bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinical impact of pharmacogenetics on the treatment of epilepsy
Authors: Löscher Wolfgang , Klotz Ulrich , Zimprich Fritz , Schmidt Dieter 
Published: July 2008

SummaryDrug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA‐B*1502, are at a higher risk for Stevens‐Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.
Role of Major NMDA or AMPA Receptor Subunits in MK‐801 Potentiation of Ethanol Intoxication
Authors: Palachick Benjamin , Chen Yi‐Chyan , Enoch Abigail J. , Karlsson Rose‐Marie , Mishina Masayoshi , Holmes Andrew 
Published: July 2008

Background: The glutamate system plays a major role in mediating EtOH’s effects on brain and behavior, and is implicated in the pathophysiology of alcohol‐related disorders.N‐methyl‐D‐aspartate receptor (NMDAR) antagonists such as MK‐801 (dizocilpine) interact with EtOH at the behavioral level, but the molecular basis of this interaction is unclear.Methods: We first characterized the effects of MK‐801 treatment on responses to the ataxic (accelerating rotarod), hypothermic and sedative/hypnotic effects of acute EtOH administration in C57BL/6J and 129/SvImJ inbred mice. Effects of another NMDAR antagonist, phencyclidine, on EtOH‐induced sedation/hypnosis were also assessed. Gene knockout of the NMDAR subunit NR2A orl‐alpha‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate GluR1 or pharmacological antagonism of the NMDAR subunit NR2B (via Ro 25‐6981) was employed to examine whether inactivating any one of these glutamate signaling molecules modified MK‐801’s effect on EtOH‐related behaviors.Results: MK‐801 markedly potentiated the ataxic effects of 1.75 g/kg EtOH and the sedative/hypnotic effects of 3.0 g/kg EtOH, but not the hypothermic effects of 3.0 g/kg EtOH, in C57BL/6J and 129/SvImJ mice. Phencyclidine potentiated EtOH‐induced sedation/hypnosis in both inbred strains. Neither NR2A nor GluR1 KO significantly altered basal EtOH‐induced ataxia, hypothermia, or sedation/hypnosis. Ro 25‐6981 modestly increased EtOH‐induced sedation/hypnosis. The ability of MK‐801 to potentiate EtOH‐induced ataxia and sedation/hypnosis was unaffected by GluR1 KO or NR2B antagonism. NR2A KO partially reduced MK‐801 + EtOH‐induced sedation/hypnosis, but not ataxia or hypothermia.Conclusions: Data confirm a robust and response‐specific potentiating effect of MK‐801 on sensitivity to EtOH’s intoxicating effects. Inactivation of three major components of glutamate signaling had no or only partial impact on the ability of MK‐801 to potentiate behavioral sensitivity to EtOH. Further work to elucidate the mechanisms underlying NMDAR × EtOH interactions could ultimately provide novel insight into the role of NMDARs in alcoholism and its treatment.
Prediction of Serotonergic Treatment Efficacy Using Age of Onset and Type A/B Typologies of Alcoholism
Authors: Roache John D. , Wang Yanmei , Ait‐Daoud Nassima , Johnson Bankole A. 
Published: July 2008

Background:  Previously, we reported that ondansetron was efficacious at treating early‐onset (≤25‐years old) but not late‐onset (≥26‐years old) alcoholics in a double‐blind, randomized, placebo‐controlled clinical trial (n = 321 enrolled patients, 271 of them randomized). Randomized participants underwent 11 weeks of treatment with ondansetron (1, 4, or 16 μg/kg twice daily; n = 67, 77, and 71, respectively) or identical placebo (n = 56), plus weekly standardized group cognitive behavioral therapy.Methods:  For this study, we reanalyzed the original sample to determine whether the Type A/B typological classification predicts ondansetron treatment response. In this comparative analysis, k‐means clustering was applied to 19 baseline measures of drinking behavior, psychopathology, and social functioning, similar to those used by Babor in the original typological derivation. A 2‐factor solution described robustly 2 groups phenomenologically consistent with Type A/B classification. Subjects were subdivided into early‐ and late‐onset alcoholics.Results:  Seventy‐two percent of Type B subjects had early‐onset alcoholism (EOA); 67% of Type A subjects had late‐onset alcoholism (LOA). The A/B typology better discriminated 2 clusters based upon baseline severity of alcoholism. There was a significant effect (p < 0.05) for Type B alcoholics to respond to ondansetron (4 μg/kg); however, Type A alcoholics receiving ondansetron showed no beneficial effect. Early‐onset vs. late‐onset classification predicted ondansetron response substantially better than Type A/B classification, which did not add to the prediction of treatment outcome. Further analyses showed that ondansetron was effective in the 33% of Type A alcoholics with EOA but ineffective in the 28% of Type B alcoholics with LOA.Conclusions:  Type A/B classification best discriminates alcoholic subtypes based upon baseline severity. Early‐ vs. late‐onset classification is, however, a better predictor of response to ondansetron treatment because it might be more closely related to fundamental neurobiological processes associated with the underlying pathophysiology of alcoholism.
Maturation‐Dependent Alcohol Resistance in the Developing Mouse: Cerebellar Neuronal Loss and Gene Expression During Alcohol‐Vulnerable and ‐Resistant Periods
Authors: Karaçay Bahri , Li Shenglan , Bonthius Daniel J. 
Published: July 2008

Background: Alcohol abuse during pregnancy injures the fetal brain. One of alcohol’s most important neuroteratogenic effects is neuronal loss. Rat models have shown that the cerebellum becomes less vulnerable to alcohol‐induced neuronal death as it matures.We determined if maturation‐dependent alcohol resistance occurs in mice and compared patterns of gene expression during the alcohol resistant and sensitive periods.Methods: Neonatal mice received alcohol daily over postnatal day (PD) 2 to 4 or PD8 to 10. Purkinje cells and granule cells were quantified on PD25. The temporal expression patterns of 4 neuro‐developmental genes and 3 neuro‐protective genes in the cerebellum were determined daily over PD0 to 15 to determine how gene expression changes as the cerebellum transitions from alcohol‐vulnerable to alcohol‐resistant. The effect of alcohol on expression of these genes was determined when the cerebellum is alcohol sensitive (PD4) and resistant (PD10).Results: Purkinje and granule cells were vulnerable to alcohol‐induced death at PD2 to 4, but not at PD8 to 10. Acquisition of maturation‐dependent alcohol resistance coincided with changes in the expression of neurodevelopmental genes. The vulnerability of cerebellar neurons to alcohol toxicity declined in parallel with decreasing levels of Math1 and Cyclin D2, markers of immature granule cells. Likewise, the rising resistance to alcohol toxicity paralleled increasing levels of GABA α‐6 and Wnt‐7a, markers of mature granule neurons. Expression of growth factors and genes with survival promoting function (IGF‐1, BDNF, and cyclic AMP response element binding protein) did not rise as the cerebellum transitioned from alcohol‐vulnerable to alcohol‐resistant. All 3 were expressed at substantial levels during the vulnerable period and were not expressed at higher levels later. Acute alcohol exposure altered the expression of neurodevelopmental genes and growth factor genes when administered either during the alcohol vulnerable period or resistant period. However, the patterns in which gene expression changed varied among the genes and depended on timing of alcohol administration.Conclusions: Mice have a temporal window of vulnerability in the first week of life, during which cerebellar neurons are more sensitive to alcohol toxicity than during the second week. Expression of genes governing neuronal maturation changes in synchrony with the acquisition of alcohol resistance. Growth factors do not rise as the cerebellum transitions from alcohol‐vulnerable to alcohol‐resistant. Thus, a process intrinsic to neuronal maturation, rather than rising levels of growth factors, likely underlies maturation‐dependent alcohol resistance.
Peptidergic Agonists of Activity‐Dependent Neurotrophic Factor Protect Against Prenatal Alcohol‐Induced Neural Tube Defects and Serotonin Neuron Loss
Authors: Zhou Feng C. , Fang Yuan , Goodlett Charles 
Published: July 2008

Introduction: Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5‐HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity‐dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity‐dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol‐induced deficits in brain development.Methods: Timed‐pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5‐HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5‐HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5‐HT‐immunostained neurons were also obtained in the rostral and caudal raphe.Results: Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5‐HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5‐HT projections) and in the caudal raphe (that gives rise to the descending 5‐HT projections). Concurrent treatment of the alcohol‐consuming dams with SAL prevented dysraphia and protected against the alcohol‐induced reductions in 5‐HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5‐HT loss in the rostral raphe, but did protect against loss in the caudal raphe.Conclusions: These findings further support the potential usefulness of these peptides for therapeutic interventions in pregnancies at risk for alcohol‐induced developmental deficits. Notably, the ascending 5‐HT projections of the rostral raphe have profound effects in regulating forebrain development and function, and the descending 5‐HT projections of the caudal raphe are critical for regulating respiration. Protection of the rostral 5‐HT‐system may help prevent structural and functional deficits linked to abnormal forebrain development, and protection of the caudal systems may also reduce the increased risk for sudden infant death syndrome associated with prenatal alcohol exposure.
The Healthy Moms Study: The Efficacy of Brief Alcohol Intervention in Postpartum Women
Authors: Fleming Michael F. , Lund Michael R. , Wilton Georgiana , Landry Mary , Scheets Dawn 
Published: July 2008

Background:  The prevention and treatment of alcohol use disorders among women of reproductive age have been well described. However, there is limited information on women specifically during the postpartum period. This period in a woman’s life is a time of transition and it provides an ideal opportunity for primary care providers to intervene.Purpose:  The goal of this report was to present the results of a brief alcohol intervention conducted in 34 obstetrical practices with women seeking routine postpartum care.Methods:  A randomized clinical trial was conducted from 2002 to 2005 in a diverse sample of women located in 15 Wisconsin counties. This report presents 6‐month follow‐up data.Results:  A total of 8,706 women were screened for high‐risk alcohol use during routine postpartum care with 997 (12%) of these women testing positive for at‐risk drinking. A total of 235 women met inclusion criteria and were randomized to either “usual care” or “brief intervention.” The 4‐session intervention was delivered by outpatient obstetrical nurses and research staff. The mean age of the women in the sample was 28, 19.3% were from minority groups, 60.8% were married, 53.2% reported current tobacco use, and 17.9% had used marijuana in the previous 30 days. At the 6 month follow‐up appointment, there were significant reductions in mean number of total drinks in the previous 28 days (p < 0.013), number of drinking days (p < 0.024) and heavy drinking days (p < 0.019). In addition to a statistical difference between groups, there was a 19% difference in the mean number of drinks and number of drinking days, and a 36% difference in the number of heavy drinking days in favor of the intervention group.Conclusion:  The findings of the Healthy Moms Trial support the implementation of brief alcohol intervention during the postpartum period.
The Role of Behavioral Impulsivity in the Development of Alcohol Dependence: A 4‐Year Follow‐Up Study
Authors: Rubio Gabriel , Jiménez Mónica , Rodríguez‐Jiménez Roberto , Martínez Isabel , Ávila César , Ferre Francisco , Jiménez‐Arriero Miguel Angel , Ponce Guillermo , Palomo Tomás 
Published: July 2008

Background:  Although many studies have established a close relation between impulsivity and alcohol use disorders, little is known about the role of behavioral impulsivity in the development of these disorders.Objectives:  To determine the role of 2 laboratory paradigms of impulsivity in the development of alcohol use disorders.Methods:  Follow‐up study carried out with 471 participants diagnosed as heavy drinkers (HD) and followed‐up for 4 years. Initially, they were compared with a healthy control group. Assessment of behavioral impulsivity was carried out with the Continuous Performance Test (CPT), and the Stop‐Signal Task (SST) assessed behavioral inhibitory control. Differential reinforcement for low‐rate responding (DRLR) was used to evaluate the delay reward dimension. The Structured Clinical Interview (SCID‐DSM‐IV) was used to diagnose alcohol dependence.Results:  The HD performed worse than the control group in all the behavioral tests of impulsivity. Performance in DRLR was the only behavioral impulsivity test that classified the HD correctly compared to controls. Logistic regression analysis indicated that performance on SST was a significant predictor [odds = 1.52(CI = 1.08–2.31)] of developing alcohol dependence.Conclusions:  Our results support the relation between behavioral impulsivity and alcohol use disorders. The paradigm related to delay of reward may be a factor associated with the use of alcohol and the incapacity to control inhibition as dependence develops.
Neonatal Alcohol‐Induced Region‐Dependent Changes in Rat Brain Neurochemistry Measured by High‐Resolution Magnetic Resonance Spectroscopy
Authors: O’Leary‐Moore Shonagh K. , McMechan Andrew P. , Galloway Matthew P. , Hannigan John H. 
Published: July 2008

Background:  Maternal drinking during pregnancy can lead to a range of deleterious outcomes in the developing offspring that have been collectively termed fetal alcohol spectrum disorders (FASDs). There is interest and recognized value in using non‐invasive neuroimaging techniques such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to characterize, respectively, structural and biochemical alterations in individuals with FASDs. To date, however, results with MRS have been inconsistent regarding the degree and/or nature of abnormalities.Methods:  High‐resolution magic angle spinning (HR‐MAS) proton (1H) MRS is an ex vivo neuroimaging technique that can acquire spectra in small punches of intact tissue, providing clinically relevant neurochemical information about discrete brain regions. In this study, HR‐MAS 1H MRS was used to examine regional neurochemistry in frontal cortex, striatum, hippocampus, and cerebellum of young rats previously exposed to ethanol as neonates. Key neurochemicals of interest included N‐acetyl‐aspartate (NAA), glutamate, GABA, glutamine, creatine, choline and myo‐inositol.Results:  Daily neonatal alcohol exposure from postnatal day 4 (PN4) through PN9 significantly reduced levels of NAA and taurine in the cerebellum and striatum, and induced sex‐dependent reductions in cerebellar glutamate when measured on PN16. In addition, myo‐inositol was significantly increased in cerebellum. The frontal cortex and hippocampus were virtually unaffected by this neonatal alcohol exposure.Conclusion:  Results of this research may have implications for understanding the underlying neurobiology associated with FASDs and aid in testing treatments in the future. Ongoing studies are assessing the developmental persistence of and/or maturational recovery from these changes.
Ethanol‐Induced Malfunction of Neutrophils Respiratory Burst on Patients Suffering From Alcohol Dependence
Authors: Breitmeier Dirk , Becker Nina , Weilbach Christian , Albrecht Knut , Scheinichen Dirk , Panning Bernhard , Schneider Udo , Jüttner Björn 
Published: July 2008

Background:  Polymorphonuclear, neutrophil granulocytes (PMN) play a major role in the control of infections, and people who abuse alcohol are susceptible to infections. Resistance against infections ensues intracellularly following initial phagocytosis of microorganisms with the oxygen‐dependent respiratory burst, the key enzyme of which is the respiratory burst oxidase, whereby oxygen radicals are produced for microbial destruction. To date there is insufficient information available in connection with the process of impaired defence against infection in patients suffering from alcohol dependence. Therefore, our investigation was carried out to determine the influence of alcohol exposition on the formation of oxygen radicals and the respiratory burst.Methods:  4.5 ml of whole blood was taken from 10 healthy adults and 10 patients suffering from alcohol dependence. An additional 3.5 ml of whole blood was taken from the alcoholic patients for determination of the blood alcohol concentration. The respiratory burst of PMN was tested using the Four‐Colour‐Continuous Flow Cytometer. Each experimental procedure consisted of 4 test samples [negative controls, Escherichia coli, FMLP‐supplement (N‐formyl‐l‐methionyl‐l‐leucyl‐l‐phenylalanin), PMA‐supplement (phorbol‐12‐myristate‐13‐acetate)]. Differing concentrations of ethanol were also introduced to each of the tests performed (0.20 to 4.00 g/l).Results:  Ethanol revealed a marked decrease of burst activity in those patients suffering from alcoholism with increased alcohol concentration. A dependence between the burst activity and the ethanol concentration was seen to be statistically significant. This effect was only evident after stimulation with E. coli and FMLP in those patients with alcohol dependence.Conclusion:  The results presented in this study show an impairment in the function of PMN in those patients addicted to alcohol due to the decrease in burst activity. In view of the results of the different stimuli, the second‐messenger effects were not evident. A clarification of this phenomenon could well be assumed as an allosteric receptor effect on the burst oxidase, namely, a direct effect on the phagocytosis interaction between circulating granulocytes and causative organisms.
Voluntary Ethanol Intake Enhances Excitatory Synaptic Strength in the Ventral Tegmental Area
Authors: Stuber Garret D. , Hopf F. Woodward , Hahn Junghyun , Cho Saemi L. , Guillory Anitra , Bonci Antonello 
Published: July 2008

Background: Addiction has been considered a disorder of motivational control over behavior, and the ventral tegmental area (VTA), in conjunction with other limbic brain structures, is thought to play a critical role in the regulation of a number of motivated behaviors including seeking of addictive drugs such as alcohol. Of particular interest is the ability of prolonged exposure of addictive drugs to enhance the function of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐type glutamatergic receptors (AMPAR) in the VTA, as glutamate receptor activation can significantly regulate VTA neuron activity. Here, we examined whether voluntary ethanol intake altered VTA AMPAR function.Methods: We utilized in vitro electrophysiology to examine glutamatergic function in the VTA neurons 12 to 24 hours after the last self‐administration bout, which occurred 35 to 50 days after the initiation of ethanol self‐administration under a 2‐bottle intermittent access model.Results: Voluntary intermittent ethanol intake in a 2‐bottle paradigm enhanced postsynaptic AMPAR function, indicated by an increased ratio of evoked AMPAR to N‐methyl‐d‐aspartic acid receptor currents, and by an increase in the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) measured in the presence of tetrodotoxin to prevent action potential‐dependent release. In contrast, ethanol self‐administration did not alter evoked presynaptic glutamate release, indicated by no change in the paired‐pulse ratio of 2 AMPAR EPSCs evoked 50 ms apart, although spontaneous glutamate release was significantly enhanced, indicated by enhanced mEPSC frequency.Conclusions: Our results suggest that postsynaptic AMPAR function in VTA neurons was significantly enhanced after ethanol self‐administration. As increased VTA AMPAR function can significantly regulate firing and enhance the reinforcing and activating effects of drugs of abuse, the increased AMPAR activity observed here may facilitate the drive to consume ethanol.