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.

Evaluation of indicators of tissue hypoxia during progressive hemorrhage and blood retransfusion.

To establish whether the indicators of oxygen metabolism reflects the improvement in tissue oxygenation during therapy, twelve rabbits subjected to progressive hemorrhage followed by retransfusion were studied. The changes in oxygen delivery (DO2), oxygen consumption (QO2), oxygen extraction ratio (O2ER), arterial lactate concentration, venous-arterial difference in PcO2 (v-aDPcO2) and arterio-venous difference in pH (a-vDpH) were analyzed during two phases (above and below) the critical DO2 with the regression coefficient (slope). The main findings during the transfusion were: a) the slope, when compared during the two phases was not significantly different for O2ER, v-aDPcO2 or a-vDpH, while during hemorrhage each variable showed a significantly different slope, b) in the phase below the critical DO2, the slope was significantly less steep than that during hemorrhage for lactate and v-aDPcO2, c) in the phase above the critical DO2, lactate alone had significantly steeper slope than that during hemorrhage. In conclusion, it is suggested that the changes in QO2 best reflect the recovery from tissue hypoxia.

[Enzyme saturation of sevoflurane in piglets at clinically-used concentrations].

To investigate if sevoflurane saturates the metabolic capacity of the enzymes responsible for sevoflurane at clinically-used concentration ranges, we compared plasma fluoride levels and urinary excretion of inorganic fluoride in piglets after (1) low concentration sevoflurane anesthesia versus (2) high concentration sevoflurane anesthesia. Eleven male piglets, weighing 18-23.5 kg, were randomly divided into two groups: 1) L group: five animals were anesthetized for two hours with sevoflurane at 0.8% end-tidal concentration (0.4 MAC); 2) H group: six animals were anesthetized for two hours with sevoflurane at 3.0% end-tidal concentration (1.4 MAC). Plasma inorganic fluoride levels, blood sevoflurane concentration, urinary inorganic fluoride concentration and urine volume were measured. The blood sevoflurance concentration in both groups reached their plateau levels 30 min after the start of anesthesia. The plateau levels in the H and L groups were 275-306 microM and 105-115 microM, respectively. The plasma fluoride concentrations reached plateau levels 60 min after the start of anesthesia in both groups. The H group showed significantly higher plasma fluoride levels than the L group during sevoflurane anesthesia. The H group also showed significantly higher urinary excretion of inorganic fluoride than the L group. Therefore, metabolite production levels in the H group were significantly higher than the L group. These results suggest that low concentration sevoflurane anesthesia did not saturate the metabolic capacity of the enzymes responsible for defluorination of sevoflurane in piglets.

[Effects of allopurinol on renal damage following renal ischemia].

We investigated the effects of allopurinol on renal damage following renal ischemia. Male Wistar rats weighing 250-300 g were classified into enflurane and allopurinol groups and anesthetized for 5 minutes using 1.7 MAC of enflurane in 30% oxygen. Then the left renal artery was dissected and clamped. Arterial occlusion was performed under 1.3 MAC enflurane for 30 minutes. Anesthesia was maintained for an additional 90 minutes after releasing the clip. In the allopurinol group, the rats were administered with allopurinol 3 mg.kg-1 intravenously prior to renal ischemia. At the end of anesthesia and 24 hours after the discontinuation of anesthesia, the necrotic areas, kidney weight/body weight ratios, gamma-GTP and NAG activities of the kidney which had been clamped were examined. Urinary gamma-GTP and NAG activities and serum inorganic fluoride concentrations were also measured. The necrotic area was significantly smaller in the allopurinol group than in the enflurane group. The activity of gamma-GTP in the kidney was higher in the allopurinol group than in the enflurane group. The kidney weight/body weight ratio was lower in the allopurinol group than in the enflurane group. There was no difference in serum inorganic fluoride concentration between the allopurinol and enflurane groups. These results suggest that allopurinol decreases renal damage following renal ischemia under enflurane anesthesia.

The effects of inhalational anesthetics on ischemic injury of rat kidney with renovascular occlusion.

The effects of halogenated inhalational anesthetics, viz. halothane, enflurane, isoflurane and sevoflurane, on ischemic rat kidneys were studied through the response of renal gamma-glutamyl transpeptidase in the brush border of proximal tubules to monoclonal antibodies. Brush border staining characteristics were evaluated as follows: a) continuous (normal), b) discontinuous (damaged) and c) indistinct (necrotic). The isoflurane group had significantly fewer damaged and/or necrotic proximal tubules compared to the other groups. These results suggest that isoflurane is the most appropriate inhalational anesthetic when renal circulation is impaired.

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.

[Clinical studies of ifosfamide for gynecological malignancies].

This study was performed to evaluate the clinical effect and the side effect of ifosfamide in the treatment of gynecological malignancies. A total of 18 cases were treated with ifosfamide: 11 of them were treated as a single agent and the remaining 7 cases were treated as a combination chemotherapy. A daily dose of 1.5-2.0 grams were given for 5 consecutive days. The number of course varied from one to five. Six (35.3%) out of 17 evaluable cases showed partial response. Three were treated with ifosfamide alone and the another three were with a combination chemotherapy. The side effect such as leukopenia, gastrointestinal disturbance and general malaise were frequently observed. Chemical cystitis (hematuria) could be prevented by adequate water intake.

Antishock effect of gabexate mesilate (FOY).

The antishock effects of gabexate mesilate (FOY) were investigated in rats subjected to hemorrhagic hypotension, with particular attention focused on the stabilizing effects of hepatic lysosomes. The survival time of rats treated with FOY, infused for 2 hours intravenously at a rate of 50 mg/kg/hr, was significantly prolonged, accompanied by a tendency to decreased activity of plasma lysosomal enzymes. FOY, at a concentration of 10(-3) M, exerted a significant decrease in the extralysosomal release of acid phosphatase (15%, P less than 0.05), beta-glucuronidase (25%, P less than 0.05) and cathepsin D (25%, P less than 0.02) following hyposmotic labilization of lysosomes. Although the release of lysosomal enzymes might be counterbalanced by 50 mg/kg/hr of FOY, favorable cytochemical findings indicating stabilization of lysosomal membranes were consistently observed. The data suggest that FOY has antishock properties, and that these properties are caused, at least partially, by the stabilization of lysosomes.

[Experimental studies on thermochemotherapy].

The combination effect of heat and anti-cancer drugs were studied by following the proliferation of cancer cells from a uterine cervix (OG cells). In animal experiment, tumor bearing mice were injected 5 microCi 14C-5FU, local hyperthermia was created in hot water baths of 37 degrees C, 43 degrees C and 45 degrees C for 30 minutes. At timed intervals, tissue was taken from the tumor and radioactivity was measured. The results were as follows: In vitro. The critical temperature for proliferation was between 40 degrees C and 41 degrees C with continuous heating. At 60 minutes of heating was between 45 degrees C and 46 degrees C. The simultaneous use of heat and anti-cancer drugs that inhibit cell proliferation was effective for Bleomycin, Cis-plantinum and Ifosfamide but not effective for Mitomycin and Adriamycin. In vivo. Immediately after the hyperthermia, the uptake of 14C-5FU within the tumor in the 37 degrees C group was (229 +/- 29) X 10dpm/g. The 43 degrees C group (1.47 times) and the 45 degrees C group (1.37 times) were significantly higher than this. Even 60 minutes after the hyperthermia, the heat-treated groups maintained levels 1.7-2. 0 times higher. The uptake within the tumor was better in the 43 degrees C group than 45 degrees C group.