Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34⁺ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34⁺ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
Acrylamides/pharmacology* ; Animals ; Blood Platelets/drug effects* ; Cell Differentiation ; Megakaryocytes/drug effects* ; Mice ; Mice, Inbred C57BL ; Piperazines/pharmacology* ; Pyrimidines/pharmacology*

BACKGROUNDStatins are potent lipid-lowering agents widely used in medical practice. There has been growing evidence suggesting the pleiotropic effects of statins in addition to the lipid-lowering effect. However, it is still unclear how rapidly the beneficial effects of statins occur. The transcriptome of peripheral blood cells can be used as a sensor to drug therapy. The purpose of the study was to investigate the acute effects of rosuvastatin both on lipids profile and gene expression of peripheral leukocytes following therapy with a single dose of rosuvastatin.

METHODSThirty healthy Chinese male volunteers were enrolled. The serum lipids, high-sensitivity C-reactive protein, and plasma fibrinogen were determined before and 72 hours after administration of 20 mg of rosuvastatin. The differentially expressed genes of peripheral leukocytes after administration of rosuvastatin were screened using human oligonucleotide microarray gene expression chips. Then four of the differentially expressed genes including ATM, CASP8, IL8RB and S100B were verified by real-time polymerase chain reaction (PCR).

RESULTSRosuvastatin decreased both serum total cholesterol and low-density lipoprotein cholesterol significantly 72 hours after administration of a single dose of 20 mg rosuvastatin. However, no significant changes occurred in blood high-density lipoprotein cholesterol, triglycerides, C-reactive protein and fibrinogen after the treatment. A total of 24 genes were differentially expressed after the treatment. They were involved in important cell biological processes such as cytokine-cytokine receptor interaction, apoptosis signaling, etc.

CONCLUSIONSRosuvastatin rapidly modulates the serum lipids and affects the gene expression of peripheral leukocytes in healthy volunteers. This finding provides some new clues for further studies on its potential pleiotropic effects.

Adult ; Caspase 8 ; genetics ; Fluorobenzenes ; pharmacology ; Gene Expression Profiling ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; pharmacology ; Leukocytes ; drug effects ; metabolism ; Lipids ; blood ; Male ; Polymerase Chain Reaction ; Pyrimidines ; pharmacology ; Receptors, Interleukin-8 ; genetics ; Rosuvastatin Calcium ; Sulfonamides ; pharmacology

DA-8159, a selective inhibitor of phosphodiesterase type 5, was developed as a new drug for erectile dysfunction. The effect of DA-8159 on the electroretinogram (ERG) and the retinal histopathology were evaluated in rabbits. The ERG was performed prior to, and 1 and 5 hr after DA-8159 (5 to 30 mg/kg) administration. The plasma concentration of DA-8159 was determined at each time point, and retinal microscopic examination was also performed. There was no statistically significant ERG change at any dose or at any time. Though the 30 Hz flicker showed a prolongation of the implicit time at 5 hr after the administration of either DA-8159 15 mg or 30 mg/kg (p<0.05), but concurrent amplitude decreases were not statistically significant. At a dose of 5 mg/kg, no test drug was detected in the blood after either 1 or 5 hr. At either 15 mg/kg or 30 mg/kg, there was a dose-dependent increase in the blood concentration after 1 hr of drug administration, which decreased with time. In light and electron microscopic examinations of the retina, there was no remarkable change at any dose. These results suggest DA-8159 has a low risk potential to the retina, but further evaluation on the visual functions in human is needed.
3',5'-Cyclic-GMP Phosphodiesterase/*antagonists & inhibitors ; Animals ; Dose-Response Relationship, Drug ; Electroretinography/*drug effects ; Humans ; Male ; Phosphodiesterase Inhibitors/blood/*pharmacology ; Pyrimidines/blood/*pharmacology ; Rabbits ; Retina/*cytology/*drug effects

As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade.
Analgesics ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Animals ; Benzimidazoles ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Blood-Brain Barrier ; Cycloheptanes ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Heterocyclic Compounds, 3-Ring ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Pain Measurement ; Pyrimidines ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Receptors, Metabotropic Glutamate ; antagonists & inhibitors ; chemistry ; Signal Transduction ; drug effects ; Structure-Activity Relationship ; Thiazoles ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology

Hypertension is associated with endothelial dysfunction and increased cardiovascular risk. Caveolin-1 regulates nitric oxide (NO) signaling by modulating endothelial nitric oxide synthase (eNOS). The purpose of this study was to examine whether HMG-CoA reductase inhibitor improves impaired endothelial function of the aorta in spontaneous hypertensive rat (SHR) and to determine the underlying mechanisms involved. Eight-week-old male SHR were assigned to either a control group (CON, n=11) or a rosuvastatin group (ROS, n=12), rosuvastatin (10 mg/kg/day) administered for eight weeks. Abdominal aortic rings were prepared and responses to acetylcholine (10-9-10-4 M) were determined in vitro. To evaluate the potential role of NO and caveolin-1, we examined the plasma activity of NOx, eNOS, phosphorylated-eNOS and expression of caveolin-1. The relaxation in response to acetylcholine was significantly enhanced in ROS compared to CON. Expression of eNOS RNA was unchanged, whereas NOx level and phosphorylated-eNOS at serine-1177 was increased accompanied with depressed level of caveolin-1 in ROS. We conclude that 3-Hydroxy-3-methylglutaryl Coenzyme-A (HMG-CoA) reductase inhibitor can improve impaired endothelial dysfunction in SHR, and its underlying mechanisms are associated with increased NO production. Furthermore, HMG-CoA reductase inhibitor can activate the eNOS by phosphorylation related to decreased caveolin-1 abundance. These results imply the therapeutic strategies for the high blood pressure-associated endothelial dysfunction through modifying caveolin status.
Acetylcholine/metabolism ; Animals ; Aorta/metabolism/physiopathology ; Blood Pressure/drug effects ; Caveolin 1/*metabolism ; Down-Regulation ; Drug Administration Schedule ; Endothelium, Vascular/*drug effects/physiopathology ; Fluorobenzenes/administration & dosage/*pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage/*pharmacology ; Hypertension/enzymology/metabolism/*physiopathology ; Male ; Nitric Oxide/blood ; Nitric Oxide Synthase Type III/*metabolism ; Phosphorylation ; Pyrimidines/administration & dosage/*pharmacology ; Rats ; Rats, Inbred SHR ; Sulfonamides/administration & dosage/*pharmacology ; Vasodilation/drug effects

This study was designed to explore the influence of STI571, a tyrosine kinase inhibitor, on the expression of c-kit in the bone marrow cells from patients with acute non-lymphocytic leukemia (ANLL). The cells were exposed to various concentration of STI571 for 72 hours, the expression of c-kit mRNA and CD117 was assayed by RT-PCR and flow cytometry, respectively. The results showed that STI571 treatment induced concentration-dependent decrease of c-kit and CD117 expression, which was significant lower than that in group before treatment and untreated control groups (P < 0.05) and 0.1 micro mol/L STI571 group was significantly higher than that in 10 micro mol/L group (P < 0.05). It is concluded that STI571 has an obvious effect on the restraint of c-kit in ANLL cells.
Adolescent ; Adult ; Aged ; Antineoplastic Agents ; pharmacology ; Benzamides ; Bone Marrow Cells ; drug effects ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Imatinib Mesylate ; Leukemia, Myeloid, Acute ; blood ; genetics ; pathology ; Male ; Middle Aged ; Piperazines ; pharmacology ; Proto-Oncogene Proteins c-kit ; genetics ; Pyrimidines ; pharmacology ; RNA, Messenger ; drug effects ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVETo investigate the effects of ST1571 on the development of dendritic cells (DC) derived from bone marrow mononuclear cells of patients with chronic myeloid leukemia (CML).

METHODSBone marrow mononuclear cells (BMMNC) from CML patients and healthy volunteers were cultured initially using multiple cytokine combinations as follows: recombinant human granulocyte/ macrophage colony-stimulating-factor (rhGM-CSF) plus recombinant human interleukin-4 (rhIL-4) as CML and normal control groups, rhGM-CSF plus rhIL-4 and ST1571 as CML experimental groups, and from day 8 recombinant human tumor necrosis factor-alpha ( rhTNF-alpha) was added to stimulate DC maturation. The morphologic features of cells were observed by Wright's staining and phenotypes were assessed by flow cytometry. Cytogenetic analysis was performed by fluorescence in-situ hybridization (FISH), and the antigen-presenting function was assayed by mixed lymphocyte reaction (MLR). The concentration of VEGF was detected by ELISA.

RESULTSCML experimental groups treated with STI571 displayed morphological features similar to those of control groups with delicate membrane projections. However, in comparison with the CML control groups, the CML experimental groups showed an increased expression of CD80, CD86, CD83 and HLA-DR and showed more intense abilities of allogeneic antigen presentation, which were similar to those of normal control groups. FISH confirmed that DCs of both CML, groups were of leukemic origin. The concentration of VEGF was dramatically reduced in CML experimental groups.

CONCLUSIONIn vitro, STI571 promotes the activation/maturation of DCs derived from BMMNCs of patients with CMI, and decreases VEGF production by the leukemic cells. The promotion of DC maturation may be partially due to decreased inhibitory effect of VEGF.

Adult ; Antigens, CD ; metabolism ; Benzamides ; Bone Marrow Cells ; drug effects ; metabolism ; pathology ; Cell Proliferation ; drug effects ; Cells, Cultured ; Dendritic Cells ; drug effects ; metabolism ; pathology ; Female ; Flow Cytometry ; Fusion Proteins, bcr-abl ; genetics ; metabolism ; HLA-DR Antigens ; metabolism ; Humans ; Imatinib Mesylate ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; pathology ; Male ; Middle Aged ; Piperazines ; Pyrimidines ; pharmacology ; T-Lymphocytes ; drug effects ; metabolism ; pathology ; Vascular Endothelial Growth Factor A ; metabolism

To evaluate the effect of imatinib mesylate (STI571) on primitive/committed malignant progenitor cells in chronic myelogenous leukemia (CML) and to further elucidate the mechanisms involved in CML relapse and in some CML cells resistant to STI571, bone marrow-derived malignant bcr/abl-positive, Flk1(+)CD31CD34(-) cells with hemangioblastic characteristics from CML patients were grown in Methocult GF+ media with or without STI571, and inhibitory effect of STI571 on proliferation of differentiated and differentiating, bcr/abl(+), Flk1(+)CD31CD34(-) cells with hemangioblastic characteristics was investigated in vitro. The results showed that in vitro exposure to 5 micromol/L STI571 (the concentration of STI571 usually achieved in patients is 1-2 micromol/L) for 96 hours inhibited bcr/abl(+) committed progenitors (colony-forming cells, CFCs). No evident suppression of normal primitive, bcr/abl(+), and Flk1(+)CD31(-)CD34(-) cells were observed. It is concluded that CML primitive stem cells remain viable in the presence of STI571 and that inhibition of bcr/abl tyrosine kinase by STI571 restores normal hematopoiesis by removing the proliferative advantage of CML committed progenitors but that elimination of all CML progenitors may not occur. So despite dramatic short-term responses in vivo, such in vitro resistance to STI571, may translate into disease relapse after prolonged therapy.
Antigens, CD34 ; analysis ; genetics ; Benzamides ; Bone Marrow Cells ; drug effects ; metabolism ; pathology ; Cell Differentiation ; drug effects ; Cell Proliferation ; drug effects ; Drug Resistance, Neoplasm ; Fluorescent Antibody Technique ; Fusion Proteins, bcr-abl ; genetics ; metabolism ; Hematopoietic Stem Cells ; drug effects ; metabolism ; pathology ; Humans ; Imatinib Mesylate ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; genetics ; metabolism ; Piperazines ; pharmacology ; Platelet Endothelial Cell Adhesion Molecule-1 ; analysis ; genetics ; Protein Kinase Inhibitors ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor Receptor-2 ; analysis ; genetics