Conventional combination therapies have not resulted in considerable progress in the treatment of acute myeloid leukemia (AML). Elderly patients with AML and poor risk factors have grave prognosis. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML. Venetoclax, a BCL-2 inhibitor, has been approved for the treatment of relapsed and/or refractory chronic lymphoid leukemia. Clinical trials on applying venetoclax in combination with cytarabine and other agents to treat various hematological malignancies are currently underway. Here, we present a case of a male patient with poor performance status and who developed AML following allogeneic hematopoietic stem cell transplant for high-risk myelodysplasia. The patient with high risk AML achieved complete response to the combined treatment regimen of low-dose cytarabine and venetoclax. Furthermore, we reviewed current clinical trials on the use of venetoclax for hematological malignancies.
Aged ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; Combined Modality Therapy ; Cytarabine ; administration & dosage ; Fatal Outcome ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; Male ; Recurrence ; Remission Induction ; Sulfonamides ; administration & dosage

OBJECTIVE: To evaluate the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using macromolecular contrast agent (P792) for assessment of vascular disrupting drug effect in rabbit VX2 liver tumor models. MATERIALS AND METHODS: This study was approved by our Institutional Animal Care and Use Committee. DCE-MRI was performed with 3-T scanner in 13 VX2 liver tumor-bearing rabbits, before, 4 hours after, and 24 hours after administration of vascular disrupting agent (VDA), using gadomelitol (P792, n = 7) or low molecular weight contrast agent (gadoterate meglumine [Gd-DOTA], n = 6). P792 was injected at a of dose 0.05 mmol/kg, while that of Gd-DOTA was 0.2 mmol/kg. DCE-MRI parameters including volume transfer coefficient (K(trans)) and initial area under the gadolinium concentration-time curve until 60 seconds (iAUC) of tumors were compared between the 2 groups at each time point. DCE-MRI parameters were correlated with tumor histopathology. Reproducibility in measurement of DCE-MRI parameters and image quality of source MR were compared between groups. RESULTS: P792 group showed a more prominent decrease in K(trans) and iAUC at 4 hours and 24 hours, as compared to the Gd-DOTA group. Changes in DCE-MRI parameters showed a weak correlation with histologic parameters (necrotic fraction and microvessel density) in both groups. Reproducibility of DCE-MRI parameters and overall image quality was not significantly better in the P792 group, as compared to the Gd-DOTA group. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging using a macromolecular contrast agent shows changes of hepatic perfusion more clearly after administration of the VDA. Gadolinium was required at smaller doses than a low molecular contrast agent.
Animals ; Antineoplastic Agents/therapeutic use ; Benzophenones/therapeutic use ; Disease Models, Animal ; Heterocyclic Compounds/administration & dosage/*chemistry ; Liver Neoplasms/drug therapy/pathology/*radiography ; *Magnetic Resonance Imaging ; Male ; Organometallic Compounds/administration & dosage/*chemistry ; Rabbits ; Reproducibility of Results ; Valine/analogs & derivatives/therapeutic use

OBJECTIVETo evaluate the efficacy and safety of patient-controlled intravenous analgesia (PCIA) of dezocine combined with sufentanil in burn patients after escharectomy or tangential excision followed by autologous skin grafting.

METHODSSixty burn patients hospitalized in Department of Burns and Plastic Surgery of our hospital from February 2011 to December 2013, conforming to the study criteria and going to have escharectomy or tangential excision followed by autologous skin grafting, were divided into sufentanil group (S, n = 30) and dezocine+sufentanil group (DS, n = 30) according to the random number table. Patients in group S were given 150 mL normal saline containing 2.5 µg/kg sufentanil citrate and 6 mg tropisetron after skin grafting for 48 hours. Patients in group DS were given 150 mL normal saline containing 0.25 mg/kg dezocine, 1.5 µg/kg sufentanil citrate, and 6 mg tropisetron for 48 hours. Visual Analog Scale (VAS), Bruggrmann Comfort Scale (BCS), and Ramsay Sedation Scale were used to evaluate the sedative effect or analgesic effect, and their scores were recorded at administration hour (AH) 2, 6, 12, 24, and 48. The times of efficient injection and incidence of adverse effect within the 48 AH were recorded. Data were processed with analysis of variance for repeated measurement, t test, chi-square test, and Fisher's exact test.

RESULTSThere were no obvious differences in the scores of VAS and BCS between two groups at each time point (with t values from -0.426 to 0.864, P values above 0.05). The scores of Ramsay Sedation Scale in group S at AH 2, 6, 12, 24, and 48 were respectively (3.2 ± 0.6), (3.2 ± 0.5), (3.3 ± 0.7), (3.2 ± 0.4), and (3.3 ± 0.4) points, which were higher than those in group DS [(2.4 ± 0.6), (2.5 ± 0.5), (2.4 ± 0.6), (2.4 ± 0.4), and (2.4 ± 0.5) points, with t values from 5.302 to 8.391, P values below 0.001]. The times of efficient injection within the 48 AH was 6.8 ± 0.7 in group S and 6.5 ± 0.9 in group DS, showing no significantly statistical difference (t = 1.260, P > 0.05). Respiratory depression was not observed in both groups; the incidence of pruritus was the same, and that of urine retention was similar between the 2 groups within the 48 AH (with P values above 0.05). Within the 48 AH, the incidence of nausea and vomiting in group S was 26.7% (8/30), which was obviously higher than that in group DS (6.7%, 2/30, P < 0.05); the incidence of drowsiness in group S was 20.0% (6/30), which was significantly higher than that in group DS (no patient, P < 0.05).

CONCLUSIONSDezocine combined with sufentanil can provide effective postoperative analgesia with little adverse effect for PCIA in burn patients after escharectomy or tangential excision followed by autologous skin grafting, therefore it can be widely used.

Analgesia, Patient-Controlled ; adverse effects ; Analgesics, Opioid ; administration & dosage ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; adverse effects ; Burns ; surgery ; Female ; Humans ; Hypnotics and Sedatives ; administration & dosage ; Infusions, Intravenous ; Male ; Pain, Postoperative ; drug therapy ; Reconstructive Surgical Procedures ; Skin Transplantation ; Sufentanil ; administration & dosage ; adverse effects ; Tetrahydronaphthalenes ; administration & dosage ; adverse effects ; Treatment Outcome

The present study is to establish Caco-2/HT29-MTX co-cultured cells and investigate the transport capability of PLGA nanoparticles with different surface chemical properties across Caco-2/HT29-MTX co-cultured cells. PLGA-NPs, mPEG-PLGA-NPs and chitosan coated PLGA-NPs were prepared by nanoprecipitation method using poly(lactic-co-glycolic acid) as carrier material with surface modified by methoxy poly(ethylene glycol) and chitosan. The particle size and zeta potential of nanoparticles were measured by dynamic light scattering. Coumarin 6 was used as a fluorescent marker in the transport of nanoparticles investigated by confocal laser scanning microscopy. The transport of furanodiene (FDE) loaded nanoparticles was quantitively determined by high performance liquid chromatography. Colchicine and nocodazole were used in the transport study to explore the involved endocytosis mechanisms of nanoparticles. Distribution of the tight junction proteins ZO-1 was also analyzed by immunofluorescence staining. The results showed that the nanoparticles dispersed uniformly. The zeta potential of PLGA-NPs was negative, the mPEG-PLGA-NPs was close to neutral and the CS-PLGA-NPs was positive. The entrapment efficiency of FDE in all nanoparticles was higher than 75%. The transport capability of mPEG-PLGA-NPs across Caco-2/HT29-MTX co-cultured cells was higher than that of PLGA-NPs and CS-PLGA-NPs. Colchicine and nocodazole could significantly decrease the transport amount of nanoparticles. mPEG-PLGA-NPs could obviously reduce the distribution of ZO-1 protein than PLGA-NPs and CS-PLGA-NPs. The transport mechanism of PLGA-NPs and mPEG-PLGA-NPs were indicated to be a combination of endocytosis and paracellular way, while CS-PLGA-NPs mainly relied on the endocytosis way. PEG coating could shield the surface charge and enhance the hydrophilicity of PLGA nanoparticles, which leads mPEG-PLGA-NPs to possess higher anti-adhesion activity. As a result, mPEG-PLGA-NPs could penetrate the mucus layer rapidly and transport across Caco-2/HT29-MTX co-cultured cells.
Biological Transport ; Caco-2 Cells ; Chitosan ; chemistry ; Coated Materials, Biocompatible ; chemistry ; Coculture Techniques ; Drug Carriers ; Furans ; administration & dosage ; chemistry ; metabolism ; HT29 Cells ; Heterocyclic Compounds, 2-Ring ; administration & dosage ; chemistry ; metabolism ; Humans ; Lactic Acid ; chemistry ; Nanoparticles ; Particle Size ; Polyethylene Glycols ; chemistry ; Polyglycolic Acid ; chemistry ; Zonula Occludens-1 Protein ; metabolism

OBJECTIVETo investigate the impact of the mobilization with the antagonist of the stromal cell-derived factor receptor CXCR4 (AMD3100) (plerixafor), granulocyte-colony-stimulating factor (G-CSF) alone and in combination on the proliferation and cytotoxic functions of the murine splenic lymphocytes.

METHODSC57BL/6(H-2(b)) mice, as donors, were mobilized by, AMD3100, G-CSF alone or in combination (n = 10 mice in each group), and phosphate buffered saline (PBS). Then, the proliferation capacity of murine lymphocytes either in response to the phytohemagglutinin (PHA) stimulation or the mixed lymphocytes reaction (MLR) with allo-lymphocytes from the BALB/C(H-2(d)) mice were detected by CCK-8 method. The cytotoxic capacity of murine lymphocytes on Yac-1 tumor cells was examined by LDH assay.

RESULTSThe proliferation capacity and the responsiveness to alloantigen of the lymphocytes derived from the mice spleen mobilized by AMD3100, G-CSF alone or in combination were significantly lower than those by PBS control (P < 0.05), and those combination of AMD 3100 and G-CSF group were significantly lower than in other groups(P < 0.05). At the effector-target ration of 40:1, the cytotoxic capacity of murine lymphocytes in above mobilization groups was lower than in control group, but no statistically significant difference (P > 0.05).

CONCLUSIONBoth the proliferation capacity and the responsiveness to alloantigen of the murine lymphocytes decreases significantly after the mobilization with AMD3100, G-CSF alone or in combination, whereas no significant alternations are demonstrated on the cytotoxic capacity of murine lymphocytes. Further studies are needed to clarify the underlying mechanisms.

Animals ; Cell Proliferation ; Granulocyte Colony-Stimulating Factor ; adverse effects ; pharmacology ; Hematopoietic Stem Cell Mobilization ; methods ; Hematopoietic Stem Cell Transplantation ; methods ; Heterocyclic Compounds ; administration & dosage ; pharmacology ; Lymphocytes ; drug effects ; immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, CXCR4 ; drug effects ; Sincalide

This study is to elucidate the metabolic pathway of 1,2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)]-ethane (BBSKE) in rats. Rats were administrated with a single dose of BBSKE 200 mg x kg(-1). The metabolites in rat urine, feces, bile and plasma were identified by LC-MSn analysis. The characterization of fragment ions from LC-MSn chromatography and mass spectrometry was applied to the investigation of structures of metabolites. Three phase I metabolites were detected in rat urine and feces. Two of them were also found in plasma and one existed in bile. These products were derived from oxidized, methylated and S-methylated BBSKE, separately. One phase II glucuronide of BBSKE was also found in bile. Therefore, it is possible that BBSKE was metabolized by oxidization, methylation and glucuronidation.
Administration, Oral ; Animals ; Antineoplastic Agents ; administration & dosage ; blood ; metabolism ; urine ; Bile ; metabolism ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; blood ; metabolism ; urine ; Chromatography, Liquid ; Feces ; chemistry ; Male ; Organoselenium Compounds ; administration & dosage ; blood ; metabolism ; urine ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization

Influenza virus is a virus causing upper respiratory tract infection disease with high morbidity and mortality. China is considered as an area with high rate of influenza morbidity. Prevention and treatment of influenza currently rely on vaccines and antiviral agents in the world. In addition, traditional Chinese medicines also have been used in clinical for influenza therapy. In vitro anti-influenza virus activities of 10 traditional Chinese medicines were studied by cytopathic effect (CPE). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Guangdong Luohu/219/2006 (H1N1); Yinhuang oral liquid had strong antiviral activity against influenza virus A/Hanfang/359/95 and A/Yuefang/243/72 (H3N2). Qingkailing oral liquid (factory G) had strong antiviral activity against influenza virus A/Jifang/15/90 (H3N2). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Jifang/15/90, A/Yuefang/243/72 (H3N2) and virus B.
Administration, Oral ; Animals ; Antiviral Agents ; administration & dosage ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; pharmacology ; Cell Line ; Chlorogenic Acid ; administration & dosage ; pharmacology ; Cytopathogenic Effect, Viral ; drug effects ; Dogs ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Flavonoids ; administration & dosage ; pharmacology ; Indoles ; administration & dosage ; pharmacology ; Influenza A Virus, H1N1 Subtype ; drug effects ; Influenza A Virus, H3N2 Subtype ; drug effects ; Influenza B virus ; drug effects ; Iridoids ; administration & dosage ; pharmacology

OBJECTIVETo study whether N, N'-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) inhibits proliferation and induces apoptosis in human lung carcinoma cell line EBC-1 cells and its molecular mechanism.

METHODSDifferent concentrations of ZGDHu-1 and different times of culture were used to treat EBC-1 cells in vitro. The inhibition of proliferation was measured by BrdU-ELISA. Cell apoptosis was detected by Annexin V/PI staining and cellular DNA fragmentation ELISA. Phosphorylated p38MAPK and STAT3 were examined by flow cytometry. The protein expressions of bcl-2, bax, p53, Fas, and caspase-3 were detected by Western blot analysis.

RESULTSZGDHu-1 inhibited EBC-1 cell proliferation within a certain range of treating times and does, with a 24 h IC(50) of (295 ± 25) ng/ml, 48 h of (112 ± 8) ng/ml and 72 h of (23 ± 2) ng/ml. The EBC-1 cell apoptosis was confirmed by Annexin V/PI labeling and cellular DNA fragmentation ELISA in a dose-related manner. When EBC-1 cells were treated with 50, 200, and 500 ng/ml ZGDHu-1 for 48 h, the expression rates of phosphor-p38MAPK protein were 67.4%, 88.2%, 91.1%, respectively, and that of the control was 10.6%. That of STAT3 protein were 56.5%, 43.6% and 34.6%, respectively, and that of the control was 89.1%. The expression of bax, p53 and Fas protein was significantly increased, that of bcl-2 was not changed, and that of caspase-3 was significantly decreased by the ZGDHu-1 treatment.

CONCLUSIONZGDHu-1 can inhibit proliferation and induce apoptosis in EBC-1 cells. The mitochondrial pathway mediated by Fas may be one of its mechanisms. The apoptosis of EBC-1 cells may associate with up-regulation of phosphor-p38MAPK and down-regulation of phosphor-STAT3 in the cells.

Apoptosis ; drug effects ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; DNA Fragmentation ; Heterocyclic Compounds, 1-Ring ; administration & dosage ; pharmacology ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; STAT3 Transcription Factor ; metabolism ; Tumor Suppressor Protein p53 ; metabolism ; bcl-2-Associated X Protein ; metabolism ; fas Receptor ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVE: To compare P792 (gadomelitol, a rapid clearance blood pool MR contrast agent) with gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA), a standard extracellular agent, for their suitability to diagnose a pulmonary embolism (PE) during a first-pass perfusion MRI and 3D contrast-enhanced (CE) MR angiography (MRA). MATERIALS AND METHODS: A perfusion MRI or CE-MRA was performed in a rabbit PE model following the intravenous injection of a single dose of contrast agent. The time course of the pulmonary vascular and parenchymal enhancement was assessed by measuring the signal in the aorta, pulmonary artery, and lung parenchyma as a function of time to determine whether there is a significant difference between the techniques. CE-MRA studies were evaluated by their ability to depict the pulmonary vasculature and following defects between 3 seconds and 15 minutes after a triple dose intravenous injection of the contrast agents. RESULTS: The P792 and Gd-DOTA were equivalent in their ability to demonstrate PE as perfusion defects on first pass imaging. The signal from P792 was significantly higher in vasculature than that from Gd-DOTA between the first and the tenth minutes after injection. The results suggest that a CE-MRA PE could be reliably diagnosed up to 15 minutes after injection. CONCLUSION: P792 is superior to Gd-DOTA for the MR diagnosis of PE.
Animals ; Contrast Media/administration & dosage ; Heterocyclic Compounds/administration & dosage/*diagnostic use ; Imaging, Three-Dimensional ; Injections, Intravenous ; Magnetic Resonance Angiography/*methods ; Magnetic Resonance Imaging/*methods ; Organometallic Compounds/administration & dosage/*diagnostic use ; Pulmonary Embolism/*diagnosis ; Rabbits

A single dose of 3H-norcantharidin solution was intragastrically given, blood, tissues, urine and feces were collected as scheduled, and radioactivity in these samples was determined by tritium tracing method to investigate the pharmacokinetics, tissue distribution and excretion of norcantharidin in Kunming mice. The pharmacokinetic characteristics of norcantharidin were evaluated by DAS version 2.0. The blood concentration reached to maximum 0. 5 h after intragastric administration. The radioactivity in tissues was high in small intestine, gallbladder, stomach, adrenal gland, kidney, heart and uterus 15 minutes after administration, descending with time, and high in gallbladder, adrenal gland and uterus 3 hours post dosing. The 24 h accumulative excretion ratio of urine and feces were 65.40% and 1.33% respectively. 3H-norcantharidin was easily absorbed after orally given to mice, the radioactivity was high and existed for a long-time in gallbladder, adrenal gland and uterus, and low but also existed for a long-time in large intestine, thymus and fat tissue. 3H-norcantharidin was declined quickly in small intestine, stomach, kidney and heart, and occurred rarely in brain. Norcantharidin was excreted mainly by urinary route and seldom in feces, which may be the cause of the urinary stimulation side effects observed. Because the radioactivity measured were the sum of 3H labeled norcantharidin and its metabolites, further studies on the disposition of norcantharidin in mammal animals, on the separation or identification of metabolites and, if any, on their activities, are fairly needed.
Administration, Oral ; Animals ; Antineoplastic Agents ; administration & dosage ; chemistry ; pharmacokinetics ; urine ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; chemistry ; pharmacokinetics ; urine ; Feces ; chemistry ; Female ; Male ; Mice ; Molecular Structure ; Random Allocation ; Tissue Distribution ; Tritium