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Unlabelled: We tested the hypotheses that the primary mechanism of action of epidural fentanyl after cesarean delivery is spinal and that very small dose epidural bupivacaine with epinephrine enhances this effect. After elective cesarean delivery, 100 parturients were randomized in a double-blinded design to four groups. Group I and II patients received a continuous 12 mL/h epidural infusion of bupivacaine 0.015% with epinephrine 1 microg/mL for 48 h and Groups III and IV received a 12 mL/h saline epidural infusion instead. Fentanyl 20 microg/mL was administered via a patient-controlled analgesia device either into the epidural infusion (Groups I and IV) or IV (Groups II and III). When compared to patients receiving epidural fentanyl, those receiving IV fentanyl required larger mean infused and total dose of fentanyl (P < 0.0001), reported more pain (P < 0.001), and had a more frequent incidence of excessive sedation (P < 0.01), nausea (P < 0.01), and vomiting (P < 0.01). Plasma concentrations of fentanyl were larger for Group II and III than for Groups I and IV (P < 0.001) at 24 and 48 h. Our results support the hypothesis that the primary mechanism of analgesia of epidural fentanyl after cesarean delivery is spinal. Our data also show that the total required dose of epidural, but not IV, fentanyl is reduced by very small dose epidural bupivacaine and epinephrine (Group I versus Group IV, P < 0.02 and Group II vs Group III, not significant)., Implications: Fentanyl administered epidurally to parturients after cesarean delivery has a primarily spinal mechanism of action and this effect is enhanced by very small dose epidural bupivacaine and epinephrine.

Background: The aim of this investigation was to determine whether chronic cocaine administration altered endogenous vasoconstrictor secretion in response to hypotension from isoflurane anesthesia and blood loss in rats., Methods: Rats received continuous intravenous infusions of saline (n=11), or cocaine 6 mg kg(-1) d(-1) (n=13) or 18 mg kg(-1) d(-1) (n=12) for 13 days. On day 14, rats were anesthetized with intraperitoneal ketamine and xylazine and a femoral artery catheter and a tracheotomy performed to allow lung ventilation (PaCO2, 30-40 mmHg). After baseline parameters were noted, isoflurane was introduced to end-tidal concentrations of 0.7% for 10 min (1/2 MAC), 1.4% for 10 min (MAC) and again 0.7% for 10 min (1/2 MAC-2) when 5 ml of blood was withdrawn (SHOCK). Blood samples were drawn to assess arterial blood gas indices at various time points as well as plasma epinephrine, angiotensin II and vasopressin at MAC, 1/2 MAC-2 and SHOCK., Results: Rats administered cocaine had higher oxygen extraction, required higher minute ventilation and had lower PaO2 values than rats administered saline despite similar body temperatures and hematocrits. Isoflurane administration resulted in significant dose dependent but similar blood pressure decreases in all study groups. Plasma epinephrine, angiotensin II and vasopressin concentrations were not different in saline or cocaine treated animals at any time point., Conclusion: These data suggest that chronic cocaine treatment in rats does not impair endogenous vasoconstrictor secretion nor alter the heart rate and blood pressure response to isoflurane and blood loss.

An improved method for the simultaneous determination of cocaine and its metabolites, benzoylecgonine (BE), norcocaine, and ecgoninemethylester (EME), in rat plasma and urine is described. Following derivatization of EME to p-fluorococaine, chromatography was performed on two high-performance liquid chromatography (HPLC) columns in series (5-microm spheric C8 and 5-microm cyanopropyl) using a mobile phase containing acetonitrile/HPLC water/trifluoroacetic acid (28:72:0.1) with bupivacaine as an internal standard. Quantitation limits were 25 ng/mL for cocaine, BE, and norcocaine and 50 ng/mL for EME using 300-500 microL rat plasma and 500 microL of rat urine. The assay was linear from the limit of quantitation to 2000 ng/mL for cocaine and its metabolites in both plasma and urine samples. Because this method uses a small amount of sample (300 microL plasma or 500 microL of urine), it is applicable to study of the pharmacokinetics and disposition of cocaine and its major metabolites.

Background: The authors studied the addition of bupivacaine and epinephrine, separately and together, to epidural fentanyl to determine whether this improved postcesarean analgesia and reduced the incidence of side effects., Methods: After elective cesarean section, 100 parturient patients who received fentanyl (3 microg/ml) epidurally for 48 h were allocated randomly in a double-blinded manner to four groups to receive, in addition to the study solution, 0.01% bupivacaine, 0.5 microg/ml epinephrine, both, or neither. A neurologic assessment of breast-fed neonates was made at 2 and 48 h of life. Plasma fentanyl concentrations were determined in a subset of patients at intervals after treatment., Results: Patients receiving fentanyl alone made more attempts at patient-controlled analgesia (P < 0.01), required a greater total dose of fentanyl (P < 0.01), reported more pain (P < 0.003) and less satisfaction (P < 0.003), and had more nausea and urinary retention (P < 0.05) than all other groups. Patients who received bupivacaine with or without epinephrine had better overall satisfaction scores than those who did not receive bupivacaine (P < 0.001), and they required less fentanyl (P < 0.02) than patients who received fentanyl with only epinephrine. Motor blockade or orthostatic hypotension did not develop in any patient, and all patients could ambulate without difficulty. Neurobehavioral scores, which were similar among all neonates, were within the normal range. Plasma concentrations of fentanyl increased after epinephrine-containing solutions were discontinued., Conclusions: During the conditions of this study, the addition of epinephrine and bupivacaine to a 3-microg/ml epidural fentanyl solution for postcesarean section pain relief provided superior analgesia compared with fentanyl alone or fentanyl with epinephrine. Whether increasing the concentration of fentanyl alone might improve the efficacy of fentanyl remains unclear.

Unlabelled: BACKGROUND. Changes in the sympathetic nervous system may be a cause of postoperative cardiovascular complications. The authors hypothesized that changes in both beta-adrenergic receptor (betaAR) function (as assessed in lymphocytes) and in sympathetic activity (assessed by plasma catecholamines and by heart rate variability [HRV] measurements obtained from Holter recordings) occur after operation., Methods: The HRV parameters were measured in 28 patients having thoracotomy (n = 14) or laparotomy (n = 14) before and for as long as 6 days after operation. Transthoracic echocardiography was performed before and on postoperative day 2. Lymphocytes were also isolated from blood obtained before anesthesia and again on postoperative days 1, 2, 3, and 5 (or 6). They were used to examine betaAR number (Bmax) and cyclic adenosine monophosphate (cAMP) production after stimulation with isoproterenol and prostaglandin E1. In addition, plasma epinephrine, norepinephrine, and cortisol concentrations were determined at similar intervals., Results: After abdominal and thoracic surgery, most time and all frequency indices of HRV decreased significantly, as did Bmax and basal and isoproterenol-stimulated cAMP production. The decrements in HRV correlated with those of Bmax and isoproterenol-stimulated cAMP throughout the first postoperative week and inversely correlated with the increase in heart rate. Plasma catecholamine concentrations did not change significantly from baseline values, but plasma cortisol levels did increase after operation in both groups. Left ventricular ejection fraction was normal in both groups and unaffected by surgery., Conclusions: Persistent downregulation and desensitization of the lymphocyte betaAR/adenylyl cyclase system correlated with decrements in time and frequency domain indices of HRV throughout the first week after major abdominal or thoracic surgery. These physiologic alterations suggest the continued presence of adaptive autonomic regulatory mechanisms and may explain why the at-risk period after major surgery appears to be about 1 week or more.

Objective: Our goal was to ascertain whether alterations in beta- and alpha-adrenergic receptor number and function (cyclic adenosine monophosphate production) occur during and after pregnancy. Because the actions of beta- and alpha2-adrenergic receptors tend to oppose each other, we hypothesized that there might be progressive, possibly reciprocal changes in these receptors during and after pregnancy., Study Design: Blood was obtained from 21 women at 10, 20, 30, and 37 weeks of pregnancy and 3 to 4 months post partum. Lymphocyte beta- and platelet alpha2-adrenergic receptor number and affinity were quantified by radioligand binding studies, and receptor function was assessed by cyclic adenosine monophosphate generation assays., Results: Although there were suggestions of progressive alterations in some of the variables studied, beta- and alpha2-adrenergic receptor number, affinity, and function did not manifest any statistically significant changes., Conclusion: Pregnancy did not produce marked alterations in beta-adrenergic receptor or alpha2-adrenergic receptor properties.

Objective: To examine intraoperative and postoperative lymphocyte adenylyl cyclase activities in children undergoing repair of congenital cardiac defects with hypothermic cardiopulmonary bypass., Design: A prospective study., Setting: Tertiary university pediatric hospital., Patients: Twelve children were enrolled into the study to examine intraoperative lymphocyte adenylyl cyclase activities and 12 children were enrolled to examine postoperative lymphocyte adenylyl cyclase activities., Interventions: None., Measurements and Main Results: Basal (unstimulated), isoproterenol, and prostaglandin E-1 stimulated adenylyl cyclase activities, and plasma norepinephrine and epinephrine concentrations were measured. Intraoperative basal (unstimulated), beta-adrenergic receptor-stimulated (in response to isoproterenol), and prostaglandin E1 (PGE1)-stimulated lymphocyte adenylyl cyclase activities all increased during cardiopulmonary bypass, then decreased immediately after cardiopulmonary bypass. In the postoperative group, a significant decrease in basal (unstimulated), beta-adrenergic receptor- and PGE1-stimulated adenylyl cyclase activities were observed on postoperative day 1 as compared with precardiopulmonary bypass values., Conclusions: In the pediatric cardiac surgical patient, there was an intraoperative enhancement of lymphocyte adenylyl cyclase activities. This increase in adenylyl cyclase activities was followed by reduced lymphocyte adenylyl cyclase activities, including beta-adrenergic receptor desensitization, postoperatively, as we have previously documented in adults.

We studied the perioperative regulation of the beta-adrenergic receptor (beta AR) system in lymphocytes obtained before and after surgery from 12 patients undergoing cesarean delivery with spinal anesthesia. Receptor number (Bmax) and binding affinity (KD) were determined by Scatchard analysis of [125I]iodopindolol saturation binding curves. Receptor function was assessed by measuring cyclic adenosine 3',5'-monophosphate (cAMP) production in the unstimulated state and in response to stimulation by isoproterenol, forskolin, and prostaglandin E1. Basal cAMP production increased 48% postoperatively (P < 0.05), while stimulated cAMP production and Bmax and KD were not significantly changed after surgery. The response to surgery of the beta AR system on these patients differed from that of patients undergoing cardiothoracic and abdominal surgery in whom we previously found postoperative down-regulation and desensitization of the beta AR system. It is possible that this difference in response is due to amelioration of the stress response to surgery by regional anesthesia, and/or alterations in beta AR status by pregnancy. We conclude that pregnancy and regional anesthesia, but not changes in lymphocyte subset distribution, contributed to the lack of effect of surgery on the beta AR system in the patients studied.

Purpose: The highly lipid soluble opioids, fentanyl and sufentanil, are used in combination with local anaesthetics with/without epinephrine to provide epidural analgesia during labour and delivery. Our aim was to determine whether wither opioid was superior when used with low dose local anaesthetic., Methods: In a double-blind study patients were randomized to two epidural infusion groups: Group I (n = 50) fentanyl 2 micrograms.ml-1 with bupivacaine 0.015% and epinephrine 2 micrograms.ml-1, Group II(n = 50) sufentanil 1 microgram.ml-1 with bupivacaine 0.015% and epinephrine 2 micrograms.ml-1. Following a 20 ml bolus of the study solution an infusion was started at 10 ml.h-1. To achieve analgesia patients could receive two boluses of 5 ml of the study solution and if analgesia was still inadequate, a further 5 ml bupivacaine 0.25% was used. Pain and overall satisfaction were assessed with a 10-point visual scale. Plasma samples obtained from the mother at the time the infusion was discontinued and from the umbilical cord vein at delivery were assayed to determine opioid concentration., Results: Pain scores were greater for Group I than for Group II patients throughout the first and second stages of labour (P = 0.002). More patients in Group I (42%) requested a dose of bupivacaine 0.25% than in Group II (6%) (P < 0.001) and the total dose of bupivacaine given to Group I patients was greater than that of Group II, 26.0 +/- 22.0 mg vs. 13.4 +/- 12.6 mg, P = 0.005. There were no differences with respect to first or second stage duration, incidence of side effects, infusion duration, outcome of labour or neonatal Apgar scores. There was no opioid accumulation in either maternal or foetal blood., Conclusion: Epidural opioid infusion with very low dose bupivacaine (0.015%) achieved an overall high level of patient satisfaction in both groups without serious maternal or neonatal side effects. At the fentanyl-to-sufentanil ratio used here patients receiving sufentanil had lower pain scores and substantially fewer patients required bupivacaine rescue.

We studied perioperative regulation of the beta-adrenergic receptor (beta AR) in lymphocytes obtained from 12 patients undergoing noncardiac thoracic surgery and 12 patients undergoing abdominal surgery. beta AR number (Bmax) and dissociation constant (KD) were determined from [125I]iodopindolol saturation binding curves. Function of the beta AR/adenylyl cyclase system was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol (ISO) and prostaglandin E1 (PGE1). In thoracic surgery patients, basal and ISO-stimulated cAMP production were significantly decreased postoperatively, by 44% and 45%, respectively, with no change in PGE1-stimulated cAMP. Bmax decreased from 1369 +/- 138 (mean +/- SE) sites/cell to 891 +/- 82 sites/cell postoperatively, while the KD increased from 26.7 +/- 5.6 pM to 37.8 +/- 5.1 pM. In the abdominal surgery patients, there were no significant alterations in cAMP production, but Bmax decreased, from 1235 +/- 146 sites/cell preoperatively to 888 +/- 65 sites/cell postoperatively, while the KD increased from 18.8 +/- 3.6 pM to 58.1 +/- 12.5 pM. The beta AR and its associated effector system are altered during the perioperative period of abdominal and thoracic surgery.

We used the beta-adrenergic receptor (beta AR) system of human lymphocytes as a model to examine perioperative adrenergic regulation in 12 patients undergoing coronary artery bypass grafting and 12 patients undergoing mitral or aortic valve replacement. beta AR function was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol and prostaglandin E1. Receptor number and dissociation constant (KD) were assessed with [125I]iodopindolol. In the valve surgery patients, basal, isoproterenol-stimulated, and prostaglandin E1-stimulated cAMP production were significantly decreased postoperatively, by 39%, 55%, and 24%, respectively. beta AR number decreased from a mean of 1333 +/- 143 sites/cell to 897 +/- 56 sites/cell postoperatively, whereas the KD increased from 12.9 +/- 1.1 pM to 37.0 +/- 7.3 pM. In the coronary artery bypass graft patients, there were no significant alterations in cAMP production or receptor number, but the KD increased from 19.8 +/- 2.9 pM to 57.5 +/- 11.8 pM. These findings suggest that cardiac surgery and/or cardiopulmonary bypass may result in significant down-regulation and desensitization of the beta AR system of lymphocytes, which may parallel alterations in other organ systems.

Background: The highly lipid-soluble opioids, fentanyl and sufentanil, frequently are used in combination with local anesthetic agents and/or epinephrine to provide postoperative epidural analgesia. The authors compared the incidence of side effects and patient satisfaction during prolonged epidural patient-controlled analgesia (PCA) infusions of these opioids in combination with bupivacaine and epinephrine., Methods: Using a double-blind study design, 250 patients scheduled for elective cesarean delivery were, on arrival in the postanesthesia care unit, randomized into two epidural PCA infusion groups: group I (n = 125) received fentanyl 2 micrograms/ml with bupivacaine 0.01% and epinephrine 0.5 micrograms/ml and group II (n = 125) received sufentanil 0.8 micrograms/ml with bupivacaine 0.01% and epinephrine 0.5 microgram/ml. The initial infusion rate was 16 ml/h with self-administered 3-ml boluses every 15 min by PCA as desired. At intervals after discontinuation of the infusion, plasma samples were obtained to determine opioid concentrations., Results: The median overall satisfaction scores were 9.0 for group I and 10.0 for group II (difference not significant). Pain relief was satisfactory and comparable in both groups, and all patients could ambulate easily. The total number of times PCA requests were made was greater (P < 0.05, by Wilcoxon rank-sum test) for group I than for group II (106.7 +/- 312 vs. 70.8 +/- 138). There were no differences between the groups with respect to incidence of pruritus, sedation, and nausea; however, vomiting occurred more frequently with sufentanil than with fentanyl (12% vs. 4.8%, respectively; P < 0.05). At approximately 1-2 h after discontinuation of the infusion, 1 patient receiving fentanyl and 42 patients receiving sufentanil complained of lightheadedness and dizziness (P < 0.0001)., Conclusions: Epidural PCA in both groups had no serious side effects and achieved a high level of patient satisfaction. Those receiving sufentanil made fewer PCA requests but had a significantly greater incidence of vomiting during the infusion and dizziness after the termination of the infusion. Epidural sufentanil offered no advantages over epidural fentanyl.

The effect of red ginseng extract on the disposition of ethanol was studied in male Fischer 344 rats. Blood was drawn from the tail vein before and at 0.5, 1, 2, 3, 4, and 5 hours after dosing rats orally with aqueous ginseng (200 mg/kg), or an equivalent volume of water, followed immediately by 50% ethanol orally (3.2 g/kg) or intraperitoneally (1.5 g/kg). When the ethanol was administered orally, the mean area under the plasma concentration-time curve (0-->5 h) of ethanol was 21.0% less in the ginseng-treated rats than in the control rats. When the ethanol was administered intraperitoneally, there was no significant difference between ginseng-treated and control rats in area under the plasma concentration-time curve. The results show that plasma levels of ethanol are lower when the ethanol is administered orally with ginseng than when it is administered alone, but that orally administered ginseng has no effect on plasma levels of ethanol administered intraperitoneally.

To develop a regimen that would provide good analgesia after cesarean section with minimal side effects in the setting of prolonged (> 24 h) epidural infusion, buprenorphine or fentanyl was combined with 0.03% bupivacaine in a double-blind study of 23 parturients. Patients were randomly assigned to two groups: group I (n = 12), patient-controlled analgesia by epidural infusion of buprenorphine (3 micrograms/mL) with 0.03% bupivacaine; group II (n = 11), patient-controlled analgesia by epidural infusion of fentanyl (2 micrograms/mL) with 0.03% bupivacaine. Plasma for determination of opioid concentrations was obtained at intermittent intervals. Pain relief was similar and satisfactory in both groups. The median overall satisfaction score was higher (10.0 vs 7.5; P < 0.03) for group II. Pruritus was mild in most patients. Nausea and vomiting, which were most disturbing to the patients, were seen only with buprenorphine. No patient had a respiratory rate of < 12 breaths/min. Mean plasma opioid concentrations did not exceed 1 ng/mL during the study. However, four patients (33%) in group I and six patients (55%) in group II experienced sensory loss in the lower extremities, which made ambulation difficult. One patient in each group developed extensive pressure blisters on both heels. These complications led us to terminate the study. We conclude that 0.03% bupivacaine used in combination with an opioid in prolonged epidural infusions produces a high incidence of sensory loss in the lower extremities and is unsuitable for situations in which early ambulation is desired.

We compared the analgesia, side effects, and plasma concentrations of buprenorphine and fentanyl in a double-blind study of 78 parturients receiving one of these drugs by patient-controlled epidural infusion after elective cesarean section with epidural anesthesia. Patients were randomized to three epidural infusion groups: group 1 (n = 26), 3 micrograms/mL buprenorphine with 0.015% bupivacaine and 1 microgram/mL epinephrine; group 2 (n = 26), 3 micrograms/mL fentanyl with 0.015% bupivacaine and 1 microgram/mL epinephrine; and group 3 (n = 26), 3 micrograms/mL fentanyl with 0.015% bupivacaine. Plasma for determination of opioid concentrations was obtained in some subjects in each group at intervals up to 48 h during the infusion and in some subjects from each group at intervals after the infusion was stopped. Pain relief was similar and satisfactory in all three groups. The median overall satisfaction scores were high for all three groups. Pruritus was more common in the fentanyl groups (P less than 0.05). However, vomiting was more disturbing to the patients and seen only with buprenorphine. No patient had a respiratory rate less than 12 breaths/min. Epinephrine use was associated with a slower infusion rate (P less than 0.05, group 2 vs 3). All patients were able to ambulate without difficulty. Mean opioid plasma concentrations did not exceed 1.5 ng/mL. Thus, epidural patient-controlled analgesia in all three groups provided excellent analgesia, permitted ambulation, and was without serious side effects. Epidural buprenorphine offered no advantages over epidural fentanyl.

The metabolism of isoflurane and the investigational volatile anaesthetic desflurane to fluoride ion was examined in 25 surgical patients. The patients were randomly assigned to four groups, to receive isoflurane or desflurane at either 0.65 MAC or 1.25 MAC. Anaesthesia was induced in all patients with thiopentone and midazolam and included nitrous oxide 60% in addition to the volatile agent. Blood was drawn before induction and at the end of the operation for determination of serum fluoride ion concentration. Plasma fluoride ion concentrations increased (+ 1.36 +/- 0.93 microM, P less than 0.01) in patients receiving isoflurane but were unchanged (-0.13 +/- 0.50 microM) in patients receiving desflurane. Metabolic release of fluoride ion is less with desflurane than with isoflurane during administration of the anaesthetics to surgical patients, and is unlikely to be of clinical significance.

Eight healthy subjects were fed a high-protein-low-carbohydrate diet and, after a 3-day washout period, an isocaloric low-protein-high-carbohydrate diet. They received acetaminophen and oxazepam, drugs metabolized primarily by conjugation, on days 11 and 13, respectively, of each diet. Changing the diets of subjects from the high-protein-low-carbohydrate diet to the low-protein-high-carbohydrate diet resulted in a 14% increase in urinary recovery of acetaminophen glucuronide and a 32% increase in urinary recovery of oxazepam glucuronide (p less than 0.05). The increases in glucuronidation were at the expense of other pathways of metabolism, and there were no significant changes in the metabolic clearance rates of acetaminophen and oxazepam. Mean renal clearances of acetaminophen glucuronide, acetaminophen sulfate, and oxazepam glucuronide decreased 45%, 32%, and 54%, respectively (p less than 0.05), when the subjects were switched to the low-protein-high-carbohydrate diet.

The present work tests the hypothesis that high fat/low carbohydrate diets elevate the level of liver microsomal cytochrome P450IIE1. Male Sprague-Dawley rats were fed liquid diets containing varied ratios of corn oil/carbohydrate for 4 d. Rats fed diets with higher fat/carbohydrate ratios produced higher serum acetone levels and higher hepatic microsomal P450IIE1 content and N-nitrosodimethylamine demethylase activity than those fed diets with lower fat/carbohydrate ratios. This dietary fat/carbohydrate effect on P450IIE1 also was observed with modified semipurified AIN-76A diets. In addition, both the quantity and the extent of unsaturation of dietary lipids affected P450IIE1 regulation. At moderate fat levels (5 and 20% diet), rats fed corn oil and menhaden oil diets produced higher P450IIE1 activity than those fed lard and olive oil diets. Rats fed a diet containing 20% corn oil or an amount of linoleic acid equivalent to the 20% corn oil diet showed twofold to threefold increases in the level of P450IIE1 over those fed a fat-free diet. Rats fed a 25% corn oil diet showed twofold higher enflurane metabolism in vivo than those fed a 0.5% corn oil diet. The present results suggest that the constitutive P450 enzyme level is regulated by dietary fat/carbohydrate ratios.

In order to examine the clinical potential of desflurane (difluoromethyl-1-fluoro-2,2,2-trifluoroethyl ether) in humans, a randomized, controlled study was designed to compare time of emergence from anesthesia in patients undergoing elective surgery under desflurane anesthesia to that of patients under isoflurane anesthesia. Twenty-eight patients were randomly divided into four groups. Group 1 received isoflurane 0.65 MAC; group 2, desflurane 0.65 MAC; group 3, isoflurane 1.25 MAC; and group 4, desflurane 1.25 MAC. Anesthesia was induced with sodium thiopental, and N2O 60% was added to the volatile agent. Mean anesthetic exposure times (min [mean +/- SD]) were 108 +/- 49 in group 1, 132 +/- 46 in group 2, 147 +/- 74 in group 3, and 166 +/- 71 in group 4, with no significant differences between groups. The times from discontinuation of anesthetic gases until patients opened their eyes and squeezed the investigator's hand in response to a command were averaged and recorded as "emergence time." Emergence time was significantly less with desflurane than with isoflurane given at the same MAC. Patients receiving isoflurane 0.65 MAC responded to commands 15.6 +/- 4.3 min after discontinuation of the anesthetic; patients in the desflurane 0.65 MAC group responded in 8.8 +/- 2.7 min (P less than 0.01). Emergence time for isoflurane 1.25 MAC was 30.0 +/- 11.0 min; for desflurane 1.25 MAC it was 16.1 +/- 6.0 min (P less than 0.05). Our results confirm that emergence from desflurane anesthesia is more rapid than from isoflurane.

To determine whether the caloric source of intravenous nutrition can influence oxidative drug metabolizing capacity, antipyrine metabolism was studied in six healthy volunteers, who were taking no food or liquid by mouth, after they had been administered an intravenous nutritional regimen of 5% dextrose, 440 kcal/day, for 4 days and after they had been switched to an essentially isocaloric intravenous nutritional regimen of amino acids ( Aminosyn 3.5%) for 1 day. The change in intravenous nutritional regimen resulted in a 21% decrease in mean half-life (range: 3-32%), a 20% decrease in mean area under the concentration-time curve (range: 4-42%), and a 24% increase in mean metabolic clearance rate (range: 2-71%) for antipyrine. These results show that the change from intravenous dextrose to intravenous amino acids for only 1 day produced in all subjects an increase in antipyrine metabolism. Interestingly, there was marked variability in the responsiveness of the different subjects to the change in intravenous caloric source.

The effects of consumption of charcoal-broiled beef on the metabolism of acetaminophen by conjugation were determined in nine normal subjects. We had reported that beef prepared in this manner accelerates the oxidative metabolism of drugs, including the oxidation of phenacetin to N-acetyl-p-aminophenol (acetaminophen). In nine normal subjects, a control diet was followed by a charcoal-broiled beef diet, which was followed by the control diet. The charcoal-broiled beef had little or no effect on the plasma-level profile of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate, or on the urinary excretion of acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, 3-methoxy-acetaminophen, or the cysteine and mercapturic acid conjugates of acetaminophen. Results indicate that the enzyme systems that conjugate acetaminophen in man are subject to little or no influence by charcoal-broiled beef. Therefore dietary factors that increase drug oxidations cannot be assumed to have a similar effect on drug conjugation.

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half-lifes and areas under the plasma concentration-time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects. The variations in rates of drug metabolism did not result from assay procedures, since there was little variation in measured concentrations when the drugs were added to plasma and assayed on multiple occasions. Intraindividual variation occurring in subjects given the drug on 5 different occasions may be due to changes in the external environment or changes in internal physiologic parameters or both. Our studies confirm the usefulness of antipyrine as a test drug in studying drug metabolism in man and also demonstrate that the antipyrine test may be able to detect those subjects whose environments are perturbed by unidentified factors.

Our goals were to determine the time-course of the increase in oxidative drug metabolism that occurs when parenteral nutrition is changed from dextrose to amino acids (23% branched-chain), whether the composition of the amino acid regimen influences this effect, and whether drug conjugation is similarly altered. We examined in healthy volunteers the effects of changing isocalorically from intravenous dextrose 440 kcal/day to amino acids, on one occasion 23% branched-chain and on another 85%. The change to the 23% regimen produced a significant increase in metabolic clearance of antipyrine, a model for oxidation (mean +/- SE 3.0 +/- 0.3 to 3.7 +/- 0.4 L/h, N = 6, P less than 0.003), but the change to the 85% regimen did not, indicating that the composition of an amino acid infusion can influence its effect on oxidative metabolism. Analysis of the concentration-time curve for antipyrine after simultaneous dosing and start of the 23% regimen suggests that the increase in metabolic capacity occurred within a few hours. Metabolic clearance of acetaminophen, a model for conjugation, was not altered by changing to either amino acid regimen.

Chlorpromazine, 75 mg, was taken by eight cigarette smokers and nine nonsmokers. Mean maximum percent decrease in mean blood pressure with change in position from lying to standing during the first 10 hr after chlorpromazine was 46% greater in nonsmokers than in smokers. Of the eight smokers, six did not become sleepy after chlorpromazine, one became slightly sleepy, and one fell asleep. Of the nine nonsmokers, three became slightly sleepy, one moderately sleepy, and five fell asleep. Mean peak plasma concentration of chlorpromazine was 24% lower and mean area under the plasma concentration-time curve (AUC) was 36% lower in smokers than in nonsmokers. There was no correlation between these plasma level parameters and either the degree of sleepiness or the degree of orthostatic hypotension in the subjects. The relatively small differences between cigarette smokers and nonsmokers in AUCs and peak plasma levels for chlorpromazine, combined with the lack of relationship between these plasma level parameters, the occurrence of drowsiness, and the magnitude of orthostatic hypotension in our subjects make it unlikely that cigarette smoking influenced these effects of chlorpromazine by enhancing its overall metabolism.

The effects on antipyrine metabolism of two levels of carbohydrate, fed intravenously as the sole source of nutrition, were compared. After a 36-hour baseline period during which they received 5% dextrose, 440 kcal per day, intravenously, 8 healthy men were administered 2 sequential intravenous nutritional regimens for 3 days each. One regimen consisted of dextrose 8.1 kcal per kg per day and the other 30.7 kcal per kg per day. The order of the 2 regimens was randomized. Antipyrine metabolism was studied on the last day of each nutritional regimen. Antipyrine kinetics were not influenced by level of carbohydrate intake. Our study indicates that in humans carbohydrate does not by itself have an effect on oxidative drug-metabolizing capacity.

Eight healthy volunteers were sequentially fed a control diet, a charcoal-broiled beef--containing diet, and the control diet a second time. The mean plasma half-lives (t1/2) of antipyrine and theophylline were each decreased by 22% after the subjects were fed the charcoal-broiled beed--containing diet. The main plasma t1/2s for these drugs returned to control values when the subjects were fed the control diet for a second time. Considerable individuality occurred in the responsiveness of the subjects to the charcoal-broiled beef--containing diet. The decreases in antipyrine plasma t1/2s among the 8 subjects ranged from 5% to 39%, and the decreases in theophylling t1/2s ranged from 0% to 42%.

Three weeks after dosing male Fischer 344 rats with streptozotocin to induce diabetes, enflurane was administered ip, and 1 h later, fluoride levels were measured in plasma and livers were removed. Hepatic microsomes were prepared, and the oxidative defluorination of enflurane, isoflurane, and methoxyflurane and the reductive defluorination of halothane were measured in vitro. In diabetic rats the defluorination of enflurane was increased 3.4-fold over control levels in vivo and 2.7-fold in vitro. Insulin treatment prevented these effects. In vitro metabolism of isoflurane by livers from diabetic rats was 2.5-fold greater than by livers from control rats, but defluorination of methoxyflurane and of halothane was not altered. The results show that streptozotocin-induced diabetes in rats enhances the defluorination of enflurane and of isoflurane but not of methoxyflurane or halothane.

The effects of a single dose of cyclosporine on anesthetic actions of pentobarbital and fentanyl were studied in mice. Mice given pentobarbital 2 hr after receiving cyclosporine, 60 mg/kg, slept a statistically significant 2.3 times longer than did controls. In a second study, each of two dose levels of cyclosporine was given before each of four dose levels of fentanyl. The analgesic effect of fentanyl, measured with the abdominal constriction test, was dose-dependent. Cyclosporine significantly increased the analgesia produced by fentanyl and did so in a dose-dependent manner. Cyclosporine by itself did not produce analgesia. Plasma levels of fentanyl and binding of fentanyl by plasma proteins were unchanged by cyclosporine treatment. The results show that a single dose of cyclosporine can increase pentobarbital hypnosis and fentanyl analgesia in mice but do not establish the mechanism of these interactions.

To determine whether intravenous nutritional repletion can influence oxidative drug metabolizing capacity, antipyrine metabolism was studied in 6 malnourished patients on the second day of a 2-day baseline period and on the last day of two sequential, 8-day intravenous nutritional repletion periods. During the baseline period they received 5% dextrose, 440 kcal per day, intravenously. During the repletion periods they received 20 mg of nitrogen per kilocalorie of baseline resting energy expenditure and, in random order, dextrose to provide a total caloric intake of either 0.95 or 1.75 times baseline resting energy expenditure. There were no statistically significant differences between the high- and low-dextrose repletion regimens in their effects on antipyrine metabolism. Seven days of nutritional repletion resulted in a 42% decrease in mean half-life (range 12%-52%) and an 87% increase in mean metabolic clearance rate (range 29%-155%) for antipyrine. An additional 8 days of nutritional repletion resulted in no further change in these pharmacokinetic parameters.

Ten healthy subjects were fed three diets for 10 days each: a control diet, a cabbage and brussels sprouts--containing diet, and the control diet a second time. Oxazepam was taken on day 7 and acetaminophen on day 10 of each dietary regimen. The test diet stimulated the metabolism of acetaminophen, at least in part by enhanced glucuronidation, as evidenced by a 16% decrease in mean plasma AUC, a 17% increase in mean metabolic clearance rate, an increased ratio of acetaminophen glucuronide to acetaminophen in plasma from 1 to 11 hr after drug and an 8% increase in mean 24-hr urinary recovery of acetaminophen glucuronide, which returned toward control when the subjects were fed the control diet a second time. There were no comparable changes in the metabolism of acetaminophen to acetaminophen sulfate. When the subjects ate the test diet, 24-hr urinary recovery of the cysteine conjugate and of 3-methoxyacetaminophen sulfate, end-products of minor oxidative pathways, the former involving a toxic intermediate, decreased 13% and 22%. Cabbage and brussels sprouts induced a 17% decrease in mean plasma AUC and a 19% increase in mean metabolic clearance rate for oxazepam, but there was no change in mean plasma t1/2 for this drug, nor was there a change in ratio in plasma of oxazepam glucuronide to oxazepam.

Two studies were initiated to determine the effect of the menstrual cycle on antipyrine metabolism. In the first study a relatively large oral dose of antipyrine (15 mg/kg) was given on days, 3, 5, 10, 14, 16, 20, and 25 after the onset of menstruation. Salivary antipyrine half-lifes (t1/2S) declined progressively, suggesting that the long-term administration of this dose had stimulated antipyrine metabolism. To minimize this possible induction, in the second study a much smaller dose of antipyrine (1 mg/kg) was given on the same days of the cycle as in the first study. There was no induction. In both experiments, the menstrual cycle had little or no effect on the mean salivary t1/2, mean metabolic clearance rate, or apparent volume of distribution of antipyrine. In the second, men served as controls. The mean kinetic parameters for the men did not differ from those for the women. Although individuals of each sex varied from day to day in each kinetic parameter, the magnitude of the intraindividual variability in antipyrine metabolism was the same for both. The mean intraindividual coefficient of variation for antipyrine t1/2S was 14.4 +/- 1.6% (SE) in women and 12.4 +/- 1.3% (SE) in men. No consistent pattern for either sex was observed in the day-to-day variations in the means of the kinetic parameters investigated. Several women in whom the t1/2 rose or fell at midcycle were found to have a different pattern when reexamined 6 mo later.

The effects of a single oral dose or chronic ingestion of ethanol on in vivo and in vitro metabolism of enflurane were studied in Fischer 344 rats. At various intervals after ethanol treatment, enflurane was administered ip and 1 h after enflurane administration fluoride and ethanol levels were measured in plasma and hepatic microsomes were prepared. The concentration of ethanol in plasma (+/- SE) was 0.138 +/- 0.035% at 9 h after the single dose of ethanol and decreased almost to control levels by 17 h. The hepatic microsomal defluorination of enflurane was enhanced 3.5-fold and 6.3-fold at 9 and 25 h after the ethanol dose and returned to the control level by 33 h. In vivo defluorination was inhibited almost completely at 8 h after the ethanol dose, increased to 3.4 times the control level at 24 h, and decreased to the control level by 32 h. At 1 h after the end of chronic ethanol treatment, the concentration of ethanol in plasma was 0.254 +/- 0.018%, and it decreased to the control level by 9 h. Hepatic microsomal enflurane defluorinating activity was increased 10.5-fold at 1 h after the end of chronic treatment and decreased to the control level by 13 h. Immediately following chronic treatment, enflurane defluorination in vivo was almost totally inhibited. It increased to 9.3 times the control level at 4 h after chronic treatment was stopped and then decreased to nearly the control level at 12 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Several dietary factors influence the oxidative metabolism of chemicals in humans. Increasing the ratio of protein to carbohydrate or fat in the diet, feeding cabbage and brussels sprouts or feeding charcoal-broiled beef for several days stimulates human drug metabolism. The chronic ingestion of ethanol stimulates drug metabolism whereas the chronic ingestion of methylxanthine-containing foods inhibits drug metabolism. In contrast, an increase in the ratio of fat to carbohydrate in the diet of normal subjects or the fasting of obese individuals for several days has little or no effect on drug metabolism. Flavonoids in edible plants influence the metabolism of foreign chemicals by human liver in vitro. The addition of flavone, tangeretin or nobiletin to human liver microsomes activates both the hydroxylation of benzo[alpha]pyrene and the metabolism of aflatoxin B1 to mutagens. On the other hand, quercetin, kaempferol, morin and chrysin, which are also normally occurring flavonoids, inhibit the hydroxylation of benzo[alpha]pyrene by human liver microsomes.