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Biomedical subjects

K Mizutani

Publications and source records attributed to K Mizutani.

At least 55 records · Page 3Linked to original sources
PubMed2000

Protective effect of inducible type nitric oxide synthase against intracellular oxidative stress caused by advanced glycation end-products in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats.

OBJECTIVE: A recent study demonstrated that free radicals were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). However, the role of oxidative stress in hypertension and its related diseases in SHRSP remains unknown. On the other hand, advanced glycation end-products (AGEs) accumulate progressively in the vasculature with ageing, and have been identified to be as relevant mediators for various vascular complications. To elucidate whether nitric oxide (NO) produced by inducible type NO synthase (iNOS) in vascular smooth muscle cells (VSMC) taken from SHRSP and Wistar-Kyoto rats (WKY) attenuate AGEs-induced oxidative stress, we investigated the effect of NO donors and iNOS-induction in VSMC on intracellular oxidant level caused by AGEs. METHODS: The cells preincubated with or without NO donor, S-nitroso-n-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1), IL-1beta and/or N(G)-monomethyl-L-arginine monoacetate (L-NMMA), were treated with AGEs, and the intracellular oxidant levels, total glutathione (GSH) levels, and gamma-glutamylcysteine synthetase (GCS) mRNA were determined. We also determined the expression of an iNOS in VSMC from SHRSP and WKY. RESULTS: The intracellular oxidant level of VSMC was induced by AGEs in a dose-dependent manner. NO donor dose-dependently reduced AGEs-stimulated intracellular oxidant level. Treatment with IL-1beta reduced the AGEs-stimulated intracellular oxidant level through increased NO production, whilst inhibition of NO production by L-NMMA reduced the inhibitory effect of IL-1beta. We also confirmed that NO production as well as the expression of iNOS mRNA and the protein itself were significantly decreased in response to IL-1beta in VSMC from SHRSP compared with WKY. We also confirmed that total GSH levels, decreased by AGEs, were restored by stimulation with IL-1beta. Increased GSH synthesis was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, GCS. These results indicate that NO release, produced by iNOS in VSMC in response to cytokines, might play a protective role against AGEs-stimulated oxidative stress in VSMC. This protective effect of NO is decreased in SHRSP compared to WKY.

Albumins↗
PubMed2000

Phytoestrogens attenuate oxidative DNA damage in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats.

OBJECTIVES: A recent study demonstrated that reactive oxygen species (ROS) were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). However, the role of oxidative stress in hypertension and its related diseases in SHRSP remains unknown. To determine whether phytoestrogens attenuate oxidative DNA damage in vascular smooth muscle cells (VSMC) from SHRSP and Wistar-Kyoto (WKY) rats, we investigated the effect of daidzein, genistein and resveratrol on oxidative DNA damage in VSMC, induced by advanced glycation end-products (AGEs). METHODS: VSMC were treated with AGEs in the presence or absence of phytoestrogens for the indicated time. Cellular degeneration induced by AGEs was characterized in terms of intracellular oxidant levels, intracellular total glutathione (GSH) levels, mRNA expression for gamma-glutamylcysteine synthetase (GCS), and a new marker of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) contents. RESULTS: AGEs stimulated 8-OHdG formation in VSMC in a time- and dose-dependent manner. We also confirmed that VSMC from SHRSP were more vulnerable to oxidative stress induced by AGEs, than VSMC from WKY rats. Daidzein, genistein or resveratrol reduced AGEs-induced 8-OHdG formation in a dose-dependent manner. The preventive effects of phytoestrogens on 8-OHdG formation remarkably paralleled changes in the intracellular oxidant levels in VSMC following AGEs treatment. We further demonstrated that phytoestrogens increase intracellular total GSH level in VSMC. Increased GSH synthesis was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, GCS. Phytoestrogens-stimulated total GSH level in VSMC could lead to decreased intracellular oxidant levels, and thus prevent oxidative DNA damage, induced by AGEs. The phytoestrogens are powerful antioxidants able to interfere with AGEs-mediated oxidative DNA damage of VSMC, and are potentially useful against vascular diseases where ROS are involved in hypertension.

Animals↗
PubMed2000

Protection of mitochondrial functions against oxidative stresses by isoflavans from Glycyrrhiza glabra.

Isoflavan derivatives, glabridin (1), hispaglabridin A (2), hispaglabridin B (3), 4'-Omethylglabridin (4) and 3'-hydroxy-4'-O-methylglabridin (5), isolated from Glycyrrhiza glabra, were investigated for their ability to protect liver mitochondria against oxidative stresses. Mitochondrial lipid peroxidation linked to respiratory electron transport and that induced non-enzymatically were inhibited by these isoflavans. Hispaglabridin A (2) strongly inhibited both peroxidations and 3'-hydroxy-4'-O-methylglabridin (5) was the most effective at preventing NADH-dependent peroxidation. 3'-Hydroxy-4'-O-methylglabridin (5) protected mitochondrial respiratory enzyme activities against NADPH-dependent peroxidation injury. Dihydroxyfumarate-induced mitochondrial peroxidation was also prevented by this isoflavan. Isoflavans from G. glabra were shown to be effective in protecting mitochondrial function against oxidative stresses.

Animals↗
PubMed2000

Inhibitory effects of amlexanox on carbachol-induced contractions of rabbit ciliary muscle and guinea-pig taenia caecum.

Instillation of amlexanox, an anti-allergic drug, over a long period improves myopia in some allergy patients and in monkeys. The relaxing effect of amlexanox on persistent contraction of ciliary muscle may be involved in the improvement of myopia. In this study, the mechanism of the noncompetitive inhibition of carbachol-induced contractions by amlexanox (1-100 microM) was investigated in isolated smooth muscle preparations of the rabbit ciliary body and guinea-pig taenia caecum. In ciliary muscles, amlexanox (100 microM) inhibited both the phasic and tonic components of carbachol-induced contractions even in the presence of cyclopiazonic acid (10 microM) where the function of the sarcoplasmic reticulum was impaired, while diltiazem (3.2, 32 microM) did not. In taenia caecum, diltiazem (3.2 microM) slightly inhibited the phasic component and abolished the tonic component of carbachol-induced contractions. Amlexanox also abolished the tonic component, but it did not decrease the 45Ca2+ uptake into taenia caecum smooth muscle cells induced by carbachol. Amlexanox did not increase the cyclic adenosine monophosphate (cyclicAMP) content of ciliary muscles in the presence of 3-isobutyl-1-methylxanthine (10 microM), while forskolin (1 microM) did. Gel-shift assay showed that the inhibition of carbachol-induced contractions by amlexanox was accompanied by a decrease in phosphorylation of the 20-kDa myosin light chain in taenia caecum tissue preparations. Amlexanox had no effect on calmodulin activity, whereas it inhibited phosphorylation of the myosin light chain by purified myosin light-chain kinase from chicken gizzard. These results suggested that amlexanox may not affect either Ca2+ mobilization or calmodulin activity, although it inhibits myosin light-chain kinase, which may inhibit carbachol-induced contraction.

Aminopyridines↗
PubMed2000

Murine Delta homologue, mDelta1, expressed on feeder cells controls cellular differentiation.

The Delta/Serrate-Notch pathway is involved in intercellular signaling that controls cell fate during the development of invertebrates and vertebrates. Delta is a prototype of Notch ligands and has been studied extensively in Drosophila. In higher vertebrates, four Delta/Serrate homologues and four Notch homologues have been identified. Recent studies showed that the murine Delta homologue, mDelta1, is essential in early embryogenesis. The biological activity of mammalian Delta and its roles in cellular differentiation, however, have remained unclear. In this study, we first surveyed expression of mDelta1 in the adult mouse and found it to be present in a wide range of tissues. For testing biological activity of mDelta1, we expressed a mDelta1 full-length cDNA in L cells using a eukaryotic expression vector. Effects of mDelta1 on cellular differentiation were examined in two independent systems, featuring C2C12 myogenic differentiation and multipotent murine bone marrow cell differentiation. Inhibition of the former was observed with mDelta1 expression on L cells, associated with suppression of myogenin, a myogenic transcription factor. Expression of mDelta1 in conjunction with GM-CSF promoted differentiation of bone marrow cells to myeloid dendritic cells at the expense of other lineages. Although the effects of mDelta1 on two differentiation systems appeared opposing, as inhibition occurring in one and induction in the other, this can be understood by the unifying concept of generation of diverse cell types from equivalent progenitors. Thus, the present study provided evidence that mammalian Delta participates in intercellular signaling, determining the cell fate in a wide variety of tissues.

Animals↗
PubMed2000

Resveratrol attenuates ovariectomy-induced hypertension and bone loss in stroke-prone spontaneously hypertensive rats.

We examined the effect of resveratrol (3,4',5-trihydroxy stilbene), a phenolic compound found in the skins of most grapes, on blood pressure and bone loss in ovariectomized (OVX), stroke-prone spontaneously hypertensive rats (SHRSP). Nineteen-week-old female SHRSP were divided into a sham-ovariectomized (sham) group fed a control diet and two OVX groups fed either a control diet (OVX-Cont) or a diet supplemented with resveratrol (5 mg/kg per d; OVX-Resv). Ovariectomy induced significant increases in systolic blood pressure (SBP). Resveratrol lowered the SBP by 15%) by the third week of administration, and this effect was maintained throughout the study. Resveratrol treatment also significantly enhanced endothelium-dependent vascular relaxation in response to acetylcholine (ACh) in OVX rats. Finally, femur breaking energies measured for the resveratrol-treated (OVX-Resv) group were significantly higher than those of the resveratrol-untreated (OVX-Cont) group. While no significant differences in calcium, magnesium and phosphorus content were found between the femurs of OVX-Cont and OVX-Resv rats, the femur hydroxyproline content in the OVX-Resv group was significantly higher than of the OVX-Cont group. We conclude that, in OVX-SHRSP, resveratrol acts by a similar mechanism to mammalian estrogens, lowering blood pressure by increasing dilatory responses to ACh. The present study also demonstrated that resveratrol was able to prevent ovariectomy-induced decreases in femoral bone strength.

Animals↗
PubMed2000

Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues.

Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule. The susceptibility of tumors to fluoropyrimidines is reported to correlate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expression levels of these two enzymes in various types of human cancer tissues (241 tissue samples) by the ELISA methods. DPD exists in all the cancer types studied, such as bladder, breast, cervical, colorectal, esophageal, gastric, hepatic, pancreatic, prostate, and renal cancers. Among them, the cervical, hepatic, pancreatic, esophageal, and breast cancer tissues expressed high levels of DPD (median >70 U/mg protein), while high concentrations of the dThdPase were expressed in esophageal, cervical, breast, and pancreatic cancers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenografts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters, the inter-patient DPD variability for each cancer type was much larger than the DPD variability among cancer types; highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD were 10-321, 7-513, and 2-293, respectively. These results indicate that measurements of the three parameters, DPD, dThdPase and dThdPase/DPD, would be useful criteria for selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.

Animals↗
PubMed2000

[Cervical echomyography in cervical dystonia and its application to the monitoring for muscle afferent block (MAB)].

Muscle afferent block (MAB) is an intramuscular injection of 0.5% lidocaine and pure ethanol with a volume ratio of 10:1, introduced as an alternative to botulinum toxin injection for focal dystonia and spasticity. As in the case of botulinum toxin injection, the precise localization of target muscles is crucial to obtain the maximal effect from MAB. For this purpose, we performed ultrasonography of cervical muscles (echomyography) in 20 patients with cervical dystonia (11 men, 9 women; mean age 46.1), with ultrasonograph SSD-5500 (Aloca Co. Ltd., Japan) and a 7.5 MHz linear probe. In untreated subjects, the boundaries of muscles could be easily identified, while they tended to become ambiguous after repeated MAB sessions. At rest, there were involuntary worm-like movements of a specific muscle group observed in all patients. Contrary to our expectation, in all but one patient abnormal contraction was limited only in a part of synergists responsible for the abnormal posture. In normal subjects there was no abnormal contraction at rest, and all the synergists were simultaneously activated by the voluntary neck deviation. Normal subjects could not mimick the pattern of muscle activity in dystonic patients. The echo-guided MAB was performed in 16 patients. We could easily observe the diffusion of lidocaine and ethanol into the targeted muscle, and injected portions of the muscle stopped their activities just after MAB. The effect persisted for 3-4 days in at least 5 out of 10 patients who had follow-up examination. On the other hand, the movement stopped only temporarily after the injection of saline or lidocaine only. In 3 out of 16 patients, some of the uninjected synergists were activated as if to substitute for the treated muscle just after the injection. We conclude that cervical echomyography is useful to investigate the pattern of muscle activity in cervical dystonia and to accurately localize the contracting muscles during MAB.

Adult↗
PubMed1999

Observation of Multi-TeV Gamma Rays from the Crab Nebula using the Tibet Air Shower Array.

The Tibet experiment, operating at Yangbajing (4300 m above sea level), is the lowest energy air shower array, and the new high-density array constructed in 1996 is sensitive to gamma-ray air showers at energies as low as 3 TeV. With this new array, the Crab Nebula was observed in multi-TeV gamma-rays and a signal was detected at the 5.5 sigma level. We also obtained the energy spectrum of gamma-rays in the energy region above 3 TeV which partially overlaps those observed with imaging atmospheric Cerenkov telescopes. The Crab spectrum observed in this energy region can be represented by the power-law fit dJ&parl0;E&parr0;&solm0;dE=&parl0;4.61+/-0.90&parr0;x10-12&parl0;E&solm0;3 TeV&parr0;-2.62+/-0.17 cm-2 s-1 TeV-1. This is the first observation of gamma-ray signals from point sources with a conventional air shower array using scintillation detectors.

Journal Article↗
PubMed1999

Optical monitoring of the neural activity evoked by mechanical stimulation in the earthworm nervous system with a fluorescent dye, FM1-43.

In the central nervous system of the earthworm, sensory and motor neurons have direct synapses on three giant fibers. To determine the locations of synapses and neural network activated by mechanical stimuli, we optically monitored the activity-dependent staining in the earthworm ventral nerve cord with a styryl dye, N-(3-triethylammoniumpropyl)-4- (4-(dibutylamino)styryl)pyridinium dibromide (FM1-43), and a confocal laser scanning microscope. When scratch stimulus was applied to the body wall of the earthworm, bright fluorescent spots with 3-10 microns in diameter localized only in the stimulated segmental ganglion of the ventral nerve cord. The fluorescent intensity of these spots decreased during dye-free high K+ saline incubation. These results suggest that FM1-43 is useful for activity-dependent staining of invertebrate neurons and their synaptic regions as well as vertebrate nervous system.

Animals↗
PubMed1999

Alternative structural state of transferrin. The crystallographic analysis of iron-loaded but domain-opened ovotransferrin N-lobe.

Transferrins bind Fe3+ very tightly in a closed interdomain cleft by the coordination of four protein ligands (Asp60, Tyr92, Tyr191, and His250 in ovotransferrin N-lobe) and of a synergistic anion, physiologically bidentate CO32-. Upon Fe3+ uptake, transferrins undergo a large scale conformational transition: the apo structure with an opening of the interdomain cleft is transformed into the closed holo structure, implying initial Fe3+ binding in the open form. To solve the Fe3+-loaded, domain-opened structure, an ovotransferrin N-lobe crystal that had been grown as the apo form was soaked with Fe3+-nitrilotriacetate, and its structure was solved at 2.1 A resolution. The Fe3+-soaked form showed almost exactly the same overall open structure as the iron-free apo form. The electron density map unequivocally proved the presence of an iron atom with the coordination by the two protein ligands of Tyr92-OH and Tyr191-OH. Other Fe3+ coordination sites are occupied by a nitrilotriacetate anion, which is stabilized through the hydrogen bonds with the peptide NH groups of Ser122, Ala123, and Gly124 and a side chain group of Thr117. There is, however, no clear interaction between the nitrilotriacetate anion and the synergistic anion binding site, Arg121.

Animals↗
PubMed1999

Enhancement of TNF-alpha production by ganglioside GM2 in human mononuclear cell culture.

Some gangliosides have been regarded as autoantigens of immune-mediated neurological disorders such as Guillain-Barré syndrome (GBS), Miller Fisher syndrome and multifocal motor neuropathy. On the other hand, proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), may be important in the pathogenesis of some neuroimmunological disorders. To clarify the interactions between immune cells and gangliosides, we investigated the effects of gangliosides on the production of proinflammatory cytokines in peripheral blood mononuclear cell (PBMC) cultures. We found that ganglioside GM2 markedly enhances the production of TNF-alpha and that TNF-alpha induction by coated GM2 is still more marked. These findings suggest that immune cells, especially monocytes/macrophages, cause inflammation upon encountering GM2.

Cell Adhesion↗
PubMed1999

Clinical efficacy of applying four-field portals to paraaortic irradiation in the treatment of cervical carcinoma.

Paraaortic nodal irradiation (PAI) was thought to be useful in the treatment of cervical cancer, but its clinical application has been limited by a relatively high morbidity. To reduce this morbidity, we routinely applied the four-field technique in PAI. To clarify its efficacy, clinical data were retrospectively analyzed. Ninety-seven patients with cervical cancer, who received a minimum 40 Gy of paraaortic irradiation between 1976 and 1994, were enrolled in the analysis. The patients were prescribed PAI using four-field portals with 10 MV photons (mean 50.4 Gy, range 40-70 Gy). The 5-year cause-specific survival rate was 32.2%. As for sequelae determined using the French-Italian glossary, G1a/G2a of stomach and duodenum developed in 26.8/1.0%, G2b of small bowel in 3.1%, G1b of nonspecific abdominal symptoms and/or signs in 12.4%, and G2 of bone in 3.1%. The operative history group had a slightly larger incidence of gastrointestinal complications than those without operative history, but the difference was not statistically significant. Application of four-field portals in PAI was useful, with acceptably low toxicity and successful compliance for moderate-to-high dose irradiation. This suggests that PAI may greatly contribute to the improvement of the therapeutic outcome of cervical carcinoma.

Adult↗
PubMed1999

Laparoscopic radical nephrectomy for renal cell carcinoma: a five-year experience.

OBJECTIVES: To evaluate the efficacy of laparoscopic radical nephrectomy for patients with small renal cell carcinoma by comparing the clinical results of patients treated laparoscopically with those of patients treated with traditional open radical nephrectomy. METHODS: Of 100 patients with localized, small (less than 5 cm in diameter) renal cell carcinoma treated by the same surgical team between 1992 and 1998, 60 patients underwent laparoscopic radical nephrectomy and 40 underwent open radical nephrectomy. Of the 60 laparoscopically treated patients, the first 11 and the most recent 34 patients were operated on transperitoneally and the other 15 retroperitoneally. RESULTS: The mean operative time of the laparoscopically treated patients was longer than that of the open nephrectomy patients (5.2 versus 3.3 hours, P<0.001). The mean blood loss of the laparoscopically treated patients was less than that of the open nephrectomy patients (255 versus 512 mL, P<0.001). One laparoscopically treated patient needed conversion to open surgery. The time to full convalescence of the laparoscopically treated patients was shorter than that of the open nephrectomy patients (23 versus 57 days, P<0.001). Two of the 59 laparoscopically treated patients and 1 of the 40 open nephrectomy patients had metastatic disease. The former 2 are alive with stable disease and the latter died of progressive disease 11 months after surgery. The 5-year disease-free rate was 95.5% in laparoscopy patients and 97.5% in open nephrectomy patients (P = NS). CONCLUSIONS: Laparoscopic radical nephrectomy is a less invasive alternative to open surgery for patients with localized small renal cell carcinoma.

Adult↗
PubMed1999

Emergence of symbolic behavior from brain like memory with dynamic attention.

An important feature of human intelligence is the use of symbols. This is seen in our daily use of language and logical thinking. However, the use of symbols is not limited to humans. We observe planned action sequences in primate behavior and prediction-based action in higher mammals. For the representation and operation of symbols by the brain neural circuit, no specific construction principle or computational theory is known so far. In this paper, we regard the brain as a complex of associative memory and dynamic attentional system, and starting from two hypotheses on information representation and operation in the brain, we propose a model of primitive symbolic behavior emergence that is consistent with the conventional symbolic processing model. We also describe a computational theory of the symbolic processing model in associative memory. Through computer simulation studies on a language-like memory search and map learning by a moving robot, we discuss the validity of the model.

Journal Article↗
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↗