bluuebunny/crossref_metadata_2025 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.
Emerging Techniques in Biomedical Research and Their Application to Alcohol Toxicity
Authors: Patel Vinood B. , Chaurand Pierre , Caprioli Richard M. , Austen Brian M. , Frears Emma R. , Manca Francesca , Davies Huw , Vrana Kent E. , Wheeler Michael , Preedy Victor R.
Published: November 2003

This article represents the proceedings of a symposium at the 2002 RSA‐ISBRA Meeting in San Francisco. The chairs were Vinood B. Patel and Victor R. Preedy. The presentations were (1) Macromolecular structural analysis, by Vinood B. Patel; (2) Profiling and imaging of proteins in tissue sections using mass spectrometry as a discovery tool in biological research, by Pierre Chaurand and Richard M. Caprioli; (3) The use of SELDI ProteinChip™ arrays, by Brian M. Austen, Emma R. Frears, Francesca Manca, and Huw Davies; (4) DNA hybridization array technologies, by Kent E. Vrana; and (5) Adeno‐ and adeno‐associated viral mediated gene transfer approaches for alcoholic liver disease, by Michael Wheeler. Concluding remarks were by Victor R. Preedy.
Neural Stem Cells and Alcohol
Authors: Crews F. T. , Miller Michael W. , Ma Wu , Nixon Kim , Zawada W. Michael , Zakhari Sam
Published: November 2003

This article summarizes the proceedings of a symposium held at the 2002 Research Society on Alcoholism Meeting in San Francisco, California. The aim of this symposium was to review research on the effects of ethanol on neural stems cells and neurogenesis. Ethanol is known to alter neurogenesis during development; however, recent studies indicate that the brain forms new neurons from stem cells throughout life. Furthermore, stem cells can be transplanted into the brain, creating exciting new possibilities to study brain function. The symposium covered these research areas. Dr. Michael W. Miller reviewed knowledge on the effects of ethanol on stem cell proliferation and differentiation during development. Dr. Wu Ma described studies in culture indicating that (1) neural stem cells express functional muscarinic acetylcholine receptors (mAchR), (2) mAchR‐mediated proliferation involves Ca2+ signaling and mitogen‐activated protein kinase phosphorylation, and (3) phosphoinositol‐3 kinase is a downstream effector for mAchR‐mediated cell proliferation via activation of Akt. Drs. Kim Nixon and Fulton T. Crews followed with in vivo studies on ethanol's effects on adult neural stem cell proliferation and differentiation. Dr. W. Michael Zawada described studies directed at dopamine neuron cell transplants into mammalian central nervous system. These studies clearly establish that ethanol has significant effects on stem cells.
Genetics of Alcoholism Using Intermediate Phenotypes
Authors: Enoch Mary‐Anne , Schuckit Marc A. , Johnson Bankole A. , Goldman David
Published: November 2003

This article represents the proceedings of a symposium at the 2002 meeting of the Research Society on Alcoholism in San Francisco, CA. It was organized by Mary‐Anne Enoch and David Goldman and chaired by David Goldman. The presentations were (1) Two functional polymorphisms and their intermediate phenotypes in complex behaviors: COMT/executive cognition and anxiety and HTT/anxiety, by David Goldman; (2) Role of the EEG in determining genetic risk for alcoholism and anxiety disorders, by Mary‐Anne Enoch; (3) The response to alcohol as an intermediate phenotype for alcoholism, by Marc A. Schuckit; and (4) Pharmacogenomic approaches to alcoholism treatment: toward a hypothesis, by Bankole A. Johnson.
Recent Research on the Comorbidity of Alcoholism and Pathological Gambling
Authors: Stewart Sherry H. , Kushner Matt G.
Published: November 2003

This article summarizes a symposium held at the 2002 Annual Meeting of the Research Society on Alcoholism in San Francisco, CA, and was prepared on behalf of the symposium participants by the symposium co‐organizers/co‐chairs. Prior research with both clinical and nonclinical populations indicates a high comorbidity between alcohol‐use disorders and pathological gambling. This symposium involved a set of papers in which exciting new research on this form of comorbidity was presented. The studies spanned populations of problem‐gambling helpline callers, problem gamblers attempting to recover, and community‐recruited gambler research volunteers. The studies used methodologies ranging from questionnaire and interview to laboratory‐based paradigms (i.e., cognitive and alcohol challenge). Study designs ranged from cross‐sectional to longitudinal and from correlation to experiment. The symposium highlighted novel approaches that researchers are using to enhance understanding of functional relations that may underlie this common comorbidity.
Services Integration and Cost‐Effectiveness
Authors: Hilton Michael E. , Fleming Michael , Glick Henry , Gutman Marjorie A. , Lu Yun , McKay James , McLellan A. Thomas , Manning Willard , Meadows Julie , Mertens Jennifer R. , Moore Charles , Mullahy John , Mundt Marlon , Parthasarathy Sujaya , Polsky Daniel , Ray G. Thomas , Sterling Stacy , Weisner Constance
Published: November 2003

Alcohol treatment services are increasingly combined with other health and social services to address the needs of multiple‐problem clients. Hence, it has been of growing policy interest to find the most effective and the most cost‐effective ways of linking these services. This symposium presents some recent studies in this area. The small but growing body of studies in this area has great potential to inform public policy debates.
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.
Coregulation of Ethanol Discrimination by the Nucleus Accumbens and Amygdala
Authors: Besheer Joyce , Cox Amy A. , Hodge Clyde W.
Published: November 2003

Background: Activation of GABAA receptors in the amygdala or nucleus accumbens produces discriminative stimulus effects that substitute fully for those of systemically administered ethanol. This study was conducted to determine if GABAA receptors in the amygdala and nucleus accumbens interactively modulate ethanol discrimination.

Methods: Male Long‐Evans rats were trained to discriminate between intraperitoneal injections of ethanol (1 g/kg) and saline on a 2‐lever drug discrimination task. The rats were then surgically implanted with bilateral injection cannulae aimed at the nucleus accumbens and the amygdala.

Results: Infusion of the GABAA agonist muscimol in the nucleus accumbens resulted in full substitution for systemically administered ethanol. Concurrent infusion of the GABAA antagonist bicuculline in the amygdala shifted the muscimol substitution curve in the nucleus accumbens 10‐fold to the right.

Conclusions: These results indicate that blockade of GABAA receptors in the amygdala significantly reduces the potency of the GABAA agonist in the nucleus accumbens. This suggests that the ethanol‐like stimulus effects of GABAA receptor activation in the nucleus accumbens are modulated by GABAA receptor activity in the amygdala. These data support the hypothesis that the addictive stimulus properties of alcohol are mediated by GABAergic transmission in a neural circuit involving the amygdala and nucleus accumbens.
Enduring Effects of Chronic Ethanol in the CNS: Basis for Alcoholism
Authors: Diana Marco , Brodie Mark , Muntoni Annalisa , Puddu Maria C. , Pillolla Giuliano , Steffensen Scott , Spiga Saturnino , Little Hilary J.
Published: November 2003

This symposium focused on functional alterations in the mesolimbic dopamine system during the abstinence phase after chronic alcohol intake. Mark Brodie first described his recordings from midbrain slices prepared after chronic alcohol treatment in vivo by daily injection in C57BL/6J mice. No changes were found in the baseline firing frequency of dopaminergic neurones in the VTA (ventral tegmental area), but the excitation produced in these neurones by an acute ethanol challenge was significantly increased in neurons from ethanol‐treated mice compared with those from the saline‐treated controls. There was also a significant decrease in the inhibitory response to GABA by the dopamine neurones following the chronic ethanol treatment. These data suggest that the timing pattern and mode of ethanol administration may determine the types of changes observed in dopaminergic reward area neurons. Annalisa Muntoni lectured on the relationship between electrophysiological and biochemical in vivo evidence supporting a reduction in tonic activity of dopamine neurons projecting to the nucleus accumbens at various times after suspension of chronic ethanol treatment and morphological changes affecting dopamine neurons in rat VTA. Hilary J. Little then described changes in dopaminergic neurone function in the VTA during the abstinence phase. Decreases in baseline firing were seen at 6 days after withdrawal of mice from chronic ethanol treatment but were not apparent after 2 months abstinence. Increases in the affinity of D1 receptors in the striatum, but not in the cerebral cortex, were seen however up to 2 months after withdrawal. Scott Steffensen then described his studies recording in vivo from GABA containing neurones in the VTA in freely moving rats. Chronic ethanol administration enhanced the baseline activity of these neurones and resulted in tolerance to the inhibition by ethanol of these neurones. His results demonstrated selective adaptive circuit responses within the VTA or in extrategmental structures that regulate VTA‐GABA neurone activity.
EEG Low‐Voltage Alpha and Alpha Power in African American Young Adults: Relation to Family History of Alcoholism
Authors: Ehlers Cindy L. , Phillips Evelyn
Published: November 2003

Background: Several studies support an association between having a low‐voltage EEG and alcohol dependence; however, it is not clear whether this measure represents a risk marker or is a result of years of heavy drinking. The present study's aims were to investigate the prevalence of low‐voltage alpha EEG variants in African American young adults who have not yet developed alcohol dependence and to test for associations between low‐voltage alpha (LVA) EEG, alpha power, and a family history of alcohol dependence.

Methods: Clinical ratings and spectral characteristics of the EEG, collected using bipolar recordings, were investigated in 81 African American young adult men and women (18–25 years old) who had no personal history of alcohol dependence. Information on psychiatric diagnoses, personality features, personal drinking and drug use history, and family history (FH) of alcoholism was obtained.

Results: Thirty‐two percent (n= 26) of the participants had an LVA EEG variant, and an additional 22% (n= 18) had borderline LVA. The presence of an LVA variant was not associated with drinking status, a family history of alcoholism, or a personal history of anxiety disorders but was associated with significantly higher extroversion scores. Participants who had an FH of alcoholism had significantly higher spectral power in the slow alpha frequencies (7.5–9 Hz). FH was not associated with any significant differences in any other EEG frequency band.

Conclusions: These findings suggest that considerable ethic variation may exist in the prevalence of LVA EEG variants. In addition, like findings in other populations of non‐African descent, having an FH of alcohol dependence may be associated with significantly higher voltage in the alpha frequency ranges.
Ethanol Potentiation of Glycine Receptors Expressed in Xenopus Oocytes Antagonized by Increased Atmospheric Pressure
Authors: Davies Daryl L. , Trudell James R. , Mihic S. John , Crawford Daniel K. , Alkana Ronald L.
Published: November 2003

Background: Behavioral and biochemical studies indicate that exposure to 12 times normal atmospheric pressure (12 ATA) of helium‐oxygen gas (heliox) is a direct, selective ethanol antagonist. The current study begins to test the hypothesis that ethanol acts by a common mechanism on ligand‐gated ion channels by expanding previous hyperbaric investigations on γ‐aminobutyric acid type A (GABAA) receptors (GABAARs) at the biochemical level to α1glycine (GlyRs) expressed in Xenopus oocytes.

Methods: Oocytes expressing wild‐type α1 homomeric GlyRs were voltage‐clamped (−70 mV) and tested in the presence of glycine (EC2) ± ethanol (50–200 mM) under 1 ATA control and 3 to 12 ATA heliox conditions. Glycine concentration response curves, strychnine/glycine interactions, and zinc (Zn2+) modulation of GlyR function was also tested.

Results: Pressure reversibly antagonized the action of ethanol. The degree of antagonism increased as pressure increased. Pressure did not significantly alter the effects of glycine, strychnine, or Zn2+, indicating that ethanol antagonism by pressure cannot be attributed to alterations by pressure of normal GlyR function. The antagonism did not reflect tolerance to ethanol, receptor desensitization, or receptor rundown.

Conclusion: This is the first use of hyperbarics to investigate the mechanism of action of ethanol in recombinant receptors. The findings indicate that pressure directly and selectively antagonizes ethanol potentiation of α1GlyR function in a reversible and concentration‐ and pressure‐dependent manner. The sensitivity of ethanol potentiation of GlyR function to pressure antagonism indicates that ethanol acts by a common, pressure‐antagonism–sensitive mechanism in GlyRs and GABAARs. The findings also support the hypothesis that ethanol potentiation of GlyR function plays a role in mediating the sedative‐hypnotic effects of ethanol.
Subjective Intoxication in Response to Alcohol Challenge: Heritability and Covariation With Personality, Breath Alcohol Level, and Drinking History
Authors: Viken Richard J. , Rose Richard J. , Morzorati Sandra L. , Christian Joe C. , Li Ting‐Kai
Published: November 2003

Background: Numerous studies have identified differences in subjective response to alcohol in subjects differentiated by family history of alcoholism. Results suggest that genetic influences on individual variation in subjective response to alcohol may be a mechanism for genetic effects on alcohol problems. However, direct evidence for genetic effects on subjective response to alcohol is very limited.

Methods: In a sample of 99 adult twin pairs, we studied genetic influences on subjective intoxication after alcohol challenge. The twins ingested a standard dose of ethanol (0.70 g/kg for men/0.65 g/kg for women), and two measures of subjective response to alcohol were assessed.

Results: Genetic effects on variation in subjective intoxication reported 1 hr after drinking were significant and substantial: heritability was 0.60 for a 22‐item scale and 0.48 for a brief 2‐item measure. Self‐report measures of neuroticism, psychasthenia, hostility, and family problems shared significant genetic covariation with subjective intoxication. Achieved breath alcohol level, rate of change in breath alcohol on the descending limb, and individual drinking history all shared familial variation with subjective intoxication. No significant genetic effects for subjective intoxication were found 2 hr after drinking, but familial influences remained present, and many of the same personality, drinking history, and breath alcohol variables were predictive of intoxication.

Conclusions: Subjective response to alcohol is heritable, and genetic effects on subjective intoxication are partly shared with genetic effects on personality.
The Reliability and Validity of the Self‐Reported Drinking Measures in the Army's Health Risk Appraisal Survey
Authors: Bell Nicole S. , Williams Jeffrey O. , Senier Laura , Strowman Shelley R. , Amoroso Paul J.
Published: November 2003

Background: The reliability and validity of self‐reported drinking behaviors from the Army Health Risk Appraisal (HRA) survey are unknown.

Methods: We compared demographics and health experiences of those who completed the HRA with those who did not (1991–1998). We also evaluated the reliability and validity of eight HRA alcohol‐related items, including the CAGE, weekly drinking quantity, and drinking and driving measures. We used Cohen's κ and Pearson's r to assess reliability and convergent validity. To assess criterion (predictive) validity, we used proportional hazards and logistical regression models predicting alcohol‐related hospitalizations and alcohol‐related separations from the Army, respectively.

Results: A total of 404,966 soldiers completed an HRA. No particular demographic group seems to be over‐ or underrepresented. Although few respondents skipped alcohol items, those who did tended to be older and of minority race. The alcohol items demonstrate a reasonable degree of reliability, with Cronbach's α= 0.69 and test‐retest reliability associations in the 0.75–0.80 range for most items over 2‐ to 30‐day interims between surveys. The alcohol measures showed good criterion‐related validity: those consuming more than 21 drinks per week were at 6 times the risk for subsequent alcohol‐related hospitalization versus those who abstained from drinking (hazard ratio, 6.36; 95% confidence interval=5.79, 6.99). Those who said their friends worried about their drinking were almost 5 times more likely to be discharged due to alcoholism (risk ratio, 4.9; 95% confidence interval=4.00, 6.04) and 6 times more likely to experience an alcohol‐related hospitalization (hazard ratio, 6.24; 95% confidence interval=5.74, 6.77).

Conclusions: The Army's HRA alcohol items seem to elicit reliable and valid responses. Because HRAs contain identifiers, alcohol use can be linked with subsequent health and occupational outcomes, making the HRA a useful epidemiological research tool. Associations between perceived peer opinions of drinking and subsequent problems deserve further exploration.
Alcohol Availability as a Predictor of Youth Drinking and Driving: A Hierarchical Analysis of Survey and Archival Data
Authors: Treno Andrew J. , Grube Joel W. , Martin Scott E.
Published: November 2003

Background: Much attention has recently been directed toward developing preventive interventions to reduce drinking and driving through efforts to limit the numbers and locations of alcohol outlets at the community level. Although evaluations of these efforts have suggested linkages between alcohol outlets and problem outcomes, they have not addressed the linkage between outlets and drinking and driving among youth. The analysis reported here investigats the relationship between alcohol outlet densities and underage drinking and driving as self‐reported on two telephone surveys conducted in California.

Methods: These analyses were based on data obtained from two telephone surveys conducted by the Prevention Research Center and archival data collected by the California Department of Alcoholic Beverage Control and the US Census Bureau. The sample for the first survey consisted of 15‐ to 20‐year‐old adolescents and young adults contacted by telephone, using a random digit dialing of exchanges in the greater San Francisco Bay Area. A second set of survey data was similarly collected by a random sample of households throughout California, and the Bay Area subset was also used for this analysis.

Results: At the individual level, older respondents were more likely to report drinking and driving and riding with drinking drivers, whereas females and Asians were less so. At the aggregate or city‐level, alcohol outlet density, as measured by the number of on‐ and off‐premises establishments licensed to sell alcohol, was associated with both drinking and driving and riding with drinking drivers. These effects were moderated by a number of individual level effects, with younger respondents and females more likely to be affected by outlet densities.

Conclusions: The findings here provide support for the implementation of policies targeting alcohol outlet density reductions. Areas with large numbers of such outlets provide ample opportunities to youth for alcohol purchases.
Protective Effect of Thalidomide on Endotoxin‐Induced Liver Injury
Authors: Enomoto Nobuyuki , Takei Yoshiyuki , Hirose Miyoko , Kitamura Tsuneo , Ikejima Kenichi , Sato Nobuhiro
Published: November 2003

Background: Activation of Kupffer cells by lipopolysaccharide (LPS) plays a pivotal role in the onset of pathophysiological events that occur during endotoxemia, and intracellular calcium concentration ([Ca2+]i) is involved in LPS‐stimulated cytokine production. Tumor necrosis factor (TNF)‐α is produced exclusively by the monocyte‐macrophage lineage, which is mostly made up of Kupffer cells, and thalidomide has been shown to reduce TNF‐α production from macrophages. However, there is increasing evidence that TNF‐α may play a role in the initiation or progression of multiple organ failure syndrome. Therefore, the purpose of this work was to determine whether thalidomide could prevent LPS‐induced liver injury.

Methods: Rats were given a single oral dose of thalidomide (5 mg/kg). To assess the sensitization of Kupffer cells, LPS (5 or 10 mg/kg) was administered intravenously, and mortality, liver histology, and transaminases were evaluated 24 hr later. Kupffer cells were isolated 2 hr after thalidomide treatment. After the addition of LPS, [Ca2+]i was measured by using a microspectrofluorometer with the fluorescent indicator fura‐2, and TNF‐α was measured by enzyme‐linked immunosorbent assay.

Results: LPS caused focal necrosis with neutrophil infiltration in the liver. Moreover, LPS dramatically increased transaminases. These pathologic parameters and increases of serum transaminases were diminished markedly by thalidomide. In isolated Kupffer cells, LPS‐induced increases in [Ca2+]i and TNF‐α production were suppressed by treatment with thalidomide. To further explore the mechanism by which thalidomide directly abrogated Kupffer cell sensitivity to LPS, we determined the effect of thalidomide (5 μM) in vitro on LPS‐induced [Ca2+]i response and TNF‐α production. With the addition of thalidomide (5 μM) in vitro to the culture media for 2 hr before LPS, these parameters were suppressed.

Conclusions: Thalidomide prevents LPS‐induced liver injury via mechanisms dependent on the suppression of TNF‐α production from Kupffer cells.
Dalteparin Sodium Prevents Liver Injury Due to Lipopolysaccharide in Rat Through Suppression of Tumor Necrosis Factor‐α Production by Kupffer Cells
Authors: Tsukada Shigeki , Enomoto Nobuyuki , Takei Yoshiyuki , Hirose Miyoko , Ikejima Kenichi , Kitamura Tsuneo , Sato Nobuhiro
Published: November 2003

Background: Sensitization of Kupffer cells (KC) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF)‐α play important roles in the pathogenesis of alcoholic liver damage and sepsis‐associated organ injury. Therefore, suppression of TNF‐α should prove useful for treatment of LPS‐induced liver injury. Recently, heparin has been reported to diminish TNF‐α production from macrophages in response to LPS. Dalteparin sodium (DS) is a low‐molecular‐weight heparin with a mean molecular weight of 5000. DS elicits an antithrombotic effect through a mechanism depending on anti–factor Xa activity but not on the antithrombin activity. DS is thus suitable for treatment of disseminated intravascular coagulation because it has a much smaller prohemorrhagic property. In this study, we evaluated whether DS could prevent LPS‐induced liver injury.

Methods: Female Wistar rats were administered DS (50 IU/kg intraperitoneally) followed by challenge with LPS (5 mg/kg intravenously) 2 hr later. Livers and sera were collected 24 hr later. KC from rats were isolated and cultured in RPMI 1640 supplemented with 10% fetal bovine serum. After the addition of LPS (10 μg/ml) to the culture media, intracellular Ca2+ was measured by using a fluorescent indicator, fura‐2.

Results: LPS (5 mg/kg intravenously) caused focal necrosis and neutrophil infiltration in the control liver. The histological changes and increased alanine aminotransferase levels caused by LPS injection were diminished by treatment with DS. LPS increased intracellular Ca2+ of KC in control rats from the basal level (26 ± 6 nmol/liter) to 280 ± 18 nmol/liter. This increase was blunted by DS (126 ± 28 nmol/liter). The DS treatment decreased the LPS‐induced TNF‐α production by KC from 911 ± 78 pg/ml to 309 ± 45 pg/ml (p < 0.05).

Conclusions: These results indicate that DS reduces the LPS‐induced liver injury through suppression of TNF‐α production.