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1.
A. C. T. Huizinga R. H. G. Vandenbrom J. M. K. H. Wierda M.D. Ph.D. F. D. M. Hommes P. J. Hennis 《Acta anaesthesiologica Scandinavica》1992,36(5):463-468
The intubating conditions and neuromuscular blocking profile following 600 micrograms.kg-1 rocuronium (Org 9426) have been investigated in patients under various experimental conditions. They were compared with conditions following 1.5 mg.kg-1 suxamethonium, preceded by a precurarising dose (10 mg) of gallamine, and with those in a control group in the absence of a muscle relaxant. Rocuronium produced good to excellent intubating conditions at 60 as well as at 90 s after administration, even though there was only a partial blockade of the adductor pollicis muscle. Intubating conditions following suxamethonium were comparable with those after rocuronium. Half of the control patients could be intubated. The clinical duration and the recovery time of 600 micrograms.kg-1 of rocuronium were 24(4) and 9(3) min (mean(s.d.)), respectively. Rocuronium may have a major advantage over existing non-depolarising muscle relaxants due to the early presence of excellent intubating conditions. The results indicate that rocuronium may replace suxamethonium in procedures in which rapid sequence induction is required. 相似文献
2.
Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children 总被引:1,自引:0,他引:1
Wierda JMKM.; Meretoja O. A.; Taivainen T.; Proost J. H. 《British journal of anaesthesia》1997,78(6):690-695
We have determined the pharmacokinetics and pharmacokinetic-
pharmacodynamic relationship of rocuronium in infants and children. We
studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II,
in the ICU while undergoing artificial ventilation under i.v. anaesthesia
with an arterial cannula in situ and the EMG of the adductor pollicis
muscle was monitored. Rocuronium 0.06 (infants) and 0.09 (children) mg kg-1
min-1 was given i.v. over +/- 5 min until 85% neuromuscular block was
obtained. Arterial blood samples were obtained over 240 min. Plasma
concentrations were measured by HPLC. Pharmacokinetic-dynamic variables
were calculated using the Sheiner model and the Hill equation. Statistical
analysis was performed using the Mann-Whitney U test (P < 0.05). The
mean administered dose was 0.32 (SD 0.08) mg kg-1 and 0.4 (0.1) mg kg-1 for
infants and children, respectively. Infants differed from children in
plasma clearance (4.2 (0.4) vs 6.7 (1.1) ml min-1 kg-1), distribution
volume at steady state (231 (32) vs 165 (44) ml kg-1), mean residence time
(56 (10) vs 26 (9) min), concentration in the effect compartment at 50%
block (1.2 (0.4) vs 1.7 (0.4) mg litre-1) and the slope of the
concentration-effect relationship (5.7 (1.3) vs 3.9 (0.5)). Calculated mean
ED90 values were 0.26 and 0.34 mg kg-1 for infants and children,
respectively. The time course of neuromuscular block after equipotent doses
did not differ.
相似文献
3.
D J Thomas A Sadler V V Subrahmanyam D Siegel M J Reasor D Wierda D Ross 《Molecular pharmacology》1990,37(2):255-262
Bone marrow stroma consists predominately of two cell types, macrophages and fibroblastoid stromal cells, which regulate the growth and differentiation of myelopoietic cells via the production of growth factors. We have previously shown that macrophages are more sensitive than fibroblastoid stromal cells (LTF cells) to the toxic effects of the benzene metabolite hydroquinone. In this study, the role of selective bioactivation and/or deactivation in the macrophage-selective effects of hydroquinone was examined. LTF and macrophage cultures were incubated with 10 microM [14C]hydroquinone to examine differential bioactivation. After 24 hr, the amount of 14C covalently bound to acid-insoluble macromolecules was determined. Macrophages had 16-fold higher levels of macromolecule-associated 14C than did LTF cells. Additional experiments revealed that hydroquinone bioactivation to covalent-binding species was hydrogen peroxide dependent in macrophage homogenates. Covalent binding in companion LTF homogenates was minimal, even in the presence of excess hydrogen peroxide. These data suggest that a peroxidative event was responsible for bioactivation in macrophages and, in agreement with this, macrophages contained detectable peroxidase activity whereas LTF cells did not. Bioactivation of [14C]hydroquinone to protein-binding species by peroxidase was confirmed utilizing purified human myeloperoxidase in the presence of hydrogen peroxide and ovalbumin as a protein source. High performance liquid chromatographic analysis of incubations containing purified myeloperoxidase, hydroquinone, and hydrogen peroxide showed that greater than 90% of hydroquinone was removed and could be detected stoichometrically as 1,4-benzoquinone. 1,4-Benzoquinone was confirmed as a reactive metabolite formed from hydroquinone in macrophage incubations using excess GSH and trapping the reactive quinone as its GSH conjugate, which was measured by high performance liquid chromatography with electrochemical detection. The activity of DT-diaphorase, a quinone reductase that has been invoked as a protective mechanism in quinone-induced toxicity, was 4-fold higher in LTF cells than macrophages. These data suggest that the macrophage-selective toxicity of hydroquinone results from higher levels of peroxidase-mediated bioactivation and/or lower levels of DT-diaphorase-mediated detoxification. 相似文献
4.
Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. 总被引:3,自引:0,他引:3
M Motta L Rassenti B J Shelvin S Lerner T J Kipps M J Keating W G Wierda 《Leukemia》2005,19(10):1788-1793
Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-na?ve patients with CLL. CD4+ and CD8+ T cells from these patients demonstrated significantly increased sCD152 and cCD152 compared to normal donors. Furthermore, these patients had an increased proportion of the regulatory CD4(+)/CD25(+)/CD152+ subset that correlated with advanced Rai stage, unfavorable cytogenetics and low serum IgG and IgA levels. The expression of sCD152 by T cells also correlated with ZAP-70 expression by CLL B cells. The proportion of CD4(+)/CD25+ cells was also correlated with unmutated immunoglobulin heavy chain variable gene status. Blockade of CD152 with monoclonal antibody (mAb) in proliferation assays was associated with potent T-cell proliferation in response to autologous and allogeneic CD40-activated CLL B cells. In summary, T cells from patients with CLL may be primed for anergy by expressing increased amounts of CD152; anti-CD152 mAb may represent a therapeutic opportunity to enhance an immune response against autologous leukemia cells. 相似文献
5.
Immobilized IgG immune complex induces secretion of tumor necrosis factor-alpha by porcine alveolar macrophages. 总被引:1,自引:0,他引:1
J W Kim W G Wierda Y B Kim 《American journal of respiratory cell and molecular biology》1991,5(3):249-255
Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory mediator produced by activated monocytes and macrophages. We have previously shown that porcine alveolar macrophages (PAM) mediate bystander cytotoxicity through hydrogen peroxide production following activation with immobilized IgG immune complex (IIC) (J. Immunol. 1983; 131:1438-1442). In this report, we have investigated whether IIC induces TNF-alpha secretion by PAM. Isolated PAM from Minnesota miniature swine were cultured for 18 h with and without recombinant human interferon-gamma (rhIFN-gamma). Cultured PAM were then incubated with IIC or IgG immune complex in suspension (SIC). The supernatants generated were assessed for cytotoxic activity using a TNF-alpha-sensitive WEHI-164 cell line. Anti-recombinant human TNF-alpha (rhTNF-alpha) monoclonal antibody neutralized the observed cytotoxicity of IIC-activated PAM supernatant completely, indicating that this cytotoxicity is mediated by TNF-alpha. IIC induced TNF-alpha secretion by PAM after 3 h of incubation, reaching a plateau from 6 to 12 h and decreasing thereafter. TNF-alpha release was enhanced by pretreatment of PAM with rhIFN-gamma. SIC did not induce significant levels of TNF-alpha secretion by PAM; however, SIC with cytochalasin B-pretreated PAM induced equivalent levels of TNF-alpha secretion as IIC-activated PAM. We conclude that IIC or SIC with cytochalasin B pretreatment, both of which prevent internalization of IgG immune complex-bound Fc receptor (FcR), provide a signal for PAM to generate TNF-alpha through FcR modulation. This suggests that in vivo, deposited (immobilized) IgG immune complexes-bound FcR may be a stimulus for activation of PAM to generate TNF-alpha rather than circulating (mobilized) immune complexes, which may contribute to the pathogenesis of diffuse interstitial fibrosis of the lung, especially in idiopathic pulmonary fibrosis. 相似文献
6.
Beaufort TM Proost JH Kuizenga K Houwertjes MC Kleef UW Wierda JM 《Journal of pharmacokinetics and biopharmaceutics》1999,27(2):173-190
In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50 and KeO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately. 相似文献
7.
Karen W L Yee Zhihong Zeng Marina Konopleva Srdan Verstovsek Farhad Ravandi Alessandra Ferrajoli Deborah Thomas William Wierda Efrosyni Apostolidou Maher Albitar Susan O'Brien Michael Andreeff Francis J Giles 《Clinical cancer research》2006,12(17):5165-5173
PURPOSE: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies. EXPERIMENTAL DESIGN: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study. RESULTS: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response. CONCLUSIONS: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted. 相似文献
8.
Wierda JM 《Current opinion in anaesthesiology》2000,13(4):475-478
Rapacuronium (Org 9487; ED90 = 1 mg x kg(-1)) is a new, low potency, short-acting, non-depolarizing neuromuscular blocking agent. An intubating dose of 1.5xED90 or 1.5 mg x kg(-1) of rapacuronium offers acceptable intubating conditions within 60-90 s in most patients. A complete block from this dose can be reversed immediately with satisfactory recovery in 12-16 min. Side-effects are dose-related and are mainly haemodynamic, i.e. an increase in heart rate and a decrease in blood pressure. 相似文献
9.
Rapacuronium 2.0 or 2.5 mg kg-1 for rapid-sequence induction: comparison with succinylcholine 1.0 mg kg-1 总被引:3,自引:0,他引:3
Blobner M Mirakhur RK Wierda JM Wright PM Olkkola KT Debaene B Pendeville P Engbaek J Rietbergen H Sparr HJ 《British journal of anaesthesia》2000,85(5):724-731
The purpose of this nine-centre study in 602 patients was toshow that the frequency of acceptable intubating conditionsafter rapacuronium 2.0 or 2.5 mg kg1 is notmore than 10% lower than the frequency after succinylcholine1.0 mg kg1 during rapid-sequence inductionof anaesthesia with fentanyl 12 µg kg1and thiopental 27 mg kg1. Laryngoscopyand intubation were carried out 60 s after administrationof muscle relaxant by an anaesthetist blinded to its identity.Intubating conditions were clinically acceptable (excellentor good) in 91.8% of patients given succinylcholine and in 84.1and 87.6% of patients given rapacuronium 2.0 and 2.5 mg kg1respectively. With respect to the percentage of clinically acceptableintubating conditions, the estimated difference (and the upperlimit of the one-sided 97.5% confidence interval) between succinylcholineand rapacuronium 2.0 mg kg1 was 7.8 (14.4)%and between succinylcholine and rapacuronium 2.5 mg kg1it was 4.0 (10.2)%. For both comparisons, the upper limit ofthe one-sided confidence interval exceeded the predefined 10%difference. Hence, it could not be demonstrated that the intubatingconditions with either of the two doses of rapacuronium werenot inferior to those with succinylcholine 1.0 mg kg1.The increase in heart rate was significantly greater duringthe first 5 min in the rapacuronium groups, but the arterialpressure increased significantly only in the succinylcholinegroup (P<0.001). Respiratory side-effects were observed in4.0, 13.5 and 18.5% of patients after succinylcholine and rapacuronium2.0 and 2.5 mg kg1 respectively (P<0.05).As the non-inferiority of intubating conditions after rapacuronium2.0 and 2.5 mg kg1 could not be proven, succinylcholineshould be considered the neuromuscular blocking agent that providesbetter intubating conditions for rapid-sequence induction. Br J Anaesth 2000; 85: 72431
* Corresponding author: Klinik für Anaesthesiologie der TechnischenUniversität München, Klinikum rechts der Isar, IsmaningerStr. 22, D-81675 München, Germany 相似文献
10.
Automatic muscle relaxation control may reduce anesthesiologists' workload freeing them for other patient care requirements. In this report we describe a muscle relaxation controller designed for routine clinical application using rocuronium and the train-of-four count. A muscle relaxation monitor (TOF Watch SX) was connected to a laptop computer running a controller algorithm program that communicates with a syringe pump to form a closed-loop muscle relaxation system. The control algorithm uses proportional-integral and lookup table components and is designed to avoid the usability restrictions of existing controllers. The controller is optimized using an objective method to avoid the uncertainties of 'hand-crafted' controller algorithms. Controller target was train-of-four count 1 or 2 and controller performance was evaluated in 15 patients. During 39 hours of closed-loop control, 96.1% of all twitches recorded were in the target range. Average rocuronium infusion rate was 0.36 mg.kg(-1).h(-1) (sd 0.18 mg.kg(-1).h(-1)). We show that the controller remains useful even in the presence of disturbances that can arise in routine clinical conditions. The muscle relaxation controller maintained the target train-of-four count values and may serve as a basis for the design of hardware and user interfaces for closed-loop muscle relaxation control in clinical conditions. 相似文献