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A Asada

Publications and source records attributed to A Asada.

At least 37 records · Page 2Linked to original sources
PubMed1999

Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study.

OBJECTIVE: To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to elucidate the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4. METHODS: In an in vivo, double-blind randomized study, 24 patients received 0.2 mg/kg midazolam and either 2 mg/kg propofol (propofol group) or placebo (placebo group) for induction of anesthesia. In the propofol group, continuous infusion of propofol at 9 mg/kg/h was started immediately after the bolus infusion of propofol and was maintained for an hour. In the placebo group the same dose of soybean emulsion as a placebo was given and infused intravenously for an hour instead of propofol. In an in vitro study the effect of propofol on the metabolism of midazolam was studied with human liver microsomes and recombinant CYP3A4. RESULTS: In the propofol group the mean clearance of midazolam was decreased by 37% (P = .005) and the mean elimination half-life was prolonged by 61% (P = .04) compared with the placebo group. The mean plasma concentrations of 1'-hydroxymidazolam were lower in the propofol group than in the placebo group at 5, 10, 15, 20, and 30 minutes after midazolam was administered (P < .05). The mean (+/-SD) Michaelis-Menten constant for midazolam 1'-hydroxylation by human liver microsomes was 5.6 +/- 3.3 micromol/L. The formation of 1'-hydroxymidazolam was competitively inhibited by propofol, and the mean inhibition constant was 56.7 +/- 16.6 micromol/L. The mean Michaelis-Menten constant and mean inhibition constant values for midazolam 1'-hydroxylation by recombinant CYP3A4 were 4.0 micromol/L and 61.0 micromol/L, respectively, consistent with the mean values obtained from human liver microsomes. CONCLUSION: Propofol decreases the clearance of midazolam, and the possible mechanism is the competitive inhibition of hepatic CYP3A4.

Adult↗
PubMed1999

Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro.

Fentanyl decreases clearance of midazolam administered i.v., but the mechanism remains unclear. To elucidate this mechanism, we have investigated the effect of fentanyl on metabolism of midazolam using human hepatic microsomes and recombinant cytochrome P450 isoforms (n = 6). Midazolam was metabolized to l'-hydroxymidazolam (l'-OH MDZ) by human hepatic microsomes, with a Michaelis-Menten constant (K(m)) of 5.0 (SD 2.7) mumol litre-1. Fentanyl competitively inhibited metabolism of midazolam in human hepatic microsomes, with an inhibition constant (Ki) of 26.8 (12.4) mumol litre-1. Of the seven representative human hepatic P450 isoforms, CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4, only CYP3A4 catalysed hydroxylation of midazolam, with a K(m) of 3.6 (0.8) mumol liter-1. Fentanyl competitively inhibited metabolism of midazolam to l'-OH MDZ by CYP3A4, with a Ki of 24.2 (6.8) mumol litre-1, comparable with the Ki obtained in human hepatic microsomes. These findings indicate that fentanyl competitively inhibits metabolism of midazolam by CYP3A4.

Anesthetics, Intravenous↗
PubMed1999

Oral clonidine to control hypertension after head injury.

Clonidine, an alpha2 agonist, was administered through a nasogastric tube for the treatment of hypertension in a head-injury patient with elevated plasma catecholamines. Haemodynamic parameters were stabilized with a reduction in sympathetic nervous activity. The plasma clonidine concentration, measured by radioimmunoassay, rapidly increased following the administration. After cessation of oral administration of clonidine, mean arterial blood pressure gradually increased. So clonidine was again administered orally and good blood pressure control was achieved and no change in consciousness level was observed. Oral clonidine was useful and effective for hypertension in this head injury patient.

Administration, Oral↗
PubMed1999

Preoperative epidural morphine using double-catheter technique for esophagectomy.

This study was undertaken to determine whether preoperative epidural morphine using double-catheter technique would improve postoperative analgesia in patients undergoing esophagectomy with or without continuous intraoperative epidural lidocaine in a randomized double-blind and controlled manner. Thirty patients undergoing esophagectomy for esophageal cancer received preoperative epidural morphine 2 mg at T 6-7 and 2 mg at L 3-4 through the catheters, respectively. Thereafter, continuous thoracic epidural infusion of either 1% lidocaine (lidocaine group, n = 15) or normal saline solution (control group, n = 15) at 6 ml/h was initiated. After surgery, mean verbal rating scale of pain (0 to 10) at rest was maintained below 4 and pain on deep breathing was maintained mild in all patients in both groups. There was no significant difference in these values between the groups. In conclusion, preoperative epidural morphine using double-catheter technique provided adequate analgesia following esophagectomy. The addition of intraoperative continuous epidural lidocaine did not improve analgesia.

Aged↗
PubMed1998

Induction of thymocyte apoptosis by Ca2+-independent protein kinase C (nPKC) activation and its regulation by calcineurin activation.

Glucocorticoids appear to participate in apoptosis of unselected CD4(+)CD8(+) thymocytes. Activation of Ca2+-independent novel protein kinase C (nPKC) precedes glucocorticoid-induced thymocyte apoptosis, while proper levels of Ca2+-dependent protein kinase C (cPKC) and calcineurin activities contribute to rescue thymocytes. To clarify the role of nPKC in thymocyte apoptosis, murine thymocytes were stimulated with the diterpene diester, ingenol 3, 20-dibenzoate (IDB). IDB induced selective translocation of nPKC-delta, -epsilon, and -theta and PKC-mu from the cytosolic fraction to the particulate fraction and induced morphologically typical apoptosis through de novo synthesis of macromolecules. The apoptosis was also induced by thymeleatoxin, a diterpene ester, at relatively high concentrations that induced translocation of cPKC, nPKC-theta, and PKC-mu. The IDB- or thymeleatoxin-induced death was inhibited by non-isoform-selective PKC inhibitors, but not by their structural analogs with weak PKC-inhibitory activity or the selective inhibitor of cPKC and PKC-mu, Gö 6976. The death was also inhibited by calcium ionophore ionomycin at concentrations within a narrow range. The range corresponded to the concentration range that contributes to the inhibition of glucocorticoid-induced apoptosis. The antiapoptotic effect was canceled by the immunosuppressant FK506 but not by rapamycin. These results indicate that activation of nPKC, especially nPKC-theta, induces apoptosis in thymocytes and that calcineurin activation regulates the apoptosis.

Animals↗
PubMed1998

A role of calcineurin in coreceptor regulation during differentiation of Cd4+Cd8+ T cells.

The immunosuppressant FK506 inhibits thymocyte positive selection. Calcineurin, a FK506-sensitive Ca2+/calmodulin-dependent protein phosphatase, is presumed to be involved in this event without direct evidence. We have previously shown that moderate stimulation of CD4(+)CD8(+) thymocytes with a combination of the calcium ionophore ionomycin and phorbol myristate acetate mimics positive selection events including downregulation of CD8 expression. Moderate stimulation of a CD4(+)CD8(+) T cell line with the same combination of drugs also induced specific downregulation of CD8 expression. FK506 inhibited the CD8 downregulation in both cell types. The T cell line was transfected with an expression vector encoding an active form of calcineurin. The transfectans remained CD4(+)CD8(+), but became CD4(+)CD8(-) or CD4(+)CD8(low) upon stimulation with phorbol myristate acetate alone. The extent of the CD8 downregulation was correlated with the expression level of the mutant calcineurin. These results suggest that the calcium signal for the CD8 downregulation is mainly delivered through calcineurin activation.

Animals↗
PubMed1998

The pharmacokinetic change of lidocaine by catecholamines using isolated perfused rat liver (IPRL).

We hypothesized that changes in the pharmacokinetics of lidocaine might reveal changes in portal circulation induced by catecholamines. Isolated perfused rat liver (IPRL) was selected as an experimental model, since experimental conditions in this model could be regulated. The liver was perfused with a recirculating system at a constant flow rate of 20 ml/min. Two milligrams of lidocaine was administered along with one of three drugs, dopamine, norepinephrine or adenosine triphosphate. The fractional transfer rate constants, k21 and k12, from medium to liver and liver to medium, respectively, and ke, the elimination rate constant, were calculated using a two-compartment model with the SAAM II program. Curves of decay of lidocaine from the recirculating medium consisted of a fast and a slow component. Norepinephrine and high-dose dopamine significantly increased k12, while low-dose dopamine significantly increased k21 and ke compared with control values. Thus, norepinephrine and high-dose dopamine increased lidocaine transfer rate from liver to medium, while low-dose dopamine increased the transfer rate from medium to liver and the rate of elimination from liver. These findings suggest that norepinephrine and high-dose dopamine inhibit hepatic drug uptake and that low-dose dopamine improves uptake in IPRL.

Anesthetics, Local↗
PubMed1998

Oral clonidine for sedation and analgesia in a burn patient.

Clonidine has both analgesic and sedative actions, and it has been used in a variety of settings as a sedative, or both. We administered oral clonidine with intravenous ketamine to a burn patient to control severe pain. Clonidine produced good analgesia and sedation. In addition, clonidine counterbalanced the sympathetic stimulation of ketamine by virtue of its action in reducing sympathetic outflow. The combination of these two drugs may be useful for burn patients with hypertension or myocardial ischemia.

Administration, Oral↗
PubMed1998

Clinical aspects of indocyanine green pharmacokinetics following portal vein administration.

AIMS: This study was performed to demonstrate that measurement of the clearance of indocyanine green (ICG) following portal vein administration (CLpv) is more useful than that following peripheral vein administration (CLiv) for evaluating intrinsic clearance and hepatic blood flow. METHODS: Eight patients, aged 55.9 +/- 8.8 years, who underwent partial hepatectomy were studied. ICG was administrated to all patients via peripheral and portal veins before and after enflurane anaesthesia and soon after surgery. ICG concentrations were measured by h.p.l.c. Non-compartmental analysis was applied to the ICG time-concentration data obtained. The area under the curve (AUC), clearance (CL), mean residence time (MRT) and volume of distribution (V) were calculated using this method of analysis. RESULTS: CLpv was significantly decreased from 26.4 +/- 13.2 ml kg(-1) min(-1) before anaesthesia, to 19.5 +/- 7.0 (P < 0.05) and 12.7 +/- 5.3 (P < 0.01) ml kg(-1) min(-1), respectively, during anaesthesia and after partial hepatectomy; These values were 72.1% (P < 0.01) and 48.5% (P < 0.01) of that observed at percutaneous transhepatic portography (PTP). CLiv was significantly decreased from 14.6 +/- 5.3 ml kg(-1) min(-1) before anaesthesia, to 9.4 +/- 3.6 (P < 0.05) and 9.8 +/- 4.1 (P < 0.05) ml kg(-1) min(-1), respectively, after partial hepatectomy and 12 h after operation; These values were 68.9% (P < 0.05) and 73.5% (P < 0.05) of the value at PTP. The other pharmacokinetic parameters examined, V and MRT, did not change significantly during anaesthesia or after surgery. CONCLUSION: The clearance of ICG after portal administration was useful for estimating hepatic blood flow and intrinsic clearance in perioperative management of liver surgery.

Aged↗
PubMed1998

Comparison of survival-promoting effects of brain-derived neurotrophic factor and neurotrophin-3 on PC12h cells stably expressing TrkB receptor.

We obtained two PC12h cell lines, PC-pAB1 and PC-pAB2, stably expressing TrkB receptor and investigated the effects of BDNF and NT-3 in these cell lines. The cells differentiated into neuron-like cells in response to BDNF as well as NGF, neurite extension being more rapid in the former case. These TrkB-expressing cells also extended neurites in response to NT-3, which is a nonpreferred ligand of TrkB. Next, we examined the survival-promoting effects of NGF, BDNF, and NT-3 under apoptotic conditions of oxygen toxicity in naive cells and NGF deprivation in differentiated cells. In both cases, BDNF prevented cell death similarly to NGF. NT-3 prevented cell death induced by oxygen toxicity in naive cells, but not that induced by NGF deprivation in differentiated cells. NT-3 induced the tyrosine phosphorylation of TrkB in naive cells, but not in differentiated cells. These results indicate that NT-3 has survival-promoting effects on naive TrkB-expressing PC12h cells, but not on differentiated cells because of its inability to induce the tyrosine phosphorylation of TrkB.

Animals↗
PubMed1998

The effects of epidural morphine on cardiac and renal sympathetic nerve activity in alpha-chloralose-anesthetized cats.

BACKGROUND: Epidural morphine yields postoperative pain relief and hemodynamic stability. However, the effects of epidural morphine on sympathetic tone are unclear. This study was designed to elucidate the effects of epidural morphine on cardiac (CSNA) and renal (RSNA) sympathetic nerve activity by direct measurement in anesthetized cats. METHODS: Thirty mongrel cats anesthetized with alpha-chloralose were randomly assigned to one of the following five groups: control (0.2 ml/kg thoracic epidural normal saline; n=5); thoracic epidural morphine (n=9); lumbar epidural morphine (n=6); vagotomized, sinoaortic denervated, thoracic epidural morphine (n=5); or intravenous morphine (n=5). Mean arterial pressure (MAP), heart rate (HR), CSNA, and RSNA were measured 0, 15, 30, 60, 90, and 120 min after saline or morphine (200 microg/kg) administration and 15 min after reversal with 200 microg naloxone given intravenously. RESULTS: In the control group, no changes in measured variables were found after either thoracic epidural saline or intravenous naloxone. Thoracic and lumbar epidural morphine both significantly reduced MAP, HR, CSNA, and RSNA 30 through 120 min after morphine administration (P < 0.05). These changes were reversed by intravenous naloxone. Changes after thoracic epidural morphine administration in vagotomized, baroreceptor-denervated cats were similar to those in intact cats. Intravenous morphine produced no significant changes except for a decrease in MAP, which was reversed by intravenous naloxone. CONCLUSION: In contrast to intravenous morphine, thoracic and lumbar epidural morphine both inhibited cardiac and renal sympathetic nerve activity and consequently reduced MAP and HR in alpha-chloralose anesthetized cats.

Analgesics, Opioid↗
PubMed1998

Effects of inhaled nitric oxide on platelet-activating factor-induced pulmonary hypertension in dogs.

BACKGROUND: Platelet-activating factor (PAF), a lipid mediator released during endotoxin shock, induces pulmonary hypertension, systemic hypotension and cardiac dysfunction. In this study, we compared the effect of inhaled nitric oxide (NO) on PAF-induced pulmonary hypertension and NO metabolism with that on pulmonary hypertension induced by a stable thromboxane A2 mimetic, U46619. Since PAF-induced hypotension might be mediated by NO, the effect of inhaled NO combined with an intravenously administered NO synthase inhibitor, NG-nitro-L-arginine (L-NNA), on PAF-induced hemodynamic change was also investigated. METHODS: In a total of 28 beagles anesthetized with pentobarbital the following substances were intravenously administered: PAF 0.56 +/- 0.30 microgram.kg-1.min-1 (group PAF), L-NNA 10 mg.kg-1 + PAF 0.04 +/- 0.03 microgram.kg-1.min-1 (group L-NNA + PAF), U46619 0.60 +/- 0.11 microgram.kg-1.min-1 (group U46619) or L-NNA 10 mg.kg-1 + U46619 0.61 +/- 0.23 microgram.kg-1.min-1 (group L-NNA + U46619) to obtain a mean pulmonary arterial pressure (MPAP) of 25 mmHg. Nitric oxide was then inhaled at 5, 10, 20 and 40 ppm for 15 min at 15-min intervals in the order of increasing concentration. An additional 7 dogs (control group) inhaled NO at normal MPAP (17 mmHg). Hemodynamic and respiratory parameters, NOHb, NO2- + NO3-, and MetHb levels in blood were measured before and during NO administration. RESULTS: In the control group, hemodynamic and respiratory values did not change significantly during NO administration. In group PAF, NO significantly reversed the PAF-induced pulmonary hypertension. PAF induced a marked systemic hypotension and cardiac output reduction, but these changes were not affected by inhalation of NO. L-NNA pretreatment markedly decreased the dose of PAF required to maintain a MPAP of 25 mmHg, and abolished the PAF-induced hypotension. In group L-NNA + PAF, the diminishing effect of inhaled NO on pulmonary vascular resistance (PVR) was significantly greater than that in group PAF. U46619 induced pulmonary hypertension and increases in blood pressure, intrapulmonary shunt and peak airway pressure. L-NNA pretreatment did not change the dose of U46619 required to maintain a MPAP of 25 mmHg. The effects of inhaled NO on PVR decrease were similar in groups U46619 and L-NNA + U46619. No NOHb was detected in any group. NO2- + NO3- concentration increased during NO administrations. There were no significant differences in NO2- + NO3- concentration among groups. CONCLUSIONS: Inhaled NO at the dose of 5-40 ppm effectively reversed PAF-induced pulmonary hypertension, especially following pretreatment with L-NNA. Inhaled NO did not affect PAF-induced hypotension or cardiac dysfunction. These findings indicate that low concentrations of inhaled NO may be useful in reversing pulmonary hypertension in the endotoxemia where PAF may be one mediator.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Elevated methemoglobin in patients with sepsis.

BACKGROUND: It has been reported that large amounts of nitric oxide (NO) are released in patients with sepsis. NO is converted to methemoglobin and nitrate. This study was designed to determine whether blood methemoglobin levels were increased in patients with sepsis or septic shock. METHODS: Forty-five critically ill patients including 8 with sepsis but without shock, 6 with septic shock and 31 non-septic patients were enrolled in the study. For septic and septic shock patients, blood methemoglobin concentrations were measured during sepsis or septic shock and at the time of recovery or just before the onset of sepsis. For the remaining non-septic patients, methemoglobin concentrations were measured at ICU admission and discharge. RESULTS: Blood methemoglobin levels in the presence of sepsis or septic shock were significantly (P < 0.05) higher than those in non-septic patients and those at recovery or just before the onset of sepsis in both septic and septic shock patients. CONCLUSIONS: Blood methemoglobin concentration may be useful as a marker of the onset of sepsis or septic shock.

APACHE↗
PubMed1998

[A comparison of the incidence of postoperative nausea and vomiting after propofol-fentanyl anesthesia and that after nitrous oxide-isoflurane anesthesia].

We compared the incidence of postoperative nausea and vomiting after total intravenous propofol-fentanyl anesthesia (TIVA group) and that after thiamylal-nitrous oxide-isoflurane anesthesia (GOI group) in 60 ASA physical I and II patients for elective abdominal simple total hysterectomy. When the patients returned to the ward, the incidence of nausea was lower in TIVA group than in GOI group (P < 0.05), but no difference was found in the incidence of vomiting between the two groups. There were no differences in the incidence of nausea and vomiting 6 hours after the operation and on the next morning between the two groups. Postoperative pain scores were similar between the two groups, while total postoperative evaluation scores (nausea, vomiting, pain, fever, and sleep disturbance) were lower in TIVA group (P < 0.05). We conclude that TIVA with propofol-fentanyl reduced the incidence of nausea and improved total evaluation scores in the immediate postoperative period.

Adult↗
PubMed1997

Regulation of thymocyte lineage commitment by the level of classical protein kinase C activity.

Thymocyte-positive selection involves signaling through TCR and accessory molecules, and the signaling intensity appears to be critical for this event. The specific inhibitor of classical Ca2+-dependent protein kinase C (cPKC), Gö 6976, inhibited positive selection in fetal thymus organ culture, indicating that cPKC activation is essential for positive selection. The major protein kinase C isoforms in CD4+ CD8+ thymocytes are cPKC-alpha, cPKC-beta, and the novel Ca2+-independent protein kinase C, nPKC-epsilon. To analyze the effect of cPKC activation level on positive selection, we used thymocytes from TCR transgenic mice with nonselecting and RAG-2 -/- backgrounds as they were developmentally arrested at the CD4+ CD8+ stage without positive selection signals. These thymocytes survived and acquired CD4/CD8 lineage commitment in suspension culture upon transient stimulation with limited concentrations of the selective activator of cPKC-alpha and -beta, thymeleatoxin, and the calcium ionophore, ionomycin. However, neither 12-deoxyphorbol 13-phenylacetate 20-acetate, which selectively activates cPKC-beta, nor ingenol 3,20-dibenzoate, which selectively activates nPKC-epsilon, exerted such an effect. The thymeleatoxin/ionomycin concentrations corresponded to those that inhibit glucocorticoid-induced apoptosis in thymocytes and were lower than those that induce proliferation of mature T cells. The CD4 lineage commitment required a higher level of cPKC activity than the CD8 lineage commitment. CD8alpha or CD4 mRNA expression was down-regulated. Functional helper and killer T cells were induced from the CD4 and CD8 lineage-committed cells, respectively, by additional stimulation. These results suggest that thymocyte lineage commitment in positive selection is regulated by the level of cPKC-alpha activity or by the levels of cPKC-alpha and -beta activities.

Animals↗
PubMed1997

Crush syndrome sustained in the 1995 Kobe, Japan, earthquake; treatment and outcome.

STUDY OBJECTIVE: To assess the treatment and outcome of patients with crush syndrome sustained in an earthquake disaster. METHODS: We conducted a retrospective analysis of eight patients with crush syndrome and subsequent acute kidney failure who were treated in the ICU of a university hospital. All eight patients had been extricated from buildings that collapsed in the 1995 Kobe, Japan, earthquake. Crush injury involved the upper extremities in one patient and the lower extremities in seven. Each patient received intravenous fluid infusion and diuretic drugs and underwent hemodialysis. Emergency fasciotomy was performed in some patients, 17 to 100 hours after extrication. RESULTS: All patients were conscious and lucid on admission, and blood pressure and heart rate were normal. All the patients demonstrated kidney failure with increased concentrations of serum creatinine (1.9 to 9.6 mg/dL [169 to 852 mumol/L]). Six patients were oliguric. Hyperkalemia (5.6 to 8.8 mEq/L) was present in six patients. We found close correlations between the serum potassium and creatine kinase concentrations, between the serum myoglobin and potassium concentrations, and between the serum myoglobin and creatine kinase concentrations. All the patients were weaned from hemodialysis. The serum creatinine concentration decreased to a normal level within 20 to 52 days of admission in all patients. No patients underwent amputation. Muscle weakness and sensory deficits persisted in all patients 6 months after the earthquake. CONCLUSION: Our findings support current therapeutic strategies for crush syndrome, despite the long delay to initiation of intensive therapy. All the patients recovered kidney function and were weaned from hemodialysis; none required amputation.

Acute Kidney Injury↗
PubMed1997

I.v. fentanyl decreases the clearance of midazolam.

We have examined the effect of fentanyl on the pharmacokinetics of midazolam in patients undergoing orthopaedic surgery. Thirty patients were allocated randomly to receive fentanyl 200 micrograms and midazolam 0.2 mg kg-1 (fentanyl group, n = 15) or placebo and midazolam 0.2 mg kg-1 (placebo group, n = 15) in a double-blind manner for induction of anaesthesia. Anaesthesia was maintained with nitrous oxide and isoflurane. Systemic clearance of midazolam was decreased by 30% (P = 0.002) and elimination half-time was prolonged by 50% (P = 0.04) in the fentanyl group compared with the placebo group. There were no differences in the distribution half-time or volume of distribution at steady state between the two groups. These findings indicate that elimination of midazolam was inhibited by fentanyl during general anaesthesia.

Adolescent↗