell lung cancer (NSCLC) patients.

METHODSTwenty-eight patients with advanced ALK-positive NSCLC were given orally crizotinib 250 mg b. i.d., and were followed up to evaluate the therapeutic efficacy and safety.

RESULTSAmong the 28 patients, the objective response rate (ORR) was 71.4% (20/28) and disease control rate (DCR) was 92.9% (26/28). Three patients achieved complete response. Seventeen patients had partial response. The most common drug-related adverse events were mild flickering vision and gastrointestinal reaction. Eleven patients experienced flickering vision. Nine patients had nausea and vomiting. Eight patients had diarrhea. They were all reversible and of grade I or II. Only one patient had grade III myelosuppression. Among the 28 patients, 16 cases were disease-free and 12 cases had progressive disease, with a progression-free survival of 8.2 months.

CONCLUSIONSCrizotinib is effective and tolerable in the treatment of advanced ALK-positive NSLCC. However, its long-term treatment efficacy requires to be further studied.

Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; pathology ; Diarrhea ; chemically induced ; Disease-Free Survival ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; pathology ; Nausea ; chemically induced ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrazoles ; adverse effects ; therapeutic use ; Pyridines ; adverse effects ; therapeutic use ; Receptor Protein-Tyrosine Kinases ; Vomiting ; chemically induced

Carcinoma, Non-Small-Cell Lung ; drug therapy ; Humans ; Lung Diseases, Interstitial ; chemically induced ; diagnosis ; Male ; Middle Aged ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrazoles ; adverse effects ; therapeutic use ; Pyridines ; adverse effects ; therapeutic use

PURPOSE: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. MATERIALS AND METHODS: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). RESULTS: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p<0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. CONCLUSION: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.
Adiponectin/metabolism ; Adiposity/drug effects ; Animals ; Cell Proliferation/drug effects ; Diabetes Mellitus, Type 2/diet therapy/*drug therapy ; Eating/*drug effects ; Glucose Intolerance/diet therapy/*drug therapy ; Insulin Resistance ; Insulin-Secreting Cells/*drug effects/pathology ; Male ; Piperidines/adverse effects/*therapeutic use ; Pyrazoles/adverse effects/*therapeutic use ; Rats ; Rats, Inbred OLETF ; Receptor, Cannabinoid, CB1/physiology ; Thiazolidinediones/*therapeutic use

This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells. One week before treatment with the drug, nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation. After drug treatment, HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting. The viability of the PC12 cells treated with different medicines was examined by MTT assay. The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA. The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP(+)-induced oxidative injury. Moreover, β-PGG induced Nrf2 nuclear translocation, which was found to be upstream of β-PGG-induced HO-1 expression, and the activation of ERK and Akt, a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. In conclusion, β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK- and Akt-dependent manner, and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.
Animals ; Cell Death ; drug effects ; genetics ; Cell Line, Tumor ; Heme Oxygenase-1 ; genetics ; Hydrolyzable Tannins ; pharmacology ; MAP Kinase Signaling System ; drug effects ; genetics ; PC12 Cells ; Piperidines ; adverse effects ; Proto-Oncogene Proteins c-akt ; genetics ; Pyrazoles ; adverse effects ; Rats

PURPOSE: Cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 play a key role in the pathogenesis of in-stent restenosis. We investigated the effect of a short-term therapy of celecoxib, a COX-2 inhibitor, with or without doxycycline, an MMP inhibitor, after coronary stenting on inflammatory biomarkers and neointimal hyperplasia. MATERIALS AND METHODS: A total of 75 patients (86 lesions) treated with bare metal stents were randomized into three groups: 1) combination therapy (200 mg celecoxib and 20 mg doxycycline, both twice daily), 2) celecoxib (200 mg twice daily) only, and 3) non-therapy control. Celecoxib and doxycycline were administered for 3 weeks after coronary stenting. The primary endpoint was neointimal volume obstruction by intravascular ultrasound (IVUS) at 6 months. The secondary endpoints included clinical outcomes, angiographic data, and changes in blood levels of inflammatory biomarkers. RESULTS: Follow-up IVUS revealed no significant difference in the neointimal volume obstruction among the three treatment groups. There was no difference in cardiac deaths, myocardial infarctions, target lesion revascularization or stent thrombosis among the groups. Blood levels of high-sensitivity C-reactive protein, soluble CD40 ligand, and MMP-9 varied widely 48 hours and 3 weeks after coronary stenting, however, they did not show any significant difference among the groups. CONCLUSION: Our study failed to demonstrate any beneficial effects of the short-term therapy with celecoxib and doxycycline or with celecoxib alone in the suppression of inflammatory biomarkers or in the inhibition of neointimal hyperplasia. Large scale randomized trials are necessary to define the role of anti-inflammatory therapy in the inhibition of neointimal hyperplasia.
Aged ; Angioplasty, Balloon, Coronary ; Anti-Bacterial Agents/therapeutic use ; Biological Markers/metabolism ; Coronary Artery Disease/immunology/metabolism/*therapy ; Cyclooxygenase 2 Inhibitors/therapeutic use ; Doxycycline/*therapeutic use ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Male ; Metals ; Middle Aged ; Neointima/*drug therapy/*immunology/metabolism ; Pyrazoles/*therapeutic use ; Stents/*adverse effects ; Sulfonamides/*therapeutic use

BACKGROUNDEnoxaparin is routinely used for prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty. The purpose of this study was to compare the efficacy and safety of apixaban, a newly oral direct inhibitor of factor Xa versus enoxaparin.

METHODSWe performed a meta-analysis of relevant randomized-controlled trials (RCTs) identified in PubMed, Cochrane Library, Embase China Biological Medical Literature database, Countries Journal full-text database, VIP database, and WanFang database. The primary efficacy outcome for our meta-analysis was all VTE and all-cause mortality. The secondary efficacy outcomes included major VTE, non-fatal pulmonary embolism, and mortality. The primary safety outcome was bleeding events, categorized as major, clinically relevant non-major, or minor events.

RESULTSFour RCTs, involving 14 065 patients, were included in our meta-analysis. Compared to enoxaparin, thromboprophylaxis with apixaban was associated with significantly fewer VTE and all-cause mortality (8346 patients, risk ratio (RR): 0.63, 95%CI 0.42 - 0.95) and similar incidence of bleeding events (major bleeding, 11 525 patients, RR 0.76, 95%CI 0.43 - 1.33; clinically relevant non-major bleeding, 11 525 patients, RR 0.83, 95%CI 0.69 - 1.01; and minor bleeding, 11 828 patients, RR 0.93, 95%CI 0.79 - 1.09). However, our meta-analysis revealed similar effects of apixaban with enoxaparin for thromboprophylaxis with regard to the secondary efficacy outcomes.

CONCLUSIONSApixaban was more effective than recommended dose of enoxaparin and had a similar safety profile for thromboprophylaxis after hip and knee arthroplasty. But more evidence, especially well designed head-to-head RCTs, is needed to confirm the superior efficacy of apixaban.

Arthroplasty, Replacement, Hip ; adverse effects ; methods ; Arthroplasty, Replacement, Knee ; adverse effects ; methods ; Enoxaparin ; therapeutic use ; Humans ; Pyrazoles ; therapeutic use ; Pyridones ; therapeutic use ; Randomized Controlled Trials as Topic ; Venous Thromboembolism ; etiology ; prevention & control

OBJECTIVETo study the effect of celecoxib on chronic hypoxia and hypercapnic pulmonary hypertension.

METHODSSD rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia+ celecoxib group (C). The content of TXB2 and 6-keto-PGF1alpha in plasma and lung were detected by the technique of radioimmunology.

RESULTS(1) Mean pulmonary arteria pressure(mPAP) was significantly higher in rats of B group than those of A group. mPAP was significantly higher in rats of C group than those of B group. Differences of mPAP were not significant in three groups. (2) The content of TXB2 in plasma and lung and the ratio of TXB2/6-keto-PGF1alpha were significantly higher in rats of B group than those of A group. The ratio of TXB2/6-keto-PGF1alpha was significantly higher and the content of 6-keto-PGF1alpha in plasma and lung was significantly lower in rats of C group than those of B group. (3) Light microscopy showed that WA/TA (vessel wall area/total area) and PAMT (the thickness of medial smooth cell layer) were significantly higher in rats of B group than those of A group. WA/TA and PAMT were significantly higher in rats of C group than those of B group. (4) Electron microscopy showed the thickening of vessel wall and the proliferation of collagen fiber in B group and augmentation of smooth muscle cell and abundance of myofilament in pulmonary arterioles in C group.

CONCLUSIONCelecoxib can aggravate hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling by increasing the ratio of TXA2/PGI2.

Animals ; Celecoxib ; Chronic Disease ; Cyclooxygenase 2 Inhibitors ; adverse effects ; pharmacology ; Epoprostenol ; blood ; Hypercapnia ; complications ; Hypertension, Pulmonary ; etiology ; physiopathology ; Hypoxia ; complications ; Male ; Pyrazoles ; adverse effects ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfonamides ; adverse effects ; pharmacology ; Thromboxane A2 ; blood

Animals ; Celecoxib ; Cyclooxygenase 1 ; genetics ; metabolism ; Cyclooxygenase 2 ; genetics ; metabolism ; Cyclooxygenase 2 Inhibitors ; pharmacology ; therapeutic use ; Cytokines ; metabolism ; Disease Models, Animal ; Ethanol ; adverse effects ; Fatty Liver, Alcoholic ; pathology ; prevention & control ; Immunohistochemistry ; Liver ; drug effects ; metabolism ; pathology ; Liver Cirrhosis, Alcoholic ; pathology ; prevention & control ; Liver Diseases, Alcoholic ; pathology ; prevention & control ; Pyrazoles ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfonamides ; pharmacology ; therapeutic use