A comparison of consumption and recovery profiles according to anaesthetic circuit mode using a new multifunctional closed-circuit anaesthesia system during desflurane anaesthesia: a clinical study.

This clinical study compared induction time, consumed anaesthetic dose, and haemodynamic and recovery profiles when using a new type of multifunctional anaesthesia machine (Zeus) in semi-closed or closed circuit modes. Sixty female patients undergoing gynaecological surgery were randomly assigned to three groups and received desflurane anaesthesia through a semi-closed circuit (SCC) at fresh gas flow rates of 4 l/min (SCC 4 l/min) or 2 l/min (SCC 2 l/min), or through a closed circuit (CC). Anaesthesia was maintained at the minimum alveolar concentration for blocking the adrenergic response to painful stimulus (MAC(BAR)) (4.6% end-tidal desflurane) during each operation. The time required to reach MAC(BAR) was significantly shorter and the dose of desflurane was significantly smaller in the CC group compared with the other groups. There were no differences in haemodynamic and recovery profiles between the groups. It is concluded that the CC mode allowed a faster and more reliable induction, lower anaesthetic consumption and stable haemodynamic and recovery profiles.

Control of the haemodynamic response to surgical stimuli in semi-closed circuit or closed circuit anaesthesia using a multifunctional anaesthesia system.

This study compared the ability of the Zeus multifunctional anaesthesia system to control haemodynamic response to surgical stimulation in semi-closed (SCA) or closed circuit anaesthesia (CCA) modes. Fifty patients undergoing gynaecological surgery were randomly assigned to SCA or CCA. Anaesthesia was induced with 2 mg propofol and 0.9 mg/kg rocuronium, intravenously, and maintained using sevoflurane (minimum alveolar concentration [MAC], 1.0) using 2 l/min oxygen plus 2 l/min nitrous oxide (SCA 4 l/min group) or 50% oxygen plus 50% nitrous oxide (CCA group). An increase in mean arterial pressure (MAP) > 20% above baseline in response to surgical stimulation provoked a stepwise increase in sevoflurane (1.3 MAC and then 1.6 MAC), followed by fentanyl 1 pg/kg intravenously (rescue drug). The time required for MAP to return to within 10% of baseline was significantly shorter in the CCA group (6.4 +/- 3.6 min) compared with the SCA 4 l/min group (10.2 +/- 6.0 min). The percentage of patients requiring fentanyl was significantly greater in the SCA 4 l/min group than in the CCA group. In conclusion, CCA controlled acute haemodynamic responses to surgical stimuli more successfully and rapidly than SCA 4 l/min, using a multifunctional anaesthesia machine.

Outcomes after combined laparoscopic gastrectomy and laparoscopic cholecystectomy in gastric cancer patients.

BACKGROUND/AIMS: The purpose of this study was to determine the effect of performing laparoscopic cholecystectomy on patients undergoing laparoscopic-assisted gastrectomy for gastric cancer. METHODS: This single center study involved a retrospective review of a database of 400 patients who underwent consecutive laparoscopic-assisted gastrectomy for early gastric cancer from June 2003 to July 2007. Outcomes in 26 patients who underwent both laparoscopic-assisted gastrectomy and laparoscopic cholecystectomy were compared with outcomes from 364 patients who underwent laparoscopic-assisted gastrectomy without laparoscopic cholecystectomy. RESULTS: There were no postoperative 30-day mortalities in the combined cholecystectomy group. The mean surgery duration, time to first flatus and postoperative hospital stay for the laparoscopic gastric resection without combined operation were 181.7 min, 2.7 days and 9.7 days, respectively, and 196.7 min, 2.6 days and 8.8 days, respectively, for the combined cholecystectomy group. None of the postoperative complications was related to combined cholecystectomy. CONCLUSION: Performing a combined cholecystectomy prolonged the mean surgery duration by approximately 15 min, but had no effect on surgical outcomes. It appears that performing a cholecystectomy at the same time as laparoscopic gastric resection is safe and feasible in patients with both early gastric cancer and gallbladder disease.

Target-controlled propofol infusion for sedation in patients undergoing transrectal ultrasound-guided prostate biopsy.

The efficacy and safety of the routine use of target-controlled infusion of propofol for the sedation of patients undergoing transrectal ultrasound-guided prostate biopsy were assessed. The optimal level of sedation was also evaluated. A total of 250 patients were randomized into five groups according to sedation level determined by the Observer's Assessment of Alertness/Sedation (OAA/S) scale. As the level of sedation was increased, the overall pain and discomfort score decreased and the satisfaction rate tended to increase, although hypoxia meant that intervention occurred more frequently at higher sedation levels. Target-controlled infusion of propofol provided safe and effective sedation during transrectal ultrasound-guided prostate biopsy, particularly if moderate sedation (OAA/S score of 3) was achieved. The effect-site concentration of propofol for this level of sedation was about 1.5 microg/ml.

Association of the ERK1/2 and p38 kinase pathways with nitric oxide-induced apoptosis and cell cycle arrest in colon cancer cells.

To investigate the mechanism by which nitric oxide (NO) induces cell death in colon cancer cells, we compared two types of colon cancer cells with different p53 status: HCT116 (p53 wild-type) cells and SW620 (p53-deficient) cells. We found that S-nitrosoglutathione (GSNO), the NO donor, induced apoptosis in both types of colon cancer cells. However, SW620 cells were much more susceptible than HCT116 cells to apoptotic death by NO. We investigated the role of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 kinase on NO-induced apoptosis in both types of colon cancer cells. GSNO treatment effectively stimulated activation of the ERK1/2 and p38 kinase in both types of cells. In HCT116 cells, pretreatment with PD98059, an inhibitor of ERK1/2, or SB203580, an inhibitor of p38 kinase, had no marked effect on GSNO-induced apoptosis. However, in SW620 cells, SB203580 significantly reduced the NO-induced apoptosis, whereas PD098059 increases NO-induced apoptosis. Furthermore, we found evidence of cell cycle arrest of the G0/G1 phase in SW620 cells but not in HCT116 cells. Inhibition of ERK1/2 with PD098059, or of p38 kinase with SB203580, reduced the GSNO-induced cell cycle arrest of the G0/G1 phase in SW620 cells. We therefore conclude that NO-induced apoptosis in colon cancer cells is mediated by a p53-independent mechanism and that the pathways of ERK1/2 and p38 kinase are important in NO-induced apoptosis and in the cell cycle arrest of the G0/G1 phase.

Structure-activity relationship studies of isoquinolinone type anticancer agent.

Substituted isoquinolin-1-ones (1) were synthesized to test their in vitro anticancer activity. 3-Biphenyl-N-methylisoquinolin-1-one (7) showed the most potent anticancer activity against five different human cancer cell lines.

Phytochemical constituents of Artemisia stolonifera.

Repeated column chromatographic separation of the CH2Cl2 extract of Artemisia stolonifera (Asteraceae) led to the isolation of a triterpene (I), a sesquiterpene (II), two aromatic compounds (III and IV) and a benzoquinone (V). Their structures were determined by spectroscopic means to be simiarenol (I), (1S,7S)-1beta-hydroxygermacra-4(15),5,10(14)-triene (II), 3'-methoxy-4'-hydroxy-trans-cinnamaldehyde (III), vanillin (IV) and 2,6-dimethoxy-1,4-benzoquinone (V), respectively. Among these products, compound V showed significant cytotoxicity against five human tumor cell lines in vitro, A549 (non small cell lung adenocarcinoma), SK-OV-3 (ovarian), SK-MEL-2 (skin melanoma), XF498 (CNS) and HCT15 (colon) with ED50 values ranging from 1.33-4.22 microg/ml.

Costunolide, a sesquiterpene from the stem bark of Magnolia sieboldii, inhibits the RAS-farnesyl-proteintransferase.

Costunolide, a germacrane sesquiterpene lactone isolated from the stem bark of Magnolia sieboldii demonstrated a significant inhibition upon the farnesylation process of human lamin-B by farnesyl-proteintransferase (FPTase), in a dose dependent manner in vitro (IC50 value was calculated as 20 microM). It was also found to exhibit an inhibition upon the proliferation of cultured human tumor cells, i.e., A549 (non small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nerve system) and HCT-15 (colon), in vitro.

Cytotoxic alkaloids from Houttuynia cordata.

Six bioactive alkaloids, aristolactam B(1), piperolactam A(2), aristolactam A(3), norcepharadione B(4), cepharadione B(5) and splendidine(6) were isolated by bioactivity-guided fractionation of a methanolic extract of the aerial part of Houttuynia cordata. Several of them exhibited significant cytotoxicity against five human tumor cell lines (A-549, SK-OV-3, SK-MEL-2, XF-498 and HCT-15) in vitro.

Cytotoxic peroxides from Artemisia stolonifera.

Two sesquiterpene endoperoxides, 1S, 4R, 6R-1, 4-endoperoxy-bisabola-2, 10-diene (I), 1R, 4S, 6R-1, 4-endoperoxy-bisabola-2, 10-diene (II), and a sesquiterpene hydroperoxide, 1beta-hydroperoxygermacra-4 (15), 5, 10 (14)-triene (III) were isolated from the aerial parts of Artemisia stolonifera (Compositae). Their chemical structures were assigned by spectral evidences. Compounds I and II exhibited cytotoxicity against five human tumor cell lines with their ED50 values ranging from 0.20 to 5.43 microg/ml and from <0.1 to 0.87 microg/ml, respectively.

New cytotoxic butanolides from Lindera obtusiloba BLUME.

Three new butanolides, 2-(1-methoxy-11-dodecenyl)-penta-2,4-dien-4-olide (1), (2Z,3S,4S)-2-(11-dodecenylidene)-3-hydroxy-4-methylbutano lide (2) and (2E,3R,4R)-2-(11-dodecenylidene)-3-hydroxy-4-methoxy-4-methylbu tanolide (3), were isolated from the stems of Lindera obtusiloba BLUME. Their chemical structures were assigned by spectroscopic evidence. They exhibited cytotoxicity against cultured human tumor cell lines with their ED50 values ranging from 3.19 to 14.63 microg/ml.

Effects of KR-30035, a novel multidrug-resistance modulator, on the cardiovascular system of rats in vivo and on the cell cycle of human cancer cells in vitro.

The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular system in vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20: 0.320+/-0.052 and 0.034+/-0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1 phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 microM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weaker in vivo effects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.

Effect of substituents on benzenesulfonyl motif of 4-phenyl-1-arylsulfonylimidazolidinones for their cytotoxicity.

To explore the effect of substituents' on phenyl motif on sulfonyl function of novel anticancer 4-phenyl-1-benzenesulfonylimidazolidinones (1), electron donating or withdrawing substituents were introduced at 3 or 4-position and the analogs were tested against human lung (A549) and colon (HCT-15) cancer cell lines. Quantitative structure activity relationship of the 4-substituted series shows that only STERIMOL L values are well correlated. The increment of substituent's volume enhances the activity against both cell lines. The small substituent at 3-position additionally increases the activity. However naphthyl group in place of phenyl reduces the activity. Therefore the phenyl motif with sterically large substituent at 4-position and small substituent at 3-position may be important for their activity. Integration of these substituents' effects into the structural design led to discover the more potent analog, 4-phenyl-1-(N-acetylindoline-5-sulfonyl) imidazolidinone (1n).

Synthesis and biology of 3'-N-acyl-N-debenzoylpaclitaxel analogues.

The, 3'-N-acyl-N-debenzoylpaclitaxel analogues 1a-d were synthesized and evaluated on biological systems. Some of the analogues 1a-d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in vivo experiment against i.p. implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition more than paclitaxel.

Two new lignans from Lindera obtusiloba blume.

Two new furanolignans (3, 5), together with three known lignans (1, 2, 4), were isolated from the stem of Lindera obtusiloba (Lauraceae). The structures of the compounds were determined as actifolin (1), pluviatilol (2), 5,6-dihydroxymatairesinol (3), (+)-syringaresinol (4), and (+)-9'-O-trans-feruloyl-5,5'-dimethoxylariciresinol (5) on the basis of physicochemical and spectroscopic evidences. Compounds 1, 2, 3, and 5 showed cytotoxicity against a small panel of human tumor cell lines with ED50 values of 3.40 to approximately 19.27 microg/ml.

P-glycoprotein (Pgp) does not affect the cytotoxicity of flavonoids from Sophora flavescens, which also have no effects on Pgp action.

Sophoraflavanone, kurarinone (GS08), norkurarinol (GS11), kurarinol (GS12) and kushenol K are cytotoxic flavonoids isolated from Sophora flavescens. In this study, we tested the cytotoxicity of those flavonoids to human cancer cells including P-glycoprotein (Pgp)-expressing HCT15 cells and its multidrug resistant subline, HCT15/CL02 cells. HCT15/CL02 cells revealed resistance to GS08, GS11 and GS12 about 2 fold in comparison with HCT15 cells. Nonetheless, verapamil, a Pgp inhibitor, could not increase the cytotoxicity of all the flavonoids tested. We also investigated that the flavonoids could modulate the Pgp action. At nontoxic concentrations, the flavonoids could not effect on the cytotoxicity of paclitaxel, a well-known Pgp-substrate. The flavonoids also had no effects on the accumulation of rhodamine 123 in all the cells tested at 10 microM. From the results, we concluded that Pgp had no effect on the cytotoxicity of the flavonoids, and the flavonoids also had no effect on the action of Pgp. Our results also suggested that HCT15/CL02 cells had additional mechanisms for drug resistance distinct from Pgp overexpression.

Cytotoxicity of two novel cisplatin analogues, (CPA)2Pt[DOLYM] and (DACH)Pt[DOLYM], to human cancer cells in vitro.

Despite the impressive antitumor activity of cisplatin, two major limitations of the drug, that is severe side effects and drug-resistance of cancer cells, make its use difficult for cancer therapy. These limitations have resulted in a great deal of effort having been expended into structural modifications of cisplatin. In this study, we tested two novel cisplatin analogues, (CPA)2Pt [DOLYM] (COMP-I) and (DACH)Pt[DOLYM] (COMP-II), for the mode of cytotoxic action against human tumor cells comparing with cisplatin and carboplatin in vitro. These two novel analogues had considerable cytotoxic activities against five kinds of human solid tumor cells, and especially COMP-II was more effective on HCT15 colon cancer cells than other compounds. In addition, COMP-II had cytostatic activity at low concentrations (10-0.3 microgram/ml), but other compounds revealed little effect on tumor growth at the low concentration.

A new cytotoxic acyclic diterpene from Carpesium divaricatum.

A new acyclic diterpene (1) and a known acyclic diterpene, 12(S)-hydroxygeranylgeraniol (2) were isolated from the aerial parts of Carpesium divaricatum. The structure of 1 was determined to be (2E,10E)-1,12-dihydroxy-18-acetoxy-3,7,15-trimethylhexadeca- 2,10,14-triene (1) on the basis of spectroscopic studies. Compounds 1 and 2 exhibited cytotoxicity against cultured human tumor cell lines, A549, SK-OV-3, SK-MEL-2, XF498, and HCT15, with ED50 values ranging from 4.3-10.2 micrograms/ml and 4.1-8.3 micrograms/ml, respectively.

Psammaplin A, a natural phenolic compound, has inhibitory effect on human topoisomerase II and is cytotoxic to cancer cells.

We evaluated the topoisomerase II (Topo II) inhibitory activity of psammaplin A (PSA), a naturally occurring biphenolic compound, and its cytotoxicity to some human cancer cells including P-glycoprotein (Pgp)-overexpressing multidrug resistant (MDR) cell line. PSA completely inhibited the DNA relaxation activity of Topo II at 75.0 microM. It also completely inhibited the DNA decatenation activity of Topo II at 75.0 microM, and showed about 50% inhibitory activity at 18.8 microM. In the cytotoxicity assay, the effective concentrations that cause 50% inhibition of cell growth (EC50) were 0.48, 0.39, 1.83 and 3.76 microM to A549, SK-OV-3, HCT15 and HCT15/CL02 (MDR cell line established from HCT15 cells) cancer cells, respectively. In the presence of 8.0 microM of verapamil (VER), a well-known MDR modulator, the EC50 of PSA to HCT15/CL02 cells was reduced about 2.1 fold. Meanwhile, the EC50s of standard Topo II inhibitory drugs such as doxorubicin, etoposide and mitoxantrone to HCT15/CL02 cells were reduced about 8.5, 9.3 and 8.1 fold in the presence of 8.0 microM VER, respectively. From the results, we conclude that PSA has Topo II inhibitory activity, and its cytotoxicity to cancer cells is not so strongly affected by Pgp-associated MDR phenotype in comparison with some Topo II inhibitory anticancer drugs used in the clinic.

Effects of flavonoids on the growth and cell cycle of cancer cells.

In this study, we investigated the cytotoxicities of flavone (F01), 3-hydroxyflavone (F02), 6- hydroxyflavone (F03), 7-hydroxyflavone (F04), 3,6-dihydroxyflavone (F05), 5,7-dihydroxyflavone (F06) and 5,6,7-trihydroxyflavone (F07) to human cancer cells including P- glycoprotein (Pgp)-expressing HCT15 cells and its multidrug resistant subline, HCT15/CL02 cells. We also examined the effects of those flavonoids on the cell cycle of these cancer cells. HCT15/CL02 cells did not reveal resistance to all the flavonoids tested in comparison with HCT15 cells. In cell cycle analysis, all the flavonoids tested, except F01 and F04, reduced the G0/G1 population of SF295 cells at growth inhibitory concentrations, and increased G2/M (F02, F03 and F06) or S (F05 and F07) populations. In addition, F02 and F03 decreased the G2/M and G0/G1 population, and increased the S and G2/M population in HCT15 cells, respectively. Meanwhile, in HCT15/CL02 cells, F02 and F03 decreased the G0/G1 populations and increased the S population. In conclusion, we deemed that the flavonoids tested had diverse cytotoxic mechanisms, and exerted their cell growth inhibitory or killing activity by distinctive ways in different cells.