Vanderbilt University

About: Vanderbilt University is a education organization based out in Nashville, Tennessee, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 45066 authors who have published 106528 publications receiving 5435039 citations. The organization is also known as: Vandy.

Serotonin receptors: their key role in drugs to treat schizophrenia.

Abstract: Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.

The development and psychometric evaluation of the Brief Resilient Coping Scale.

Abstract: This article introduces the Brief Resilient Coping Scale (BRCS), a 4-item measure designed to capture tendencies to cope with stress in a highly adaptive manner. Two samples of individuals with rheumatoid arthritis (ns = 90 and 140) provide evidence for the reliability and validity of the BRCS. The BRCS has adequate internal consistency and test-retest reliability. Convergent validity of the scale is demonstrated by predictable correlations with measures of personal coping resources (e.g., optimism, helplessness, self-efficacy), pain coping behaviors, and psychological well-being. Resilient coping, as assessed by the BRCS, also buffers the effects of high levels of arthritis-related and non-arthritis-related stressors on depressive symptoms. The sensitivity of the BRCS to changes associated with a cognitive-behavioral intervention is also demonstrated. The BCRS may be useful for identifying individuals in need of interventions designed to enhance resilient coping skills.

Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.

Abstract: Objective: To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. Design: Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. Setting: Hospital and community based casecontrol and cohort studies. Main outcome measures: (a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. Results: 12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. Conclusions: The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs. Key messages Because there are no important differences in efficacy, choice of first line treatment with these drugs should be based on their relative toxicity Meta-analysis of the available epidemiological studies shows wide differences between individual drugs in the risk of inducing gastrointestinal bleed- ing and ulcer perforation Of the drugs in common use, ibuprofen and diclofenac rank low in toxicity whereas azapropa- zone, ketoprofen, and piroxicam rank high Some of the differences between drugs may be explained by dose, and the advantage of “low risk” drugs may be lost once their dose is increased

The Effects of Ibuprofen on the Physiology and Survival of Patients with Sepsis

Abstract: Background In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. Methods From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. Results In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis....

Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies

Abstract: In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.