bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of α2Adrenoceptors Dilates the Rat Middle Cerebral Artery
Authors: Bryan Robert M. , Eichler M. Y. , Swafford M. W. G. , Johnson T. D. , Suresh M. S. , Childres W. F. 
Published: November 2003

Background
Because alpha 2 adrenoceptor agonists are used as adjuncts to anesthetics, their effects on the cerebrovascular circulation are of prime importance. We studied changes in the diameter of rat middle cerebral arteries after stimulation of alpha 2 adrenoceptors with UK14,304.

Methods
Rat middle cerebral arteries were isolated, cannulated at each end with a glass micropipette, and pressurized to 85 mmHg. The middle cerebral arteries were immersed in a bath (37 degrees C) containing physiologic saline solution, and luminally perfused with physiologic saline solution (100 microliters/ min). Changes in vessel diameter were measured after magnification with a microscope.

Results
Resting diameter of the middle cerebral arteries was 239 +/- 13 microns (n = 8) for the first study. A dose-dependent dilation was produced by addition of UK14,304 to the extraluminal bath; a 10-15% increase in diameter occurred at a concentration of 10(-4)M. The dilations produced by UK14,304 were blocked with selective alpha 2-antagonists, idazoxan and rauwolscine, but not by the selective alpha 1-antagonist, prazosin. The dilations could be blocked by removal of the endothelium, or the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (10(-5) M). The inhibitory effects of N-nitro-L-arginine methyl ester were reversed with the addition of 10(-3) M L-arginine, but not 10(-3) M D-arginine. Furthermore the dilation produced by UK14,304 was completely abolished with pertussis toxin (100 ng/ml).

Conclusions
It was concluded that the stimulation of alpha 2 adrenoceptors with UK14,304 produced a dilation in the rat middle cerebral artery that (1) was dependent on intact endothelium, (2) involved nitric oxide, and (3) acted via a pertussis toxin-sensitive G protein.
Comparative Pharmacology of Cisatracurium (51W89), Atracurium, and Five Isomers in Cats
Authors: Wastila William B. , Maehr Robert B. , Turner Geoffrey L. , Hill Derek A. , Phil. M. , Savarese John J. 
Published: November 2003

Background
Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development.

Methods
Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium.

Results
Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95NMB values varied approximately tenfold (43 +/- 2 microgram/kg -488 +/- 56 microgram/kg. The "R-series" isomers were more potent than the corresponding "S-series" isomers. With the exception of the S,Trans-S', Trans isomers, the NMB effects, i.e., onset times (range 2.6 +/- 0.2 min to 4.7 +/- 0.3 min) and total durations (range 9.9 +/- 1.4 min to 14 +/- 0.9 min), of the other five isomers were very similar to that atracurium. The former isomers had relatively short duration of action. The 25-75% recovery times after cisatracurium at 1 x ED95 (4.4 +/- 0.4 min), 4 x ED95 (4.5 +/- 0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8% +/- 0.4 min) indicated a noncumulative effect. The vagal ID50:NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25:NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micrograms/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60X the NMB ED95 (62 +/- 8 micrograms/kg).

Conclusions
Cisatracurium has neuromuscular blocking effects identical to those of atracurium, is more potent, and does not produce cardiovascular effects or increase plasma histamine concentrations.
Isoflurane Produces Marked and Nonlinear Decreases in the Vasoconstriction and Shivering Thresholds
Authors: Xiong Junyu , Kurz Andrea , Sessler Daniel I. , Plattner Olga , Christensen Richard , Dechert Martha , Ikeda Takehiko 
Published: November 2003

Background
Desflurane decreases the vasoconstriction and shivering thresholds disproportionately at high anesthetic concentrations. This result contrasts with the authors' previous report that isoflurane decreases the vasoconstriction threshold linearly. It is surprising that the basic shape of the concentration-response curve should differ with these two otherwise similar anesthetics. Therefore, the hypothesis that isoflurane produces a nonlinear reduction in the vasoconstriction threshold was tested. Because the effect of isoflurane on shivering remains unknown, the extent to which isoflurane reduces the shivering threshold also was determined.

Methods
Eight men volunteered to be studied on four randomly ordered days: (1) a target end-tidal isoflurane concentration of 0.55%, (2) a target concentration of 0.7%, (3) control (no anesthesia) and a target end-tidal concentration of 0.85%, and (4) a target end-tidal concentration of 1.0%. Volunteers were surface-cooled until peripheral vasoconstriction and shivering were observed. We arithmetically compensated for changes in skin temperature using the established linear cutaneous contributions to control for each response. From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C), the concentration-response relation was determined.

Results
Isoflurane administration produced a dose-dependent reduction in the vasoconstriction and shivering thresholds, decreasing each approximately 4.6 degrees C at an end-tidal concentration of 1%. Residual analysis indicated that the vasoconstriction and shivering thresholds were decreased in a nonlinear fashion during isoflurane administration. The vasoconstriction-to-shivering range was 1.5 +/- 0.8 degree C without isoflurane, and did not change significantly during isoflurane administration.

Conclusions
The vasoconstriction-to-shivering range remained unchanged by isoflurane administration. In this regard, the effects of isoflurane are similar to those of desflurane, propofol, and alfentanil. The current data differ from the authors' previous report, in that the dose-dependence for vasoconstriction was nonlinear, with isoflurane reducing the threshold disproportionately at higher anesthetic concentrations. Differing dose-dependence in the two studies may result either because the current study's volunteers were not exposed to surgical stimulation and were given less isoflurane, or because of design limitations in the previous protocol.
Intravenous Ondansetron in Established Postoperative Emesis in Children
Authors: Khalil Samia , Rodarte Alexander , Weldon Craig B. , Weinstein Michael , Grunwald Zvi , Ginsberg Brian , Kaye Robert , Otto Alice , Wheeler Melissa , Lawhorn David C. , Prillaman Barbara A. , Creed Mary 
Published: November 2003

Background
In pediatric postsurgical patients, postoperative vomiting is a common occurrence that can delay recovery and result in unplanned hospital admissions after outpatient surgery. This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of ondansetron in the control of established postoperative emesis in outpatients aged 2-12 yr.

Methods
Screened for the study were 2,720 ASA physical status 1-3 children undergoing outpatient surgery during general anesthesia, which included nitrous oxide. Children experiencing two emetic episodes within 2 h of discontinuation of nitrous oxide were given intravenous ondansetron (n = 192; 0.1 mg/kg for children weighing < or = 40 kg; 4 mg for children weighing > 40 kg) or placebo (n = 183).

Results
The proportion of children with no emetic episodes and no use of rescue medication was significantly greater (P < 0.001) in the ondansetron group compared with placebo for both 2- and 24-h periods after study drug administration (78% of the ondansetron group and 34% of the placebo group for 2 h; 53% of the ondansetron group and 17% of the placebo group for 24 h). Among patients with at least one emetic episode or with rescue medication use, the median time to onset of emesis or rescue was 127 min in the ondansetron group compared with 58 min in the placebo group (P < 0.001). The median time from study drug administration until discharge was significantly shorter (P < 0.01) in the ondansetron group (153 min, range 44-593 min) compared with the placebo group (173 min, range 82-622 min). The incidence of potentially drug-related adverse events was similar in the ondansetron (3% of patients) and the placebo (4% of patients) groups.

Conclusion
A single dose of ondansetron (0.1 mg/kg up to 4 mg) is effective and well tolerated in the prevention of further episodes of postoperative emesis in children after outpatient surgery. Administration of ondansetron also may result in a shorter time to discharge.
Thermoregulatory Vasoconstriction Does Not Impede Core Warming during Cutaneous Heating
Authors: Clough David , Kurz Andrea , Sessler Daniel I. , Christensen Richard , Xiong Junyu 
Published: November 2003

Background
Although forced-air warming rapidly increases intraoperative core temperatures, it is reportedly ineffective postoperatively. A major difference between these two periods is that arteriovenous shunts are usually dilated during surgery, whereas vasoconstriction is uniform in hypothermic postoperative patients. Vasoconstriction may decrease efficacy of warming because its major physiologic purposes are to reduce cutaneous heat transfer and restrict heat transfer between the two thermal compartments. Accordingly, we tested the hypothesis that thermoregulatory vasoconstriction decreases cutaneous transfer of applied heat and restricts peripheral-to-core flow of heat, thereby delaying and reducing the increase in core temperature.

Methods
Eight healthy male volunteers anesthetized with propofol and isoflurane were studied. Volunteers were allowed to cool passively until core temperature reached 33 degrees C. On one randomly assigned day, the isoflurane concentration was reduced, to provoke thermoregulatory arteriovenous shunt vasoconstriction; on the other study day, a sufficient amount of isoflurane was administered to prevent vasoconstriction. On each day, forced-air warming was then applied for 2 h. Peripheral (arm and leg) tissue heat contents were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. Core (trunk and head) heat content was determined from core temperature, assuming a uniform compartmental distribution. Time-dependent changes in peripheral and core tissue heat contents were evaluated using linear regression. Differences between the vasoconstriction and vasodilation study days, and between the peripheral and core compartments, were evaluated using two-tailed, paired t tests. Data are presented as means +/-SD; P < 0.01 was considered statistically significant.

Results
Cutaneous heat transfer was similar during vasoconstriction and vasodilation. Forced-air warming increased peripheral tissue heat content comparably when the volunteers were vasodilated and vasoconstricted: 48 +/- 7 versus 53 +/- 10 kcal/h. Core compartment tissue heat content increased similarly when the volunteers were vasodilated and vasoconstricted: 51 +/- 8 versus 44 +/- 11 kcal/h. Combining the two study days, the increase in peripheral and core heat contents did not differ significantly: 51 +/- 8 versus 48 +/- 10 kcal/h, respectively. Core temperature increased at essentially the same rate when the volunteers remained vasodilated (1.3 degrees C/h) as when they were vasoconstricted (1.2 degrees C/h).

Conclusions
The authors failed to confirm their hypothesis that thermoregulatory vasoconstriction decreases cutaneous transfer of applied heat and restricts peripheral-to-core flow of heat in anesthetized subjects. The reported difference between intraoperative and postoperative rewarming efficacy may result from nonthermoregulatory anesthetic-induced vasodilation.
Analgesic Efficacy of Low-dose Ketamine
Authors: Kochs Eberhard , Scharein Eckehard , Mollenberg Oliver , Bromm Burkhart , Schulte am Esch Jochen 
Published: November 2003

Background
Low-dose ketamine has been shown to exert analgesic effects. Whether ketamine-induced pain relief may be quantitated by somatosensory evoked cerebral potentials has not been established.

Methods
Thirty healthy volunteers were assigned randomly to one of three groups. Subjects of group 1 (n = 10, control) were given saline as placebo. In groups 2 (n = 10) and 3 (n = 10), intravenous ketamine (0.25 mg. kg-1 and 0.50 mg. kg-1, respectively) was administered. The following variables were recorded at baseline and for 50 min after drug administration: electroencephalographic (EEG) data, somatosensory-evoked late cortical responses (SEP) elicited by intracutaneous stimulation of the fingertip (2-3 fold pain threshold), heart rate, mean arterial blood pressure, and end-tidal PETCO2 via a tight-fitting mask. Electroencephalographic spectral power in selected frequency bands and frequency percentiles were calculated from the spontaneous EEG segment preceding each somatosensory stimulus. Somatosensory-evoked late cortical response parameters were calculated from the respective poststimulus EEG segments. After recording of each EEG response, subjects were asked to rate the individual pain sensation.

Results
In group 1, all variables did not change over time. Ketamine administration resulted in dose-dependent decreases in alpha-activity and increases in theta power (group 2: 190%, group 3: 440%). Electroencephalographic changes were not related to changes in pain perception. For the first 30 min after ketamine injection, a dose-dependent decrease of the long-latency N150-P250 somatosensory-evoked late cortical response component was observed (group 2: 15-20%; group 3: 25-30%). Subjective pain ratings were also different between groups, with a higher degree of pain relief in group 3 for the first 30 min. At the end of the observation period, pain relief and the N150-P250 amplitude were comparable in both ketamine groups.

Conclusions
These data indicate that pain relief induced by low-dose ketamine is dose-dependent for the first 30 min after bolus injection. Changes in pain perception may be quantitated by somatosensory-evoked cortical responses. Also, EEG changes are not specific for changes in nociception, but the increase in theta power may reflect the hypnotic effect of low-dose ketamine.
Sustained-release Morphine for Epidural Analgesia in Rats
Authors: Kim Taehee , Murdande Sharad , Gruber Andras , Kim Sinil 
Published: November 2003

Background
Epidural opioid analgesia often requires either continuous infusion or repeated injections, which are inconvenient for patients, increase risk of infection, and consume expensive physician and nursing time. In addition, potential respiratory depression is a major safety concern. The authors studied whether a single dose of epidurally administered, sustained-release morphine could prolong analgesia and reduce toxic effects in rats.

Methods
Sustained-release morphine (DTC401) was prepared by encapsulating morphine sulfate in DepoFoam (Dep. Tech, San Diego, CA), a lipid-based, sustained-release drug delivery system. A standard hot-plate test for analgesia, pulse oximetry for hemoglobin oxygen saturation, corneal-reflex loss, and incidence of catalepsy were used to assess efficacy and toxicities. Cerebrospinal fluid and serum pharmacokinetic studies were performed after a single epidural dose, using a commercially available radioimmunoassay kit.

Results
Single epidural doses of DTC401 resulted in equivalent onset time to peak analgesia but significantly prolonged analgesia compared with morphine sulfate. Hemoglobin oxygen saturation was decreased minimally, and the incidences of catalepsy and corneal-reflex loss were minimal, even at large doses of DTC401. In contrast, the larger doses of morphine sulfate significantly decreased hemoglobin oxygen saturation, and caused catalepsy and loss of the corneal-reflex. The Cmax for DTC401 was 32% in cerebrospinal fluid and 6% in serum, relative to morphine sulfate. The terminal half-life for DTC401 was increased 32 fold in the cerebrospinal fluid compared with morphine sulfate.

Conclusions
A single epidural dose of DTC401, compared with morphine sulfate, prolonged duration of analgesia, with minimal supraspinal toxic effects, in rats.
Heparinase I (Neutralase) Reversal of Systemic Anticoagulation
Authors: Michelsen Luis G. , Kikura Mutsuhito , Levy Jerrold H. , Lee Mi Kyoung , Lee King C. , Zimmermann Joseph J. , Szlam Fania 
Published: November 2003

Background
Protamine causes multiple adverse reactions. Heparinase I, a specific enzyme that inactivates heparin, is a possible alternative to protamine. In this study, the authors examined the efficacy of heparinase I to reverse heparin-induced anticoagulation in vitro and compared heparinase I to protamine as an antagonist of heparin-induced anticoagulation in dogs.

Methods
In the in vitro study, blood was obtained from the extracorporeal circuits of 12 patients, and activated clotting times were determined after adding different concentrations of heparinase I. In the in vivo study, 24 anesthetized dogs received 300 units/kg heparin injected intravenously for 5 s, then 10 min later, 3.9 mg/kg protamine, 5-41 micrograms/kg heparinase I, or the vehicle (n = 4/group) were administered intravenously, and activated clotting times and hemodynamics were measured.

Results
In the in vitro study, heparin concentrations of 3.3 +/- 1.0 (mean +/- SD) units/ml (approximately 0.033 mg/ml; n = 12) were reversed in the blood of patients by heparinase I at concentrations > 0.490 microgram/ml. In the canine study, heparinase at all doses studied and protamine effectively reversed the anticoagulating effects of heparin within 10 min of administration. Protamine produced adverse hemodynamic effects, whereas heparinase or its vehicle produced no significant change in arterial pressure.

Conclusion
Both heparinase I and protamine effectively reversed heparin anticoagulation. However, as opposed to protamine, heparinase I did not produce any significant hemodynamic changes when given as a bolus to dogs.
Effects of Halothane and Isoflurane on Carbon Monoxide-induced Relaxations in the Rat Aorta
Authors: Jing Ming , Bina Saiid , Verma Ajay , Hart Jayne L. , Muldoon Sheila M. 
Published: November 2003

Background
Halothane and isoflurane previously were reported to attenuate endothelium-derived relaxing factor/nitric oxide-mediated vasodilation and cyclic guanosine monophosphate (cGMP) formation in isolated rat aortic rings. Carbon monoxide has many chemical and physiologic similarities to nitric oxide. This study was designed to investigate the effects of halothane and isoflurane on carbon monoxide-induced relaxations and cGMP formation in the isolated rat aorta.

Methods
Isometric tension was recorded continuously from endothelium denuded rat aortic rings suspended in Krebs-filled organ baths. Rings precontracted with submaximal concentrations of norepinephrine were exposed to cumulative concentrations of carbon monoxide (26-176 microM). This procedure was repeated three times, with anesthetics delivered 10 min before the second procedure. Carbon monoxide responses of rings contracted with the same concentration of norepinephrine (10(-6) M and 2 x 10(-6) M) used in the anesthetic-exposed preparations also were examined. The concentrations of cGMP were determined in denuded rings using radioimmunoassay. The rings were treated with carbon monoxide (176 microM, 30 s) alone, or carbon monoxide after a 10-min incubation with halothane (0.34 mM or 0.72 mM). To determine whether the sequence of anesthetic delivery influenced results, vascular rings pretreated with halothane were compared with nonpretreated rings.

Results
Carbon monoxide (26-176 microM) caused a dose-dependent reduction of norepinephrine-induced tension, with a maximal relaxation of 1.51 +/- 0.07 g (85 +/- 7% of norepinephrine-induced contraction). Halothane (0.34 mM and 0.72 mM) significantly attenuated the carbon monoxide-induced relaxations, but only the highest concentration of isoflurane (0.53 mM) significantly attenuated the carbon monoxide-induced relaxations. Carbon monoxide (176 microM) significantly increased cGMP content (+88.1 +/- 7.1%) and preincubation of the aortic rings with halothane (0.34 mM and 0.72 mM) inhibited this increase (-70.7 +/- 6.8% and -108.1 +/- 10.6%, respectively). When aortic rings and carbon monoxide were added simultaneously to Krebs solution equilibrated with halothane (0.72 mM), no inhibition of cGMP formation occurred.

Conclusion
Carbon monoxide-induced endothelium-independent relaxations of rat aortic rings were decreased by clinically relevant concentrations of halothane and isoflurane. The carbon monoxide-induced elevations of cGMP were attenuated by halothane only when the anesthetic was incubated with aortic rings before carbon monoxide treatment. The possible clinical significance of the actions of the anesthetics on this endogenous vasodilator is yet to be determined.
Genetic Differences Affecting the Potency of Stereoisomers of Isoflurane
Authors: Morgan Phil G. , Usiak Marianne F. , Sedensky Margaret M. 
Published: November 2003

Background
In previous studies, researchers demonstrated the ability of a variety of organisms and in vitro sites of anesthetic action to distinguish between stereoisomers of isoflurane or halothane. However, it was not shown whether organisms with differing sensitivities to stereoisomers of one volatile anesthetic are able to distinguish between stereoisomers of another. In this study, the responses of mutants of Caenorbabditis elegans to stereoisomers of isoflurane were determined for comparison to previous results in halothane.

Methods
Mutant strains of C. elegans were isolated and grown by standard techniques. The EC50s (the effective concentrations of anesthetia at which 50% of the animals are immobilized for 10 s) of stereoisomers of isoflurane and the racemate were determined in wild type and mutant strains of C. elegans.

Results
Wild type C. elegans and strains with high EC50S of the racemate were more sensitive to the (+) isomer of isoflurane by approximately 30%. The racemate showed a EC50s similar to the less potent isomer, the (-) form. In the strains with low EC50s, one strain showed no ability to differentiate between the stereoisomers, whereas two showed a 60% difference between the (+) and (-) forms.

Conclusions
The ability to distinguish between stereoisomers of isoflurane is associated with genetic loci separate from those that distinguish between stereoisomers of halothane. These results are consistent with multiple sites of action for these anesthetics.