Current drug metabolism
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Current drug metabolism · Sep 2008
ReviewDysfunction of pulmonary vascular endothelium in chronic obstructive pulmonary disease: basic considerations for future drug development.
Chronic obstructive pulmonary disease (COPD) is one of the leading health problems worldwide and continues to be a major cause of morbidity and mortality in developed countries. The clinical features of COPD are chronic obstructive bronchiolitis and emphysema. Pulmonary vascular endothelial dysfunction is a characteristic pathological finding of COPD at different stages of the disease. ⋯ Changes in the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin, selectins, and adhesion molecules in pulmonary endothelial cells as well as complex regulation and interaction of vasoactive substances and growth factors released from endothelium may underlie the mechanisms of pulmonary endothelial dysfunction in COPD. The mechanism of endothelial repair/regeneration in COPD, although not fully understood, may involve upregulation of vascular endothelial growth factors in the early stages along with an increased number of bone marrow-derived progenitor cells. These factors should be taken into account when developing new strategies for the pharmacological therapy of patients with COPD.
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Current drug metabolism · Aug 2007
Multicenter StudyDifferent inflammatory biomarker patterns in the cerebro-spinal fluid following heart surgery and major non-cardiac operations.
Cognitive decline occurs frequently after cardiac surgery and it may lead to patient morbidity. The purpose of this study is to focus on the static incidence of neuro-psychiatric impairment associated with altered inflammatory biomarkers in the cerebro-spinal fluid (CSF) that may provide an insight into the mechanisms of acute peri-operative cognitive disturbances related to heart surgery. Immuno-assays were used to evaluate concentrations of several cytokines in CSF of patients undergoing either off-pump coronary artery bypass grafting (OP-CABG) or major non-cardiac surgeries. ⋯ IP-10 and MCP-1 did not show significant changes in their concentrations in either patient population (OP-CABG: 254.41+/-160.01 vs. 224.55+/-214.39, and 140.37+/-40.98 vs. 147.16+/-37.98; non-cardiac: 274.99+/-219.44 vs. 395.09+/-468.30, and 126.56+/-31.24 vs. 124.41+/-49.89, respectively). These findings suggest that cardiac surgery provokes alterations in the levels of various cytokines in the CSF, and the OP-CABG induced changes in biomarker profile differs from that seen after major non-cardiac surgeries. This, along with other biomarkers, may offer an explanation for relationships between the pronounced incidence of cognitive impairment after heart operations.
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Current drug metabolism · Feb 2006
ReviewThe role of blood-brain barrier studies in the pharmaceutical industry.
The blood-brain barrier (BBB) remains one of the greatest challenges for the discovery and development of treatments for CNS disorders, which to this day remains one of the riskiest disease areas in terms of clinical success rates. Although the BBB is currently seen predominantly as a permeability obstacle for CNS drug delivery, it is becoming increasingly clear that the BBB has many more implications for the pharmaceutical industry impacting on CNS pharmacology and pathology, CNS pharmacokinetics and pharmacodynamics, and adverse CNS effects, to name but a few areas. The present review does not intend to summarize the activities in the field of BBB research per se, which has been accomplished by a number of excellent recent reviews, but instead to provide an overview of the role of BBB studies from a pharmaceutical industry perspective. ⋯ It becomes clear that few of the existing BBB models fully meet the requirements of the industrialized drug discovery process, highlighting the need for an array of new or modified tools and approaches that are more effective in helping make decisions which are more specifically tailored to the various stages of the lengthy process from target to the clinic. In looking at the numerous ongoing activities in the area of BBB research from the drug discovery and development point of view, an attempt has been made to place a stronger emphasis on the applicability of particular techniques and approaches, to identify gaps and areas for future activities. In order to materialize the considerable knowledge gained in recent years, the review is intended to foster an increased awareness of the need to better integrate basic academic research with the specific requirements of the pharmaceutical industry for the search of effective and safe new CNS medicines.
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Current drug metabolism · Feb 2005
The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings.
Serum concentrations of homocysteine (Hcy) and methylmalonic acid (MMA) become increased in B12-deficient subjects and are therefore, considered specific markers of B12 deficiency. Serum level of holotranscobalamin (holoTC) becomes decreased before the development of the metabolic dysfunction. We investigated the usefulness of holoTC in diagnosing B12 deficiency in some clinical settings. ⋯ Serum concentrations of holoTC as well as MMA can be affected by renal dysfunction. Elevated MMA and normal holoTC in patients with renal insufficiency may not exclude vitamin B12 deficiency. HoloTC seems not to be a promising marker in predicting B12 status in renal patients.
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Current drug metabolism · Dec 2001
ReviewApplication of an in vivo brain microdialysis technique to studies of drug transport across the blood-brain barrier.
There is a wide range of methods available for studying the transport of drugs across the blood-brain barrier (BBB) which is equipped with several systems to transport drugs as well as endogenous nutrients and waste products. The in vivo brain microdialysis technique, which allows direct sampling of the brain interstitial fluid (ISF), is a powerful means of characterizing influx and efflux transport across the BBB. In this paper, we review our results from the successful application of this technique to BBB drug transport studies. The drugs investigated include novel and CNS-active peptides, some agents that are actively removed from the brain ISF across the BBB, and a brain-directed prodrug.