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991.
Kranzler HR Armeli S Tennen H Covault J Feinn R Arias AJ Pettinati H Oncken C 《Journal of clinical psychopharmacology》2011,31(1):22-30
Late-onset/low-vulnerability alcoholics (LOAs) appear to drink less when treated with a selective serotonin reuptake inhibitor than placebo, whereas early-onset/high-vulnerability alcoholics (EOAs) show the opposite effect. We conducted a 12-week, parallel-group, placebo-controlled trial of the efficacy of sertraline in alcohol dependence (AD). We compared the effects in LOAs versus EOAs and examined the moderating effects of a functional polymorphism in the serotonin transporter gene. Patients (N = 134, 80.6% male, 34.3% EOAs) with Diagnostic and Statistical Manual of Mental Disorders-IV AD received up to 200 mg of sertraline (n = 63) or placebo (n = 71) daily. We used urn randomization, and patients were genotyped for the tri-allelic 5-hydroxytryptamine transporter protein linked promoter region polymorphism. Planned analyses included main and interaction effects of medication group, age of onset (≤ 25 years vs >25 years), and genotype (L'/L' vs S' carriers) on drinking outcomes. Results showed that the moderating effect of age of onset on the response to sertraline was conditional on genotype. There were no main or interaction effects among S' allele carriers. However, in L' homozygotes, the effects of medication group varied by age of onset (P = 0.002). At the end of treatment, LOAs reported fewer drinking and heavy drinking days when treated with sertraline (P = 0.011), whereas EOAs had fewer drinking and heavy drinking days when treated with placebo (P < 0.001). The small cell sizes and high rate of attrition, particularly for L' homozygotes, render these findings preliminary and their replication in larger samples necessary. Because AD is common, particularly in medical settings, and selective serotonin reuptake inhibitors are widely prescribed by practitioners, these findings have potential public health significance and warrant further evaluation. 相似文献
992.
Erstad BL Haas CE O'Keeffe T Hokula CA Parrinello K Theodorou AA 《Pharmacotherapy》2011,31(2):128-137
The field of critical care medicine began to flourish only within the last 40 years, yet it provides some of the best examples of collaborative pharmacy practice models and evidence for the value of pharmacist involvement in interdisciplinary practice. This collaborative approach is fostered by critical care organizations that have elected pharmacists into leadership positions and recognized pharmacists through various honors. There is substantial literature to support the value of the critical care pharmacist as a member of an interdisciplinary intensive care unit (ICU) team, particularly in terms of patient safety. Furthermore, a number of economic investigations have demonstrated cost savings or cost avoidance with pharmacist involvement. As the published evidence supporting pharmacist involvement in patient care activities in the ICU setting has increased, surveys have demonstrated an increase in the percentage of pharmacists performing clinical activities. In addition, substantial support of pharmacists has been provided by other clinicians, safety officers, and administrative personnel who have been involved with the initiation and expansion of critical care pharmacy services in their own institutions. Although there is still room for improvement in the range of pharmacist involvement, particularly with respect to interdisciplinary activities related to education and scholarship, pharmacists have become essential members of interdisciplinary care teams in ICU settings. 相似文献
993.
Zhong Y Carmella SG Upadhyaya P Hochalter JB Rauch D Oliver A Jensen J Hatsukami D Wang J Zimmerman C Hecht SS 《Chemical research in toxicology》2011,24(2):246-252
Polycyclic aromatic hydrocarbons (PAH) are among the likely major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and one important pathway proceeds through a three-step sequence resulting in the formation of diol epoxides, which react with DNA to produce adducts that can cause mutations and initiate the carcinogenic process. However, no previous published studies have examined this critical pathway in humans specifically exposed to PAH by inhalation of cigarette smoke. This study used a unique approach employing a stable isotope derivative of phenanthrene, the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Twelve subjects each smoked a cigarette to which [D(10)]phenanthrene had been added. Plasma was analyzed for [D(10)]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D(10)]PheT), the major end product of the diol epoxide metabolism pathway of phenanthrene. The analysis was performed by gas chromatography--negative ion chemical ionization--tandem mass spectrometry, using [(13)C(6)]PheT as internal standard. The results demonstrated that the three-step pathway resulting in the formation of diol epoxides, as monitored by [D(10)]PheT, occurred with remarkable rapidity. Levels of [D(10)]PheT in plasma of all subjects were maximal at the earliest time points examined, 15-30 min after smoking the cigarette containing [D(10)]phenanthrene, and decreased thereafter. These results demonstrate that the formation of a PAH diol epoxide occurs rapidly in smokers. Because PAH diol epoxides are mutagenic and carcinogenic, the results clearly demonstrate immediate negative health consequences of smoking, which should serve as a major warning to anyone contemplating initiating tobacco use. 相似文献
994.
Li CS Zhang L Haske T Dounay A Gray D Barta N Brodfuehrer J Lepsy C Campbell B 《The AAPS journal》2012,14(2):365-376
Evidence suggests that compounds possessing both norepinephrine reuptake inhibition and 5-HT(1A) partial agonism (NRI/5-HT(1A)) activities may have a greater efficacy in treating neuropsychiatric disorders than compounds possessing either activity alone. The objectives of the present study were first to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the plasma concentrations of atomoxetine (NRI) and buspirone (5-HT(1A) partial agonist), administered alone and in combination, on the prefrontal cortex dopamine levels in rats, and second to use the model developed to characterize the PK/PD relationship of novel NRI/5-HT(1A) compounds, PF-04269339 and PF-03529936, in a NRI/5-HT(1A) drug discovery program. Maximal dopamine elevation was twofold higher after administration of atomoxetine and buspirone in combination, PF-04269339, or PF-03529936 than after administration of atomoxetine or buspirone alone. A mechanism-based extended indirect response model characterized the time profiles of the prefrontal cortex dopamine response to atomoxetine and buspirone, administered alone or in combination. After fixing three mechanism-specific pharmacodynamic parameters (I (max) and γ2 for NRI and γ1 for 5-HT(1A)) based on the model for atomoxetine and/or buspirone, the model fitted the exposure-response profiles of PF-04269339 and PF-03529936 well. Good in vitro-to-in vivo correlation was demonstrated with the compound-specific pharmacodynamic parameters (IC(50) for NRI and SC(50) and S (max) for 5-HT(1A)) across the compounds. In summary, a piecewise modeling approach was used successfully for the characterization of the PK/PD relationship of novel NRI/5-HT(1A) compounds on prefrontal cortex dopamine levels in rats. The application and value of the mechanism-based modeling in the dual pharmacology drug discovery program are also discussed. 相似文献
995.
Liu J Nguyen TT Dupart PS Sridhar J Zhang X Zhu N Stevens CL Foroozesh M 《Chemical research in toxicology》2012,25(5):1047-1057
To discover new selective mechanism-based P450 inhibitors, eight 7-ethynylcoumarin derivatives were prepared through a facile two-step synthetic route. Cytochrome P450 activity assays indicated that introduction of functional groups in the backbone of coumarin could enhance the inhibition activities toward P450s 1A1 and 1A2, providing good selectivity against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin (7ETMC) showed IC(50) values of 0.46 μM and 0.50 μM for P450s 1A1 and 1A2 in the first six minutes, respectively, and did not show any inhibition activity for P450s 2A6 and 2B1 even at the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin (7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2. In order to explain this mechanistic difference in inhibitory activities, X-ray crystallography data were used to study the difference in conformation between 7E3M4PC and the other compounds studied. Docking simulations indicated that the binding orientations and affinities resulted in different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC with its two-plane structure fits into the P450 1A2's active site cavity with an orientation leading to no reactive binding, causing it to act as a competitive inhibitor. 相似文献
996.
Munjal I Gialanella P Goss C McKitrick JC Avner JR Pan Q Litman N Levi MH 《Journal of clinical microbiology》2011,49(3):1151-1153
We report the results of the 3M rapid detection respiratory syncytial virus (RSV) assay. This study includes pediatric patient results from nasopharyngeal swabs submitted from October to December 2009. There was a sensitivity of 74% and specificity approaching 100% compared to the PCR-based xTAG respiratory viral panel. 相似文献
997.
Walk A Callahan J Srisawangvong P Leuschner J Samaroo D Cassilly D Snyder ML 《Developmental and comparative immunology》2011,35(8):850-856
Innate immune cells respond to invading microbes upon detection of pathogen-associated molecular patterns (PAMPS). PAMP-recognition machinery is evolutionarily conserved, allowing for characterization in model organisms. The model organism Dictyostelium discoideum can exist as single-celled amoebae, which phagocytize bacteria for nutrients. Although D. discoideum is used extensively to study phagocytosis, it has not been determined if D. discoideum detects bacterial PAMPs using pattern-recognition machinery. Here we show that D. discoideum mounts responses against the bacterial cell wall PAMP, lipopolysaccharide (LPS). Upon treatment with LPS or its active component Lipid A, D. discoideum cells more efficiently clear phagocytized bacteria. LPS-enhanced bactericidal activity appears dependent both on MAPK signaling pathways as well as on the D. discoideum toll/interleukin-1 receptor domain-containing protein, TirA. These findings indicate that pattern-recognition machinery required to detect and respond to bacterial PAMPs may be conserved in D. discoideum. 相似文献
998.
Holt CL Wang MQ Caplan L Schulz E Blake V Southward VL 《Journal of behavioral medicine》2011,34(6):437-448
The present study tested a mediational model of the role of religious involvement, spirituality, and physical/emotional functioning
in a sample of African American men and women with cancer. Several mediators were proposed based on theory and previous research,
including sense of meaning, positive and negative affect, and positive and negative religious coping. One hundred patients
were recruited through oncologist offices, key community leaders and community organizations, and interviewed by telephone.
Participants completed an established measure of religious involvement, the Functional Assessment of Chronic Illness Therapy-Spiritual
Well-Being Scale (FACIT-SP-12 version 4), the Positive and Negative Affect Schedule (PANAS), the Meaning in Life Scale, the
Brief RCOPE, and the SF-12, which assesses physical and emotional functioning. Positive affect completely mediated the relationship
between religious behaviors and emotional functioning. Though several other constructs showed relationships with study variables,
evidence of mediation was not supported. Mediational models were not significant for the physical functioning outcome, nor
were there significant main effects of religious involvement or spirituality for this outcome. Implications for cancer survivorship
interventions are discussed. 相似文献
999.
Marchand WR Lee JN Garn C Thatcher J Gale P Kreitschitz S Johnson S Wood N 《Journal of affective disorders》2011,133(3):638-645
Background
Considerable evidence implicates dysfunction of striatal and cortical midline structure (CMS) circuitry in mood disorders. Whether such aberrations exist in bipolar II depression is unknown.Methods
Sixteen unmedicated subjects with bipolar II depression and 19 healthy controls were studied using functional MRI and a motor activation paradigm. Analyses of both activation and functional connectivity were conducted.Results
A history of suicidal ideation (SI) was negatively correlated with activation of the left putamen while depression severity was positively correlated with activation of the left thalamus. The superior bilateral putamen was simultaneously correlated with depression severity and anti-correlated with SI. Striatal functional connectivity was altered with the bilateral CMS and right inferior parietal lobule. Depression severity was correlated with strength of connectivity between the bilateral striatum and the right lingual gyrus and left cerebellum.Limitations
Only males experiencing an episode of major depression were studied.Conclusions
Striatal and CMS circuit abnormalities likely contribute to the neurobiology of bipolar II depression. Altered connectivity of the striatum may directly impact depression severity. Further, dissociable components of activation associated with depression severity and suicidal ideation may exist. Finally, the motor activation paradigm used in this study appears to be a useful probe of some neural processes underlying bipolar II depression. 相似文献1000.