Nozomu Yoshimura

Identification and Quantitative Determination of Fentanyl Metabolites in Patients by Gas Chromatography-Mass Spectrometry

Although fentanyl has been used widely as a short-acting narcotic analgesic, its metabolism in humans has not been clarified. In this study, three fentanyl metabolites were identified in the urine of eight surgical patients receiving 0.3-0.5 mg of fentanyl intravenously. The metabolites 4-N-(N-propionylanilino)piperidine, 4-N-(N-hydroxypropionylanilino)piperidine and 1-(2-phenethyl)-4-N-(N-hydroxypropionylanilino)piperidine, and unchanged fentanyl were identified by GC-mass spectrometry in urine collected 6 h after administration. Fentanyl and its main metabolite, 4-N-(N-propionylanilino)piperidine, were determined quantitatively in the urine of five additional patients receiving 0.5 mg fentanyl intravenously. Urinary excretion of fentanyl and 4-N-(N-propionylanilino)-piperidine during the first 12 h after injection accounted for 0.3-4.0% and 26 to 55% of the dose, respectively.

The effects of vasopressin on endotoxin-induced attenuation of contractile responses in human gastroepiploic arteries in vitro

UNLABELLED We studied the effects of vasopressin on contraction in normal and endotoxin-treated human gastroepiploic arterial rings in vitro. In this tissue, vasopressin (50-500 pg/mL) produced concentration-dependent, endothelium-independent contractions. Vasopressin also potentiated the contraction elicited by 1.0 micromol/L norepinephrine (NE) in both the presence and absence of endothelium. Endotoxin (10 microg/mL) attenuated the 1.0 micromol/L NE-induced contractions, and this attenuation was reversed by 300 micromol/L N(G)-nitro-L-arginine-methyl ester (L-NAME) and by 300 micromol/L N(G)-nitro-L-arginine (L-NoArg). After 12 h endotoxin treatment, the vasopressin-induced contraction was attenuated, and the enhancing effect of vasopressin was diminished. However, both before and after endotoxin, the enhancement produced by vasopressin was larger than the vasopressin-contraction itself. An antagonist of the vasopressin V1 receptor, 1.0 micromol/L beta-mercapto-[beta,beta-cyclopentamethylenpropionyl1,O-MeTyr2+ ++,Arg8]-vasopressin, and an antagonist of V1 + V2 receptor receptor, 1.0 micromol/L des-Gly9-[beta-mercapto-beta,beta-cyclopentamethylenepropionyl1 ,O-Et-Tyr2,Val,Arg8]-vasopressin, each diminished the vasopressin-induced enhancement of the NE contraction. IMPLICATIONS The results of our study suggest that, in addition to its direct vasoconstrictor effect, vasopressin strongly enhances the responses to norepinephrine through V1-receptor stimulation and that vasopressin could find a role in the management of endotoxin-induced vasodilation.

The effects of sevoflurane anesthesia on insulin secretion and glucose metabolism in pigs.

We investigated the effects of two different concentrations of sevoflurane, 0.4 minimum alveolar anesthetic concentration (MAC) and 1.0 MAC, on insulin secretion before, during, and after sevoflurane anesthesia using three successive intravenous glucose tolerance tests (IVGTT) in pigs with indwelling catheters. We also investigated changes in the levels of plasma glucose, catecholamines (epinephrine [E], norepinephrine [NE]), and cortisol (Cor). The pigs were grouped as awake, 0.4 MAC, or 1.0 MAC. Sevoflurane decreased the ratio of insulin/glucose (INS/GLU) in the basal condition (P < 0.05 awake versus 1.0 MAC) and during IVGTT (P < 0.01 awake versus 1.0 MAC and 0.4 MAC). These decreases were quickly reversible (control levels were regained within 2 h of the end of anesthesia), were probably dose-related, appeared not to be mediated by E, NE, or Cor. In addition, the INS/GLU ratio 2.5-4 h after the end of anesthesia was significantly higher in the anesthetized groups than in the awake group. We conclude that sevoflurane anesthesia has a rapidly reversible inhibitory effect on basal and glucose-stimulated insulin secretion, as do other inhaled anesthetics, and might induce insulin resistance. (Anesth Analg 1997;84:1359-65)

Does the redox state of cytochrome aa3 reflect brain energy level during hypoxia? Simultaneous measurements by near infrared spectrophotometry and 31P nuclear magnetic resonance spectroscopy.

We studied cerebral oxygen metabolism during hypoxia to demonstrate whether the redox state of cytochrome aa3 (cyt.aa3), as measured by near infrared spectrophotometry (NIRS), reflects brain energy level. Rats (n = 6) subjected to hypoxia were simultaneously monitored by NIRS and31 P nuclear magnetic resonance spectroscopy (NMRS). Brain function was evaluated using the electroencephalogram (EEG). After a reduction of the fraction of inspired oxygen (FIO2) from 0.21 to 0.15, we observed a significant increase in reduced cyt.aa3 (from 16.5% +/- 2.1% to 41.2% +/- 2.8%; P < 0.01), without significant changes in phosphocreatine (PCr) and beta-adenosine triphosphate (beta-ATP) levels. The PCr decreased significantly at a FIO2 of 0.10 (53.8% +/- 6.4% as compared with 97.7% +/- 10.9% at a FIO (2) of 0.21; P < 0.05), and reached a minimum at a FIO2 of 0.04. beta-ATP did not change significantly at a FIO2 of 0.10 or 0.08. With a FIO2 of less than 0.08, cyt.aa3 was almost totally reduced. EEG activity slowed at a FIO2 of 0.08 and became isoelectric at 0.04. Significant correlations were found between the levels of cyt.aa3 and PCr (P < 0.001, r = 0.83) as well as between cyt.aa3 and beta-ATP (P < 0.001, r = 0.73) by using the overall values at FIO (2) levels from 0 to 1.0. However, no significant correlations were observed among these variables when the FIO2 was less than 0.10. These findings suggest that the increase in reduced cyt.aa3 reflects brain energy depletion; however, the redox state of cyt.aa3 will not indicate brain energy depletion during extreme hypoxia because cyt.aa3 is reduced totally during hypoxia insufficient to deplete intracellular ATP. (Anesth Analg 1996;83:513-8)

Effects of midazolam on contractions in smooth muscle of the rabbit mesenteric artery

We investigated the undetermined effects of midazolam on agonist-induced contraction in vascular smooth muscle strips from the rabbit mesenteric resistance artery. Midazolam, in concentrations more than 10 micro M, attenuated norepinephrine ([NE] 0.3-10 micro M)-induced contractions in Krebs solution. The attenuating effect was more potent on the tonic and oscillatory responses than on the rapid phasic response. When voltage-operated Ca2+ channels (VOC) were blocked by nifedipine, midazolam, in concentrations more than 1 micro M, attenuated both phasic and tonic responses. In Ca2+-free solution, midazolam, in concentrations more than 1 micro M, attenuated NE-induced contractions, but not caffeine-induced contractions. When NE and caffeine were applied successively, midazolam attenuated NE-induced contractions, but enhanced caffeine-induced contractions. Because the attenuating effect of midazolam on NE-induced contractions in high K+, Ca2+-free solution were not different from the effect in normal Ca2+-free solution, the attenuating effects of midazolam could not have been induced via membrane hyperpolarization. These results indicate that midazolam attenuated the agonist-induced contractions by inhibition of Ca2+ influx occurring not only through VOC, but also through agonist-mediated Ca2+ channels and by the inhibition of Ca2+ release from intracellular store sites. (Anesth Analg 1997;84:199-205)

Anesthetic considerations in myelopathy associated with human T-cell lymphotropic virus type I (HTLV-I-associated myelopathy:HAM)

H uman T-cell lymphotropic virus type I (HTLV@associated myelopathy (HAM) is a rare neurogenic disease. Patients with this disease exhibit spasticity and muscle weakness in the lower extremities, urinary bladder disturbance, and sensory disturbances (1,2). Since HAM patients have high antibody titers to HTLV-I in serum and cerebrospinal fluid, HTLV-I is thought to be the causative agent (3). Recently, many clinical signs of the involvement of structures outside the central nervous system have been described in patients with HAM, arthropathy being an example of such an HTLV-I-associated disorder (4). Since HAM is a neuromuscular disease possibly induced by blood-to-blood viral transmission, care must be taken in the use of muscle relaxants and in prevention of infection. We describe a patient with HAM who underwent knee arthroscopy under general anesthesia quite uneventfully and discuss the conduct of anesthesia and surgery on patients with HAM.