251 research outputs found
Effect of a small molecule inhibitor of nuclear factor-ΞΊB nuclear translocation in a murine model of arthritis and cultured human synovial cells
A small cell-permeable compound, dehydroxymethylepoxyquinomicin (DHMEQ), does not inhibit phosphorylation and degradation of IΞΊB (inhibitor of nuclear factor-ΞΊB [NF-ΞΊB]) but selectively inhibits nuclear translocation of activated NF-ΞΊB. This study aimed to demonstrate the antiarthritic effect of this novel inhibitor of the NF-ΞΊB pathway in vivo in a murine arthritis model and in vitro in human synovial cells. Collagen-induced arthritis was induced in mice, and after onset of arthritis the mice were treated with DHMEQ (5 mg/kg body weight per day). Using fibroblast-like synoviocyte (FLS) cell lines established from patients with rheumatoid arthritis (RA), NF-ΞΊB activity was examined by electrophoretic mobility shift assays. The expression of molecules involved in RA pathogenesis was determined by RT-PCR, ELISA, and flow cytometry. The proliferative activity of the cells was estimated with tritiated thymidine incorporation. After 14 days of treatment with DHMEQ, mice with collagen-induced arthritis exhibited decreased severity of arthritis, based on the degree of paw swelling, the number of swollen joints, and radiographic and histopathologic scores, compared with the control mice treated with vehicle alone. In RA FLS stimulated with tumor necrosis factor-Ξ±, activities of NF-ΞΊB components p65 and p50 were inhibited by DHMEQ, leading to suppressed expression of the key inflammatory cytokine IL-6, CC chemokine ligand-2 and -5, matrix metalloproteinase-3, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. The proliferative activity of the cells was also suppressed. This is the first demonstration of an inhibitor of NF-ΞΊB nuclear translocation exhibiting a therapeutic effect on established murine arthritis, and suppression of inflammatory mediators in FLS was thought to be among the mechanisms underlying such an effect
MOLECULAR DESIGN OF SUGAR-FREE MIGRACIN ANALOG MIGRACINAL THAT INHIBITS OVARIAN CANCER CELL MIGRATION AND INVASION
Introduction. Cancer metastasis consists of several steps including detachment from the primary tumor, migration, invasion, transport in the blood or lymphatic vessels, attachment at the secondary site, and growth of secondary tumor. Migration and invasion areinvolved in the mechanism of all types of cancer metastasis. We previously isolated novel cellular migration inhibitor migracin A and B from a culture filtrate of Streptomyces sp. Migracin A was shown to inhibit IGF-1-mediated cellular migration and invasion in ovarian carcinoma cells. However, it is difficult to prepare large amount of migracin A. Migracin A consists of substituted benzene and an alkylated sugar moiety. In the present research, we have designed and synthesized a simplified dialdehydederivative of migracin called migracinal having no sugar moiety. Material and methods. Migracinal was purchased from Techno Chem Co., Ltd., Tokyo, Japan. Migracinal was prepared from 2,4-dihydroxybenzaldehyde (2,4-DHBA). The structure was confirmed by proton and carbon NMR spectra and ESI mass spectroscopy. The antitumor activity of the new derivative was studied by standard tests under conditions in vitro. Results. Migracinal inhibited cellular migration and invasion in ovarian clear cell carcinoma ES-2 cells. It also inhibited IGF-1 expression as migracin A. Moreover, it induced anoikis rather than apoptosis in ES-2 cells.Conclusions. Migracinal is easier to prepare than migracins, and it may be useful for the mechanistic study and suppression of metastasis.Β ΠΠ²Π΅Π΄Π΅Π½ΠΈΠ΅. ΠΡΠΎΡΠ΅ΡΡ ΠΌΠ΅ΡΠ°ΡΡΠ°Π·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΠ°ΠΊΠ° ΡΠΎΡΡΠΎΠΈΡ ΠΈΠ· Π½Π΅ΡΠΊΠΎΠ»ΡΠΊΠΈΡ
ΡΡΠ°ΠΏΠΎΠ²: ΠΎΡΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠ΅ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΎΡ ΠΏΠ΅ΡΠ²ΠΈΡΠ½ΠΎΠΉ ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ, ΠΌΠΈΠ³ΡΠ°ΡΠΈΡ, ΠΈΠ½Π²Π°Π·ΠΈΡ, ΠΏΠ΅ΡΠ΅ΠΌΠ΅ΡΠ΅Π½ΠΈΠ΅ Π² ΠΊΡΠΎΠ²ΠΈ ΠΈΠ»ΠΈ Π»ΠΈΠΌΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΎΡΡΠ΄Π°Ρ
, ΠΏΡΠΈΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠ΅ ΠΈ ΡΠΎΡΡ Π²ΡΠΎΡΠΈΡΠ½ΠΎΠΉ ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ. ΠΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΡ ΠΌΠΈΠ³ΡΠ°ΡΠΈΠΈ ΠΈ ΠΈΠ½Π²Π°Π·ΠΈΠΈ ΡΠ½ΠΈΠ²Π΅ΡΡΠ°Π»ΡΠ½Ρ Π΄Π»Ρ Π²ΡΠ΅Ρ
Π²ΠΈΠ΄ΠΎΠ² ΡΠ°ΠΊΠ°. Π Π°Π½Π΅Π΅ ΠΈΠ· ΠΊΡΠ»ΡΡΡΡΡ Streptomyces SP ΠΌΡ Π²ΡΠ΄Π΅Π»ΠΈΠ»ΠΈ Migracin Π ΠΈ Π - Π½ΠΎΠ²ΡΠ΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΡ ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠΉ ΠΌΠΈΠ³ΡΠ°ΡΠΈΠΈ. ΠΡΠ»ΠΎ ΠΏΡΠΎΠ΄Π΅ΠΌΠΎΠ½ΡΡΡΠΈΡΠΎΠ²Π°Π½ΠΎ ΠΊΠ°ΠΊ Migracin Π ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΠ΅Ρ IGF-1-ΠΎΠΏΠΎΡΡΠ΅Π΄ΠΎΠ²Π°Π½Π½ΡΡ ΠΌΠΈΠ³ΡΠ°ΡΠΈΡ ΠΈ ΠΈΠ½Π²Π°Π·ΠΈΡ ΠΊΠ»Π΅ΡΠΎΠΊ ΡΠ°ΠΊΠ° ΡΠΈΡΠ½ΠΈΠΊΠΎΠ². ΠΠ΄Π½Π°ΠΊΠΎ Π±ΠΎΠ»ΡΡΠΎΠ΅ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²ΠΎ Migracin Π, ΡΠΎΡΡΠΎΡΡΠ΅Π³ΠΎ ΠΈΠ· Π·Π°ΠΌΠ΅ΡΠ΅Π½Π½ΠΎΠ³ΠΎ Π±Π΅Π½Π·ΠΎΠ»Π° ΠΈ Π°Π»ΠΊΠΈΠ»ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠ³ΠΎ ΡΠ³Π»Π΅Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΡΡΠ°Π³ΠΌΠ΅Π½ΡΠ°, ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°ΡΡ ΡΡΡΠ΄ΠΎΠ΅ΠΌΠΊΠΎ. Π Π½Π°ΡΡΠΎΡΡΠ΅ΠΌ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΈ ΠΌΡ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠ°Π»ΠΈ ΠΈ ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π»ΠΈ ΡΠΏΡΠΎΡΠ΅Π½Π½ΠΎΠ΅ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ΅ Π΄ΠΈΠ°Π»ΡΠ΄Π΅Π³ΠΈΠ΄Π° Migracin, Π½Π΅ ΠΈΠΌΠ΅ΡΡΠ΅Π³ΠΎ ΡΠ³Π»Π΅Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΊΠΎΠΌΠΏΠΎΠ½Π΅Π½ΡΠ°, Π½Π°Π·Π²Π°Π½Π½ΠΎΠ΅ Migracinal. ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈ ΠΌΠ΅ΡΠΎΠ΄Ρ. Migracin ΠΏΡΠΈΠΎΠ±ΡΠ΅ΡΠ°Π»ΡΡ Ρ ΠΊΠΎΠΌΠΏΠ°Π½ΠΈΠΈ Β«Π’Π΅Ρ
Π½ΠΎΠ₯ΠΈΠΌ Co., ΠΡΠ΄Β» (Π’ΠΎΠΊΠΈΠΎ, Π―ΠΏΠΎΠ½ΠΈΡ). ΠΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ΅ Migracinal ΠΏΠΎΠ»ΡΡΠ°Π»ΠΈ Π²Π·Π°ΠΈΠΌΠΎΠ΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ΠΌ Migracin Ρ 2,4-Π΄ΠΈΠ³ΠΈΠ΄ΡΠΎΠΊΡΠΈΠ±Π΅Π½Π·Π°Π»Π΄Π΅Π³ΠΈΠ΄ΠΎΠΌ. Π‘ΡΡΡΠΊΡΡΡΠ° Π±ΡΠ»Π° ΠΏΠΎΠ΄ΡΠ²Π΅ΡΠΆΠ΄Π΅Π½Π° ΡΠΏΠ΅ΠΊΡΡΠ°ΠΌΠΈ Π―ΠΠ ΠΈ ΠΌΠ°ΡΡ-ΡΠΏΠ΅ΠΊΡΡΠΎΡΠΊΠΎΠΏΠΈΠ΅ΠΉ. ΠΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²Π°Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π½ΠΎΠ²ΠΎΠ³ΠΎ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΈΠ·ΡΡΠ°Π»Π°ΡΡ ΡΡΠ°Π½Π΄Π°ΡΡΠ½ΡΠΌΠΈ ΡΠ΅ΡΡΠ°ΠΌΠΈ Π² ΡΡΠ»ΠΎΠ²ΠΈΡΡ
in vitro. Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ. Π£ΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΎ, ΡΡΠΎ Migracinal ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΠ΅Ρ ΠΊΠ»Π΅ΡΠΎΡΠ½ΡΡ ΠΌΠΈΠ³ΡΠ°ΡΠΈΡ ΠΈ ΠΈΠ½Π²Π°Π·ΠΈΡ ΠΊΠ»Π΅ΡΠΎΠΊ ES-2 ΡΠ°ΠΊΠ° ΡΠΈΡΠ½ΠΈΠΊΠ° ΠΈ Π°Π½Π°Π»ΠΎΠ³ΠΈΡΠ½ΠΎ Migracin A ΠΈΠ½Π³ΠΈΠ±ΠΈΡΡΠ΅Ρ IGF-1 ΡΠΊΡΠΏΡΠ΅ΡΡΠΈΡ. ΠΡΠΎΠΌΠ΅ ΡΠΎΠ³ΠΎ, ΠΎΠ½ ΠΈΠ½Π΄ΡΡΠΈΡΠΎΠ²Π°Π» Π°Π½ΠΎΠΈΠΊΠΈΡ, Π° Π½Π΅ Π°ΠΏΠΎΠΏΡΠΎΠ· Π² ΠΊΠ»Π΅ΡΠΊΠ°Ρ
ES-2.ΠΠ°ΠΊΠ»ΡΡΠ΅Π½ΠΈΠ΅. Π‘ΠΈΠ½ΡΠ΅Π· Migracinal Π»Π΅Π³ΡΠ΅ Π² ΡΡΠ°Π²Π½Π΅Π½ΠΈΠΈ Ρ Migracin, Π° ΡΠΏΠ΅ΠΊΡΡ ΠΏΡΠΎΡΠΈΠ²ΠΎΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈΠ΄Π΅Π½ΡΠΈΡΠ΅Π½, ΡΡΠΎ ΠΌΠΎΠΆΠ΅Ρ Π±ΡΡΡ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΎ Π΄Π»Ρ ΠΏΠΎΠ΄Π°Π²Π»Π΅Π½ΠΈΡ ΠΏΡΠΎΡΠ΅ΡΡΠΎΠ² ΠΌΠ΅ΡΠ°ΡΡΠ°Π·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ.
Dehydroxymethylepoxyquinomicin Inhibits Expression and Production of Inflammatory Mediators in Interleukin-1Ξ² Ξ² Ξ² Ξ² Ξ²-induced Human Chondrocytes
The present research was carried out to determine the effects of a nuclear factor-kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), derivative of the antibiotic epoxyquinomicin C, on normal human chondrocytes treated with interleukin-1beta (IL-1beta). This is a cell model particularly useful to reproduce the mechanisms involved in degenerative arthropathies, where oxidative-inflammatory stress determines a progressive destruction of the articular cartilaginous tissue. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inter-cellular adhesion molecule (ICAM)-1 was evaluated through Western blot analysis. The release of chemokines like monocyte chemoattractant protein-1 (MCP-1), regulated upon normal activation T-cell expressed and secreted (RANTES), and interleukin-8 (IL-8) were determined by ELISA assays. DHMEQ acts as a potent inhibitor of iNOS and COX-2 gene expression while also suppressing the production of nitrite in human chondrocytes. In addition, DHMEQ induces a significant dose-dependent decrease in ICAM expression, MCP-1, RANTES, and IL-8 release. DHMEQ helps to decrease the expression and production of pro-inflammatory mediators in IL-1beta-induced chondrocytes. DHMEQ may become a therapeutic agent for treatment of chondro-degenerative diseases
Stimulation of ultraviolet-induced apoptosis of human fibroblast UVr-1 cells by tyrosine kinase inhibitors
AbstractDamnacanthal is an anthraquinone compound isolated from the root of Morinda citrifolia and was reported to have a potent inhibitory activity towards tyrosine kinases such as Lck, Src, Lyn and EGF receptor. In the present study, we have examined the effects of damnacanthal on ultraviolet ray-induced apoptosis in ultraviolet-resistant human UVr-1 cells. When the cells were treated with damnacanthal prior to ultraviolet irradiation, DNA fragmentation was more pronounced as compared to the case of ultraviolet irradiation alone. The other tyrosine kinase inhibitors, herbimycin A and genistein, also caused similar effects on ultraviolet-induced apoptosis but to a lesser extent. Serine/threonine kinase inhibitors, K252a, staurosporine and GF109203X, rather suppressed the ultraviolet-induced DNA cleavage. Immunoblot analysis showed that pretreatment with damnacanthal followed by ultraviolet irradiation increased the levels of phosphorylated extracellular signal-regulated kinases and stress-activated protein kinases. However, the other tyrosine kinase inhibitors did not increase the phosphorylation of extracellular signal-regulated kinases but stimulated phosphorylation of stress-activated protein kinases. Consequently, the ultraviolet-induced concurrent increase in both phosphorylated extracellular signal-regulated kinases and stress-activated protein kinases after pretreatment with damnacanthal might be characteristically related to the stimulatory effect of damnacanthal on ultraviolet-induced apoptosis
Inhibition of NF-ΞΊB and Akt pathways by an antibody-avidin fusion protein sensitizes malignant B-cells to cisplatin-induced apoptosis
Multiple myeloma (MM) is an incurable disease of malignant plasma cells. Recent therapeutic advancements have resulted in improved response rates, however, there is no improvement in overall survival, therefore, new therapeutics are needed. Since the transferrin receptor is upregulated on the surface of MM cells, we previously developed an antibody fusion protein consisting of an IgG3 specific for the human transferrin receptor 1 (TfR1, CD71) genetically fused to avidin at its carboxy-terminus (ch128.1Av). We have previously shown that ch128.1Av exhibits intrinsic cytotoxicity against certain malignant B-cells by disrupting the cycling of the TfR and decreasing TfR cell surface expression resulting in lethal iron starvation. In addition, ch128.1Av can sensitize malignant cells to apoptosis induced by gambogic acid, a herbal drug used in Chinese medicine. In this study, we hypothesized that ch128.1Av may also sensitize drug-resistant malignant B-cells to chemotherapeutic agents by inhibiting key survival pathways. In this study we show that ch128.1Av sensitizes malignant B-cells to apoptosis induced by cisplatin (CDDP). The sensitization by ch128.1Av resulted in the inhibition of the constitutively activated Akt and NF-ΞΊB survival/antiapoptotic pathways and downstream decreased expression of antiapoptotic gene products such as BclxL and survivin. The direct role of the inhibition of the Akt and NF-ΞΊB pathways by ch128.1Av in CDDP-mediated cytotoxicity was demonstrated by the use of specific chemical inhibitors and siRNA which mimicked the effects of ch128.1Av. Overall, this study provides evidence of the therapeutic potential of ch128.1Av as a chemo-sensitizing agent in drug-resistant tumor cells.Fil: Suzuki, Eriko. Keio University; JapΓ³nFil: Daniels, Tracy R.. University of California at Los Angeles; Estados UnidosFil: Helguera, Gustavo Fernando. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones CientΓficas y TΓ©cnicas; ArgentinaFil: Penichet, Manuel L.. University of California at Los Angeles; Estados UnidosFil: Umezawa, Kazuo. Keio University; JapΓ³nFil: Bonavida, BenjamΓn. University of California at Los Angeles; Estados Unido
NF-ΞΊB inhibitor dehydroxymethylepoxyquinomicin suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting expression of RANKL, osteoprotegerin or macrophage colony-stimulating factor
Inhibition of NF-ΞΊB is known to be effective in reducing both inflammation and bone destruction in animal models of arthritis. Our previous study demonstrated that a small cell-permeable NF-ΞΊB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), suppresses expression of proinflammatory cytokines and ameliorates mouse arthritis. It remained unclear, however, whether DHMEQ directly affects osteoclast precursor cells to suppress their differentiation to mature osteoclasts in vivo. The effect of DHMEQ on human osteoclastogenesis also remained elusive. In the present study, we therefore examined the effect of DHMEQ on osteoclastogenesis using a mouse collagen-induced arthritis model, and using culture systems of fibroblast-like synovial cells obtained from patients with rheumatoid arthritis, and of osteoclast precursor cells from peripheral blood of healthy volunteers. DHMEQ significantly suppressed formation of osteoclasts in arthritic joints, and also suppressed expression of NFATc1 along the inner surfaces of bone lacunae and the eroded bone surface, while serum levels of soluble receptor activator of NF-ΞΊB ligand (RANKL), osteoprotegerin and macrophage colony-stimulating factor were not affected by the treatment. DHMEQ also did not suppress spontaneous expression of RANKL nor of macrophage colony-stimulating factor in culture of fibroblast-like synovial cells obtained from patients with rheumatoid arthritis. These results suggest that DHMEQ suppresses osteoclastogenesis in vivo, through downregulation of NFATc1 expression, without significantly affecting expression of upstream molecules of the RANKL/receptor activator of NF-ΞΊB/osteoprotegerin cascade, at least in our experimental condition. Furthermore, in the presence of RANKL and macrophage colony-stimulating factor, differentiation and activation of human osteoclasts were also suppressed by DHMEQ, suggesting the possibility of future application of NF-ΞΊB inhibitors to rheumatoid arthritis therapy
Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer.
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is expressed in up to 70% of epithelial ovarian cancers (EOCs), where it correlates with poor prognosis. The majority of EOCs are diagnosed at an advanced stage, and at least 50% present malignant ascites. High levels of IL-6 have been found in the ascites of EOC patients and correlate with shorter survival. Herein, we investigated the signaling cascade led by EGFR activation in EOC and assessed whether EGFR activation could induce an EOC microenvironment characterized by pro-inflammatory molecules. In vitro analysis of EOC cell lines revealed that ligand-stimulated EGFR activated NFkB-dependent transcription and induced secretion of IL-6 and plasminogen activator inhibitor (PAI-1). IL-6/PAI-1 expression and secretion were strongly inhibited by the tyrosine kinase inhibitor AG1478 and EGFR silencing. A significant reduction of EGF-stimulated IL-6/PAI-1 secretion was also obtained with the NFkB inhibitor dehydroxymethylepoxyquinomicin. Of 23 primary EOC tumors from advanced-stage patients with malignant ascites at surgery, 12 co-expressed membrane EGFR, IL-6 and PAI-1 by immunohistochemistry; both IL-6 and PAI-1 were present in 83% of the corresponding ascites. Analysis of a publicly available gene-expression data set from 204 EOCs confirmed a significant correlation between IL-6 and PAI-1 expression, and patients with the highest IL-6 and PAI-1 co-expression showed a significantly shorter progression-free survival time (P=0.028). This suggests that EGFR/NFkB/IL-6-PAI-1 may have a significant impact on the therapy of a particular subset of EOC, and that IL-6/PAI-1 co-expression may be a novel prognostic marker
Determination of topological structure of ARL6ip1 in cells: Identification of the essential binding region of ARL6ip1 for conophylline
AbstractConophylline (CNP) has various biological activities, such as insulin production. A recent study identified ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) as a direct target protein of CNP. In this study, we revealed that ARL6ip1 is a three-spanning transmembrane protein and determined the CNP-binding domain of ARL6ip1 by deletion mutation analysis of ARL6ip1 with biotinyl-amino-CNP. These results suggest that CNP is expected to be useful for future investigation of ARL6ip1 function in cells. Because of the anti-apoptotic function of ARL6ip1, CNP may be an effective therapeutic drug and/or a novel chemosensitizer for human cancers and other diseases
Is the combination therapy of IKr-channel blocker and left stellate ganglion block effective for intractable ventricular arrhythmia in a cardiopulmonary arrest patient?
Background: We have previously reported that the defibrillation success rate of intravenous nifekalant
hydrochloride (NIF), a pure IKr-channel (IKr: the rapid components of the delayed rectifier potassium
current) blocker, was more than 75% for lidocaine-resistant ventricular tachycardia and fibrillation
(VT/VF) in patients with out-of-hospital cardiopulmonary arrest (CPA). However, there was no
effective treatment for the remaining 25% of patients in whom defibrillation was unsuccessful. We
hypothesised that the combination therapy of NIF and left stellate ganglion block (LSGB) was useful for
defibrillation in NIF-resistant VT/VF and investigated its efficacy in a retrospective study.
Methods and results: We investigated sequentially 272 out-of-hospital CPA patients treated
at Tokai University between April and December 2006. VT/VF occurred in 55 patients on
arrival or during cardiopulmonary resuscitation (CPR). On the basis of our CPR algorithm,
NIF was administered (0.15-0.3 mg/kg, i.v.) after the first direct-current cardioversion.
NIF-resistant VT/VFs were observed in 15 out of 55 patients and LSGB was performed on
11 of these with administration of NIF. Sinus rhythm was restored in 7 patients following
LSGB (64%) and complete recovery was achieved in 2 patients. In the non-LSGB group,
however, all the patients died.
Conclusions: The combination therapy of intravenous NIF and LSGB was useful for defibrillation
in intractable VT/VF. It is a potential and innovative treatment strategy for
IKr-channel blocker resistant VT/VF. (Cardiol J 2007; 14: 355-365
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