bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of an Implanted Osmotic Pump Delivering Sufentanil for the Treatment of Chronic Pain
Authors: Fisher Dennis M. , Kellett Norma , Lenhardt Rainer 
Published: November 2003

Background
A matchstick-sized implanted osmotic pump (Chronogesic) that delivers sufentanil subcutaneously for more than 90 days is being developed to treat chronic pain. This study evaluates pharmacokinetic characteristics related to the absorption of sufentanil using a prototype 60-day system.

Methods
Twelve opioid-naive volunteers were given naltrexone to prevent opioid effects. Sufentanil, 60 microg, was infused intravenously over 6 h, then 48 h later, the pump was implanted subcutaneously in the upper arm under local anesthesia. Pumps were removed 9 days later. In six volunteers, fever (1.6-3.3 degrees C) was induced with interleukin-2. Plasma was sampled and population pharmacokinetic modeling was performed to estimate in vivo release rate and absorption half-life. Bioavailability was calculated by comparing in vivo to in vitro release rates. The impact of perturbations in release rate on sufentanil plasma concentration (Cp) was simulated.

Results
Fever had no systematic effect on Cp. Release rate estimated in vivo was similar to that measured in vitro; bioavailability did not differ from 100%. Absorption half-life was 16.2 h. Simulation demonstrated that supplemental release of sufentanil from the implant (as might occur with local heating) increases Cp an average of 2.5-2.8% per hours supplemental dose.

Conclusions
An implantable osmotic pump delivered sufentanil in vivo at the rate predicted from in vitro experiments. The rate at which sufentanil was absorbed from the subcutaneous space (half-life > 16 h) was markedly slower than reported with subcutaneous or intramuscular administration of large volumes of dilute opioids; this slow absorption dampens potential changes in Cp if release rate is perturbed.
The “Intubating Dose” of Succinylcholine
Authors: Kopman Aaron F. , Zhaku Bledi , Lai Kane S. 
Published: November 2003

Background
The usually cited "intubation dose" of succinylcholine is 1.0 mg/kg. In the majority of patients, this dose will produce apnea of sufficient duration that significant hemoglobin desaturation may occur before neuromuscular recovery takes place in those whose ventilation is not assisted. This study was undertaken to examine the extent to which reducing this dose would decrease the duration of action of succinylcholine.

Methods
During stable desflurane/oxygen/opioid anesthesia and after adequate twitch stabilization, neuromuscular function was recorded with an acceleromyographic monitor. Supramaximal stimuli were delivered at 0.10 Hz. Patients received 0.40, 0.60, or 1.0 mg/kg succinylcholine, and twitch height was monitored for at least 20 min thereafter.

Results
The onset times to maximal effect were 105 +/- 23 s, 81 +/- 19 s, and 71 +/- 22 s, respectively. The lowest dose (0.40 mg/kg) did not reliably produce 100% twitch depression. The times to 90% twitch recovery at the adductor pollicis in the three groups were 6.6 +/- 1.5 min, 7.6 +/- 1.6 min, and 9.3 +/- 1.2 min, respectively.

Conclusions
Reducing the dose of succinylcholine from 1.0 mg/kg to 0.60 mg/kg shortens the duration of effect at the adductor pollicis by more than 90 s. The authors believe that even this modest decrease in the duration of drug-induced paralysis is often worth pursuing.
Deleterious Effects of Mild Hypothermia in Septic Rats Are Ameliorated by Granulocyte Colony-stimulating Factor
Authors: Torossian Alexander , Ruehlmann Sebastian , Middeke Martin , Sessler Daniel I. , Lorenz Wilfried , Wulf Hinnerk F. , Bauhofer Artur 
Published: November 2003

Background
The authors studied the effects of mild hypothermia on the outcome in a rat model of intraabdominal sepsis and tested whether granulocyte colony-stimulating factor (G-CSF) augments the host response and improves outcome during mild hypothermia.

Methods
A rat model of peritoneal contamination and infection with human stool bacteria was used to simulate clinical trials that included increasing complexity. In trial 1, postoperative hypothermia (32 degrees C) was compared with normothermia (38 degrees C), without supportive treatment (10 rats per group). In trial 2, with a more severe infection, rats were given antibiotic prophylaxis. Using 20 rats per group, the authors compared postoperative hypothermia (32 degrees C), normothermia, and postoperative hypothermia (32 degrees C) with 20 mug/kg G-CSF prophylaxis given 12 h before surgery and 12 h and 36 h after surgery. The primary endpoint was death at 120 h. Secondary endpoints were systemic cytokine concentrations, leukocyte counts, and the phagocytic activity of granulocytes and monocytes.

Results
In trial 1, 50% of the normothermia group and 10% of the postoperative hypothermia group survived. In trial 2, 50% of the normothermia group, 20% of the hypothermia group, and 60% of the hypothermia plus G-CSF group survived. Postoperative hypothermia plus G-CSF reduced plasma concentrations of interleukin-6 (hypothermia group, 511 +/- 104 pg/ml; hypothermia plus G-CSF group, 247 +/- 51 pg/ml) and macrophage inflammatory protein-2 (hypothermia group, 239 +/- 43 pg/ml; hypothermia plus G-CSF group, 178 +/- 21 pg/ml).

Conclusions
In this rat model of intraabdominal sepsis, postoperative hypothermia was deleterious. However, G-CSF treatment, initiated before contamination, reduced the mortality rate, increased the neutrophil count, and downgraded the systemic cytokine response.
Open-lung Protective Ventilation with Pressure Control Ventilation, High-frequency Oscillation, and Intratracheal Pulmonary Ventilation Results in Similar Gas Exchange, Hemodynamics, and Lung Mechanics
Authors: Sedeek Khaled A. , Takeuchi Muneyuki , Suchodolski Klaudiusz , Vargas Sara O. , Shimaoka Motomu , Schnitzer Jay J. , Kacmarek Robert M. 
Published: November 2003

Background
Pressure control ventilation (PCV), high-frequency oscillation (HFO), and intratracheal pulmonary ventilation (ITPV) may all be used to provide lung protective ventilation in acute respiratory distress syndrome, but the specific approach that is optimal remains controversial.

Methods
Saline lavage was used to produce acute respiratory distress syndrome in 21 sheep randomly assigned to receive PCV, HFO, or ITPV as follows: positive end-expiratory pressure (PCV and ITPV) and mean airway pressure (HFO) were set in a pressure-decreasing manner after lung recruitment that achieved a ratio of Pao2/Fio2 > 400 mmHg. Respiratory rates were 30 breaths/min, 120 breaths/min, and 8 Hz, respectively, for PCV, ITPV, and HFO. Eucapnia was targeted with peak carinal pressure of no more than 35 cm H2O. Animals were then ventilated for 4 h.

Results
There were no differences among groups in gas exchange, lung mechanics, or hemodynamics. Tidal volume (PCV, 8.9 +/- 2.1 ml/kg; ITPV, 2.7 +/- 0.8 ml/kg; HFO, approximately 2.0 ml/kg) and peak carinal pressure (PCV, 30.6 +/- 2.6 cm H2O; ITPV, 22.3 +/- 4.8 cm H2O; HFO, approximately 24.3 cm H2O) were higher in PCV. Pilot histologic data showed greater interstitial hemorrhage and alveolar septal expansion in PCV than in HFO or ITPV.

Conclusion
These data indicate that HFO, ITPV, and PCV when applied with an open-lung protective ventilatory strategy results in the same gas exchange, lung mechanics, and hemodynamic response, but pilot data indicate that lung injury may be greater with PCV.
Cholinergic Reversal of Isoflurane Anesthesia in Rats as Measured by Cross-approximate Entropy of the Electroencephalogram
Authors: Hudetz Anthony G. , Wood James D. , Kampine John P. 
Published: November 2003

Background
Pharmacologic modulation of the state of consciousness is of interest for clinical practice and for a better understanding of anesthetic mechanisms. The cholinergic activating system is an important regulator of the state of consciousness during general anesthesia. Entropy of the electroencephalogram has been proposed as a promising measure of anesthetic depth. The authors have shown that volatile anesthetics decrease cross-approximate entropy (C-ApEn) of the bihemispheric frontal electroencephalogram in rats. The effect of cholinergic agents on C-ApEn has not been examined. Here, the authors test the hypothesis that cholinergic activation reverses the effect of isoflurane anesthesia on C-ApEn.

Methods
An electroencephalogram in the 1- to 100-Hz range was recorded bipolarly, with epidural leads from the frontal cortex of both hemispheres, and used to calculate C-ApEn, which reflects statistical independence of bihemispheric electroencephalographic activity. Cholinesterase inhibitor, neostigmine (25 mug), or the muscarinic agonist oxotremorine (25 mug) were infused intracerebroventricularly while the rats were inhaling 1.0% (0.7 minimum alveolar concentration) isoflurane. In other animals, isoflurane was lowered to 0.4% (0.3 minimum alveolar concentration) to assess the electroencephalogram in a sedated, waking state.

Results
At 1.0% isoflurane, C-ApEn decreased by 54% compared with that at 0.4%, but the motor reflex response to tail pinch was still present. Cholinergic agents reversed the electroencephalogram-depressant effect of isoflurane, i.e., C-ApEn rose to the level measured at 0.4% isoflurane. The rise in C-ApEn was paralleled by the appearance of spontaneous limb and orofacial explorative movements, suggesting a return of consciousness. In contrast, cholinergic agents fully blocked the motor reflex to tail pinch.

Conclusions
C-ApEn of the bihemispheric electroencephalogram correlates with the return of spontaneous motor signs but not with the nociceptive reflex. Cerebral cholinergic activation dissociates central and peripheral anesthetic effects. C-ApEn, a novel measure of interhemispheric electroencephalogram independence, is a promising correlate of depth of sedation and state of consciousness.
Effects of Spontaneous Breathing during Airway Pressure Release Ventilation on Intestinal Blood Flow in Experimental Lung Injury
Authors: Hering Rudolf , Viehöfer Andreas , Zinserling Jörg , Wrigge Hermann , Kreyer Stefan , Berg Andreas , Minor Thomas , Putensen Christian 
Published: November 2003

Background
In critical illness, the gut is susceptible to hypoperfusion and hypoxia. Positive-pressure ventilation can affect systemic hemodynamics and regional blood flow distribution, with potentially deleterious effects on the intestinal circulation. The authors hypothesized that spontaneous breathing (SB) with airway pressure release ventilation (APRV) provides better systemic and intestinal blood flow than APRV without SB.

Methods
Twelve pigs with oleic acid-induced lung injury received APRV with and without SB. When SB was abolished, either the tidal volume or the ventilator rate was increased to maintain pH and arterial carbon dioxide tension constant as compared to APRV with SB. Systemic hemodynamics were determined by double indicator dilution. Blood flow to the intestinal mucosa-submucosa and muscularis-serosa was measured using colored microspheres.

Results
Systemic blood flow increased during APRV with SB. During APRV with SB, mucosal-submucosal blood flow (ml. g-1. min-1) was 0.39 +/- 0.21 in the stomach, 0.76 +/- 0.35 in the duodenum, 0.71 +/- 0.35 in the jejunum, 0.71 +/- 0.59 in the ileum, and 0.63 +/- 0.21 in the colon. During APRV without SB and high tidal volumes, it decreased to 0.19 +/- 0.03 in the stomach, 0.42 +/- 0.21 in the duodenum, 0.37 +/- 0.10 in the jejunum, 0.3 +/- 0.14 in the ileum, and 0.41 +/- 0.14 in the colon (P < 0.001, respectively). During APRV without SB and low tidal volumes, the respective mucosal-submucosal blood flows decreased to 0.24 +/- 0.10 (P < 0.01), 0.54 +/- 0.21 (P < 0.05), 0.48 +/- 0.17 (P < 0.01), 0.43 +/- 0.21 (P < 0.01), and 0.50 +/- 0.17 (P < 0.001) as compared to APRV with SB. Muscularis-serosal perfusion decreased during full ventilatory support with high tidal volumes in comparison with APRV with SB.

Conclusion
Maintaining SB during APRV was associated with better systemic and intestinal blood flows. Improvements were more pronounced in the mucosal-submucosal layer.
Cyclooxygenase-1 in the Spinal Cord Is Altered after Peripheral Nerve Injury
Authors: Zhu Xiaoying , Eisenach James C. 
Published: November 2003

Background
The mechanisms underlying neuropathic pain are incompletely understood and its treatment is often unsatisfactory. Spinal cyclooxygenase-2 (COX-2) expression is upregulated after peripheral inflammation, associated with spinal prostaglandin production leading to central sensitization, but the role of COX isoenzymes in sensitization after nerve injury is less well characterized. The current study was undertaken to determine whether COX-1 was altered in this model.

Methods
Male rats underwent partial sciatic nerve transsection (PSNT) or L5-L6 spinal nerve ligation (SNL). Four weeks after PSNT and 4 h, 4 days, or 2 weeks after SNL, COX-1 immunohistochemistry was performed on the L2-S2 spinal cord.

Results
COX-1 immunoreactivity (COX-1-IR) was unaffected 4 h after SNL. In contrast, 4 days after SNL, the number of COX-1-IR cells increased in the ipsilateral spinal cord. COX-1-IR increased in cells with glial morphology in the superficial laminae, but decreased in the rest of the ipsilateral spinal cord 4 weeks after PSNT and 2 weeks after SNL. These changes in immunostaining were greatest at the L5 level.

Conclusion
These data suggest that COX-1 expression in the spinal cord is not static, but changes in a time- and laminar-dependent manner after nerve injury. These anatomic data are consistent with observations by others that spinally administered specific COX-1 inhibitors may be useful to prevent and treat neuropathic pain.
Ethanol‐Induced Cephalic Apoptosis Requires Phospholipase C‐Dependent Intracellular Calcium Signaling
Authors: Debelak‐Kragtorp Katherine A. , Randall Armant D. , Smith Susan M. 
Published: November 2003

Background: Although the ability of ethanol to elicit neural crest cell apoptosis is well documented, the initial target of ethanol in these cells, and the biochemical pathway leading to their apoptosis, have yet to be determined. Recent work in preimplantation mouse embryos demonstrates that ethanol induces a phospholipase‐C (PLC)‐dependent calcium transient that mediates ethanol's effects. We tested whether a similar effect on calcium and PLC is involved in ethanol‐induced neural crest apoptosis.Methods: Chicken embryos were collected and loaded with Fluo‐3‐AM to assess the effects of ethanol on intracellular calcium levels. Pharmacological agents were used to determine the sources and mechanism of intracellular calcium increases. In separate experiments, embryos were treated in ovo with pharmacological modulators of calcium signaling prior to ethanol exposure, and resulting levels of cell death were assessed by using the vital dye acridine orange.Results: Ethanol exposure caused a localized increase in intracellular calcium levels in embryonic neural folds within 15 sec of ethanol exposure. Ethanol‐induced apoptosis was specifically blocked by chelation of intracellular calcium before ethanol exposure. Pretreatment with the PLC inhibitor U73122 blocked ethanol‐induced apoptosis as well as the intracellular calcium transient. Depletion of extracellular calcium resulted in a partial block of ethanol‐induced apoptosis.Conclusions: Ethanol exposure alters calcium signaling within the neurulation‐stage chicken embryo in a PLC‐dependent manner. Increases in intracellular calcium and PLC activity are necessary for ethanol's induction of apoptosis within cephalic populations. These effects likely represent an early and crucial event in the pathway leading to ethanol‐induced cell death.
Effects of Acamprosate on Excitatory Amino Acids During Multiple Ethanol Withdrawal Periods
Authors: Dahchour Abdelkader , De Witte Philippe 
Published: November 2003

Background: Our previous studies on the effects of acamprosate on enhanced locomotion during repeated withdrawals are now extended to the effects of acamprosate on excitatory amino acids in the hippocampus during repeated ethanol withdrawals.Methods: In this study, Wistar rats were made ethanol dependent by 4 weeks of vapor inhalation. After this first cycle of chronic ethanol treatment, rats underwent repeated and alternate cycles of 24 hr withdrawals and 1 week of chronic ethanol treatment. The microdialysis technique was used together with high‐performance liquid chromatography and electrochemical detection to quantify different amino acids such as aspartate and glutamate.Results: An intraperitoneal administration of acamprosate (400 mg/kg) to naïve rats did not alter aspartate or glutamate levels compared with the saline groups. During the first cycle of ethanol withdrawal, the administration of acamprosate (400 mg/kg, intraperitoneally) 2 hr after the commencement of ethanol withdrawal decreased both aspartate and glutamate microdialysate levels when compared with their respective saline group. Acamprosate administration also significantly decreased glutamate levels during the third withdrawal compared with the saline group, whereas no changes were seen in aspartate levels.Conclusion: The results of this work demonstrate that acamprosate reduced the excitatory amino acid glutamate increase observed during repeated ethanol withdrawal. These effects of acamprosate may provide a protective mechanism against neurotoxicity by reducing excitatory amino acids, particularly glutamate.
Ethanol Drinking Experience Attenuates (‐)Sulpiride‐Induced Increases in Extracellular Dopamine Levels in the Nucleus Accumbens of Alcohol‐Preferring (P) Rats
Authors: Engleman Eric A. , McBride William J. , Li Ting‐Kai , Lumeng Lawrence , Murphy James M. 
Published: November 2003

Background:The reinforcing properties of ethanol may be partly mediated through the mesolimbic dopamine (DA) system. This study examines the effects of local application of the DA D2receptor antagonist (‐)sulpiride (SUL) on ethanol drinking of alcohol‐preferring (P) rats, and extracellular DA levels in the nucleus accumbens (NAc) of P rats that were either ethanol‐naive or had been chronically drinking ethanol.Methods:Microdialysis was used to sample NAc DA levels, and reverse microdialysis was used to locally administer the D2antagonist (‐)sulpiride (SUL) into the NAc of adult female P rats that were either drinking ethanol (n= 17) or were ethanol‐naive (n= 24). Stable intake of 15% (v/v) ethanol (≥0.75 g/kg) was established for the ethanol‐drinking group in daily 1‐hr access periods over a minimum of 4 weeks before surgery. Naive and ethanol‐drinking rats were implanted with bilateral guide cannulae aimed 4 mm above the NAc shell. After recovery from surgery, microdialysis probes (active area = 2 mm) were inserted bilaterally into the NAc. Two days later, rats in the ethanol‐drinking and naive groups were each divided into two groups; one group was bilaterally perfused (1.0 μl/min) with artificial cerebrospinal fluid (aCSF) and the other group was further divided into three subgroups that were perfused with aCSF + either 50, 100, or 200 μM SUL for 240 min. During the last 60 min of perfusion, the ethanol‐drinking rats were given their daily 1‐hr ethanol access period. Following ethanol access, the aCSF + SUL subgroups were then given aCSF only. The entire perfusion procedure was repeated 24 hr later, but the aCSF only and aCSF + SUL group treatment conditions were transposed.Results:In ethanol‐drinking rats, 100 and 200 μM SUL increased extracellular NAc DA levels to approximately 200% of basal values, but did not significantly alter ethanol intake. In ethanol‐naive P rats, 100 and 200 μM SUL increased extracellular NAc DA levels significantly more (450% of basal;p< 0.05) than in the ethanol‐drinking group.Conclusions:The findings are consistent with the hypothesis that ethanol‐drinking experience causes a desensitization or a down‐regulation of D2autoreceptors in the NAc of P rats.
Cognitive Efficiency in Stimulant Abusers With and Without Alcohol Dependence
Authors: Lawton‐Craddock Andrea , Nixon Sara Jo , Tivis Rick 
Published: November 2003

Background: Although previous studies have found stimulant (i.e., cocaine, methamphetamine) abusers and alcoholics to have neuropsychological deficits, research examining which cognitive abilities are most affected by concurrent exposure to these substances is lacking. To address this issue, detoxified men and women who met criteria for dependence of (a) alcohol only (ALC) (n= 15); (b) stimulants only (STIM) (n= 15); and (c) both alcohol and stimulants (A/STIM) (n= 15) were compared with age‐ and education‐matched community controls (n= 15).Methods: Tasks that measured visual spatial skills, problem‐solving and abstraction, short‐term memory, cognitive flexibility, and gross motor speed were administered to participants. For each test, both speed and accuracy were assessed and an efficiency ratio (accuracy/time) was derived. Based on an average of these efficiency ratios, an overall performance index of cognitive efficiency was obtained.Results: Overall, controls performed more efficiently than all other groups. However, they were statistically significantly better only in relation to the A/STIM and STIM groups (p < 0.01). Individual comparisons revealed that the ALC group performed significantly better than the STIM group, although the ALC group did not differ from either the control or A/STIM groups (p≤ 0.05). This pattern of results was relatively consistent across the individual subtests of problem‐solving/abstraction, short‐term memory, and cognitive flexibility.Conclusions: As expected, substance abuse was associated with cognitive inefficiency. More importantly, these findings suggest that the cognitive effects of chronic stimulant abuse are not additive with those of alcohol abuse. That is, singly addicted stimulant abusers demonstrated similar or greater neurocognitive impairments than individuals who abuse alcohol and stimulants concurrently. The reason for this pattern is speculative but may be attributed to alcohol's opposing actions on cerebrovascular effects brought on by stimulant abuse.
Phagocytosis and Production of Reactive Oxygen Species by Peripheral Blood Phagocytes in Patients With Different Stages of Alcohol‐Induced Liver Disease: Effect of Acute Exposure to Low Ethanol Concentrations
Authors: Parlesak Alexandr , Schäfer Christian , Paulus Sonja Barbara , Hammes Susanne , Diedrich Jens Peter , Bode Christiane 
Published: November 2003

Background: In rodents, the development of alcoholic liver disease (ALD) after chronic alcohol feeding was shown to depend on the activity of enzymes that are necessary for production of reactive oxygen species (ROS) in phagocytes. The aim of this study was to determine the formation of ROS by resting and challenged phagocytes of patients with different stages of ALD in the presence of ethanol concentrations commonly found in the blood of alcohol abusers.Patients and Methods: The release of ROS and the phagocytosis of bacteria by neutrophils and monocytes obtained from 60 patients, who were categorized in three groups due to the severity of ALD, were compared to that of 28 healthy controls. ROS release by these phagocytes was measured after challenging with endotoxin and the addition of ethanol (22 and 44 mM).Results: Resting neutrophils but not monocytes from patients with severe stages of ALD produced significantly more ROS than those of healthy controls. Basal values of ROS production from neutrophils correlated closely to markers of the severity of ALD. ROS formation was depressed dose‐dependently by ethanol in the healthy controls but not in alcohol abusers.Conclusions: Changes in the ROS metabolism of phagocytes found in this study might contribute to both the development of ALD and the impaired immune response occurring in patients with severe ALD.