Patterns of chronic inflammation in extensively treated patients with arachnoiditis and chronic intractable pain.

OBJECTIVE: To use biomarkers to gain insight into and gauge the residual (post-treatment) level of inflammation in two groups of intensively treated patients with severe chronic pain. METHODS: Three study groups were analyzed, and included: (i) patients (n = 90) with chronic intractable pain (CIP), (ii) patients (n = 26) with chronic pain and MRI-documented arachnoiditis (ARC) and (iii) normal subjects without a diagnosis of chronic pain (n = 86). We determined and compared the serum concentrations of Alpha-1 Antitrypsin (A1AT), Myeloperoxidase (MPO) and soluble Tumor Necrosis Factor receptor type 2 (sTNFR2) in each of the patient populations studied. RESULTS: Patients treated for ARC or CIP had higher serum levels of A1AT and MPO than normal untreated subjects without a diagnosis of chronic pain. ARC patients had an A1AT mean serum concentration of 167.9 ± 41.9 mg/dL as compared to 148.9 ± 35.2 mg/dL for normal subjects (p = 0.023). CIP patients had the highest mean serum A1AT level 183.6 ± 39.2 mg/dL with p values of <0.0001 or 0.08 when compared to normal subjects or ARC patients respectively. ARC patients had an MPO mean serum concentration of 344.6 ± 227.9 ng/mL as compared to 188.2 ± 107.5 ng/mL for normal subjects (p = < 0.0001). CIP patients had a similar mean serum MPO level of 352.3 ± 164 ng/mL with p values of <0.0001 or 0.85 when compared to normal subjects or ARC patients respectively. In addition, we noted a difference in the pattern of MPO expression in patients with ARC in that 34% had levels of MPO at normal or below and 31% had levels 2-fold or greater than normal. CONCLUSION: This data supports the concept that in centralized pain, sites of neuroinflammation elaborate MPO and other inflammatory factors which may not be completely cleared from the system despite extensive and complex treatment regimens.

The agony and ecstasy of "OMIC" technologies in drug development.

Over the last decade we have witnessed a fundamental change in how biomedical research is carried out and we can now assess the impact of the Human Genome Project on drug discovery and development. Advances in "omics" technologies (genomics, transcriptomics, proteomics and metabonomics) were touted as having the potential to revolutionize our approach to disease diagnosis, prognostication and development of novel therapeutics. However, the promise of rapid advances in medicine "from the lab bench to the bedside" has not manifested as of yet. Indeed it appears that the translational applications of genomic-based research have preceded the development of both (i) a conceptual framework for disease understanding and (ii) effective tools that can exploit the vast amounts of data derived from these efforts. In reality great progress has been made, however understanding processes such as disease progression (or drug response) requires systematic insight into dynamic (and temporal) differences in gene regulation, interaction and function. This review will discuss "omic" technologies with the emphasis upon advances in our understanding of the human genome derived transcriptome (RNA), and its proteome (proteins), while focusing upon the translation of this information into the drug development paradigm.

Seeking an objective diagnosis of depression.

Major depressive disorder (MDD: unipolar depression) is widely distributed in the USA and world-wide populations and it is one of the leading causes of disability in both adolescents and adults. Traditional diagnostic approaches for MDD are based on patient interviews, which provide a subjective assessment of clinical symptoms which are frequently shared with other maladies. Reliance upon clinical assessments and patient interviews for diagnosing MDD is frequently associated with misdiagnosis and suboptimal treatment outcomes. As such, there is increasing interest in the identification of objective methods for the diagnosis of depression. Newer technologies from genomics, transcriptomics, proteomics, metabolomics and imaging are technically sophisticated and objective but their application to diagnostic tests in psychiatry is still emerging. This brief overview evaluates the technical basis for these technologies and discusses how the extension of their clinical performance can lead to an objective diagnosis of MDD.

MDDScore: confirmation of a blood test to aid in the diagnosis of major depressive disorder.

BACKGROUND: Previously, a biomarker panel was developed for use as an aid to major depressive disorder (MDD) diagnosis; it consisted of 9 biomarkers associated with the neurotrophic, metabolic, inflammatory, and hypothalamic-pituitary-adrenal axis pathways. This panel and associated algorithm produced good clinical sensitivity and specificity (92% and 81%, respectively) in differentiating MDD patients from individuals without MDD. To further validate the panel, we performed a prospective study using a larger set of new prospectively acquired MDD patients and a similarly collected population of nondepressed subjects. The addition of gender and body mass index (BMI) effects to the algorithm was also evaluated. METHOD: Blood samples were obtained from MDD patients (n = 68) clinically evaluated at multiple sites in 2011 and 2012 using standard psychiatric assessment tools and structured clinical interviews according to DSM-IV criteria. Blood samples (n = 86) from nondepressed subjects were obtained as controls. MDD and nondepressed samples were randomized into independent training (n = 102) and validation sets (n = 52). Analytes in sera were quantified by immunoassay. RESULTS: Training set biomarker data were used to develop a logistic regression model that included gender and BMI in a manner that allowed for their interaction with the biochemical analytes. For the training set, the sensitivity and specificity of the test (with 95% CI) were 93% (0.80-0.98) and 95% (0.85-0.99), respectively. This method (designated the MDDScore) was then applied to the independent validation set and had a sensitivity and specificity of 96% (0.77-0.98) and 86% (0.66-0.95), respectively. The overall accuracy for the training set was 94%; the validation set accuracy was 91%. CONCLUSION: Examination of a randomized independent set of samples confirms the ability of the previously established biomarker panel to identify persons with MDD; the accuracy was over 90%. The improved model that adds gender and BMI to the previously established panel of 9 biomarkers is robust and simple; it provides the most rigorously tested, objective diagnostic test for MDD to date.

Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.

IMPACT: This study explores the use of measuring plasma biomarkers at exacerbation of chronic obstructive pulmonary disease (COPD), providing insight into the underlying pathogenesis of these important events. RATIONALE: The use of measuring C-reactive protein (CRP) to confirm exacerbation, or to assess exacerbation severity, in COPD is unclear. Furthermore, it is not known whether there may be more useful systemic biomarkers. OBJECTIVE: To assess the use of plasma biomarkers in confirming exacerbation and predicting exacerbation severity. METHODS: We assessed 36 biomarkers in 90 paired baseline and exacerbation plasma samples from 90 patients with COPD. The diagnosis of exacerbation fulfilled both health care use and symptom-based criteria. Biomarker concentrations were related to clinical indices of exacerbation severity. Interrelationships between biomarkers were examined to gain information on mechanisms of systemic inflammation at exacerbation of COPD. MEASUREMENTS AND MAIN RESULTS: To confirm the diagnosis of exacerbation, the most selective biomarker was CRP. However, this was neither sufficiently sensitive nor specific alone (area under the receiver operating characteristic curve [AUC], 0.73; 95% confidence interval, 0.66-0.80). The combination of CRP with any one increased major exacerbation symptom recorded by the patient on that day (dyspnea, sputum volume, or sputum purulence) significantly increased the AUC to 0.88 (95% confidence interval, 0.82-0.93; p<0.0001). There were no significant relationships between biomarker concentrations and clinical indices of exacerbation severity. Interrelationships between biomarkers suggest that the acute-phase response is related, separately, to monocytic and lymphocytic-neutrophilic pathways. CONCLUSIONS: Plasma CRP concentration, in the presence of a major exacerbation symptom, is useful in the confirmation of COPD exacerbation. Systemic biomarkers were not helpful in predicting exacerbation severity. The acute-phase response at exacerbation was most strongly related to indices of monocyte function.

In vitro-in vivo model for evaluating the antiviral activity of amprenavir in combination with ritonavir administered at 600 and 100 milligrams, respectively, every 12 hours.

The study objective was to evaluate the pharmacodynamics of amprenavir in an in vitro system, develop an exposure target for maximal viral suppression, and determine the likelihood of target attainment based on the pharmacokinetics of amprenavir and ritonavir in human immunodeficiency virus (HIV)-infected patients. Population pharmacokinetic data were obtained from 13 HIV-infected patients receiving amprenavir and ritonavir in doses of 600 and 100 mg, respectively, every 12 h. A 2,500-subject Monte Carlo simulation was performed. Target attainment was also estimated for a target derived from clinical data. Maximal viral suppression (in vitro) was achieved when amprenavir free-drug concentrations remained greater than four times the 50% effective concentration (EC(50)) for 80% of the dosing interval. At an amprenavir EC(50) of 0.03 microM, the likelihood of target attainment is 97.4%. For reduced-susceptibility isolates for which the EC(50)s are 0.05 and 0.08 microM, target attainment is 91.0 and 75.8%, respectively. For the clinical target of a trough concentration/EC(50) ratio of 5, the target attainment rates were similar. Treatment with amprenavir and ritonavir at doses of 600 and 100 mg, respectively, twice a day provides excellent suppression of wild-type isolates and reduced-susceptibility isolates up to an EC(50) of 0.05 micro M. Even at 0.12 microM, target attainment likelihood exceeds 50%, making this an option for patients with extensive exposure to protease inhibitors when this treatment is used with additional active antiretroviral agents.