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Current Drug Therapy (v.1, #3)

Effect of Antipsychotic Drugs on Cerebrovascular Morbidity and Mortality: A Systematic Review by Sara Mazzucco, Andrea Cipriani, Camilla Lintas, Corrado Barbui (pp. 241-248).
Background: Since 2002, there has been contrasting evidence indicating an increased risk of adverse cerebrovascular outcomes in people treated with the two most commonly prescribed atypical antipsychotics, risperidone and olanzapine. Objective: The objective of this systematic review is to examine the evidence of the correlation between antipsychotic drug use and the risk of cerebrovascular diseases. Method: We used the Medline computer database to search the relevant papers published in English from January 1966 to October 2005. We used the following key words: antipsychotic agents, transient ischaemic attack, cerebrovascular accident, stroke, vascular diseases, risk factors and mortality. Articles that investigated the relationship between antipsychotic drug exposure and subsequent cerebrovascular morbidity and mortality were collected and reviewed. Results: We found one meta-analysis based on a systematic review of randomised controlled trials (RCTs), 4 pooled analyses of RCTs, 4 database analyses, 1 case-control study and 1 cross-sectional study. A total of 11 RCTs suggested that 48 out of 2187 (2.2%) subjects exposed to antipsychotics experienced cerebrovascular adverse events, compared with 10 out of 1190 (0.8%) placebo-treated subjects. In terms of risks, the relative risk was statistically significant for risperidone (3.2, 95% Confidence Interval (CI) 1.4 to 7.2) but not for olanzapine 1.8 (95% Confidence Interval (CI) 0.5 to 6.3). In general, data from large observational administrative databases suggested no increased risk of cerebrovascular events with the atypical antipsychotics, compared with typical antipsychotics, although the evidence seems still inconclusive. Conclusion: So far, randomised and non-randomised studies provided contrasting findings on the risk of cerebrovascular accidents in subjects exposed to antipsychotic drugs. Individual patient data meta-analyses, carried out by independent organisations, are urgently needed to systematically summarise factors associated with cerebrovascular morbidity and mortality in individuals treated with first and second-generation antipsychotic drug.

Antiplatelet Therapy and Oral Anticoagulation for Prevention of Ischemic Stroke by Christian Weimar, Hans-Christoph Diener (pp. 249-256).
Purpose of Review: To provide an update on stroke prevention strategies with oral anticoagulants (vitamin K antagonists) and platelet inhibitors. Recent Findings: In asymptomatic women, aspirin reduces the risk of stroke but not of myocardial infarction while in men only the risk of myocardial infarction but not stroke could be significantly reduced. No benefit of oral anticoagulants could be shown in patients with non-cardioembolic stroke. Patients with symptomatic intracranial stenosis had a higher risk of intracerebral bleeding with oral anticoagulation compared to high dose aspirin. The combination of aspirin plus extended-release dipyridamole significantly reduces the risk of recurrent stroke as well as the risk of a combined cardiovascular outcome compared to aspirin alone. The combination of aspirin plus clopidogrel did not reduce the risk of stroke in patients with non-cardioembolic ischemic events compared to clopidogrel monotherapy. Summary: For primary prevention in patients < 65 years without risk factors, no antithrombotic treatment should be given. The choice between oral anticoagulants and antiplatelet agents depends on the stroke etiology and individual risk factor profile. Patients with non-cardioembolic stroke generally are candidates for antiplatelet therapy. New anticoagulation strategies will facilitate dosing and may reduce under-use in patients with atrial fibrillation and clear indications for oral anticoagulation.

Drug Targeting in Bronchial Asthma: Inhaled Corticosteroids Should Reach the Peripheral Airways by P.N.R. Dekhuijzen (pp. 257-261).
Bronchial asthma is characterised by an eosinophilic inflammatory process in the airways, and manifests itself functionally by bronchial hyperresponsiveness and variable airflow obstruction. In the past this inflammatory process was presumed to be predominantly present in the large and intermediate airways. This is not surprising since functional abnormalities in the small airways (or so-called silent zone) are much more difficult to establish in comparison to changes in the larger airways. As a consequence, changes in airway calibre and bronchial hyperresponsiveness are mainly measured in the central part of the lung, i.e. by means of the FEV1 at rest or after challenge with bronchoconstrictive stimuli like histamine and methacholine. Recently, advanced physiological, radiological and morphological studies show that the inflammatory process extends to the peripheral airways and even the alveolar compartment. This so-called peripheral inflammation is related to the clinical manifestation of the severity of asthma. Targeting the small airways with new inhaled corticosteroids with a small particle size and a high peripheral deposition may result in better control of the disease. The presence and clinical consequences of peripheral inflammation and its therapeutic approach are discussed in this review.

An Increasing Incidence of Treatment Resistance in Hypertension? by Ivar Eide (pp. 263-272).
According to recent experience there is an unexpected high prevalence of treatment resistance in hypertension, i.e. an inefficiency of even complex treatment modalities, increasing the need for multi-drug regimens. Mostly, this applies to systolic hypertension which over the years was found to cause at least as much target organ damage as diastolic. In view of the high prevalence of hypertension, such resistance may be a rising concern. This might not only be due to inefficiency of drugs, but also to low blood pressure levels as treatment goals and to increasing patient age with more systolic hypertension. Over the past few years, some new evidence has accumulated that will contribute to a break-down of the complex of treatment resistance into several categories of both primary and secondary hypertension, the most important may be the high frequency of white-coat hypertension, aldosteronism, low-renin hypertension and adiposity. In turn, the new evidence may lead to effective treatment for nearly every patient suffering therapy resistance. Such efficiency is all the more wanted since blood pressures in these patients are often severe and fraught with serious complications.

Use of Topiceuticals (Topically Applied, Peripherally Acting Drugs) in the Treatment of Chronic Pain by Bradley Galer, Arnold Gammaitoni (pp. 273-282).
Due to partial efficacy and adverse-event burdens, limited success has been achieved in the treatment of many chronic pain conditions with traditional, systemically administered analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, opioids, antidepressants, and anticonvulsants. Additionally, it is not uncommon for patients suffering from chronic pain to have complex medication regimens to treat their pain and other medical conditions and yet still experience both their pain and bothersome medication adverse events. An alternative to systemic analgesics for the treatment of chronic pain is the use of analgesics applied directly to the site of pain on the skin, ie, topically, that possess a peripheral mechanism of action. Apparent clinical advantages of topical drug delivery include significant reduction of systemic adverse events secondary to extremely low systemic exposure to medication, minimized risk of drug interactions, and elimination of what can often be a lengthy dose titration period. Over the past decade, further knowledge of the anatomy and neurochemistry of peripheral nociceptors has identified a number of viable targets for topically applied analgesics (topiceuticals). Moreover, studies in both inflammatory nociceptor and neuropathic pain models have clearly demonstrated pain behaviors can be significantly reduced by blocking or dampening pain generation in the periphery. We provide here some background on the physiology and pathophysiology of peripheral nociceptive afferents and the mechanisms of action of various topical analgesics. Over the past decade, there has been a significant increase in the use of topiceutical analgesic drugs worldwide and a growing body of evidence for their efficacy, safety, and tolerability. A review of the clinical data on the treatment of chronic pain with topical analgesics is also presented.

Topical Anesthetics for Procedural Pain in Children: What Does the Future Hold? by William Zempsky (pp. 283-290).
Minor procedures are a major source of pain and anxiety for children. Topical anesthetics are one component of a systematic approach to procedural pain in children. Topical anesthetics are underutilized due to inconvenience, slow onset, cost and inconsistent efficacy. New topical anesthetic systems are available or under investigation which may reduce the barriers to topical anesthetic use. These include systems which utilize technologies such as iontophoresis, ultrasound, lasers, heat and pressurized delivery. Hopefully, the advent of new topical anesthetic systems will contribute to a comprehensive effort to decrease procedural pain in children.

Multidrug-Resistance (MDR) Proteins Develops Refractory Epilepsy Phenotype:Clinical and Experimental Evidences by Alberto Lazarowski, Lililana Czornyj, Fabiana Lubieniecki, Silvia Vazquez, Carlos D'Giano, Gustavo Sevlever, Ana Lia Taratuto, Alicia Brusco, Girardi Elena (pp. 291-309).
Epilepsy affects approximately 3% of the population. Majority of epileptic patients may control their crisis with anticonvulsant drugs, however, 30%-40% became refractory to pharmacological therapies and could require surgical treatment. The causes of pharmacological refractoriness are poorly understood. Multidrug-resistance (MDR) mechanisms observed in cancer, could be also present in Refractory Epilepsy (RE). The ATP-binding-cassette (ABC) transporters may develop MDR phenotype preventing anti-epileptic drugs (AEDs) to reach their parenchyma brain targets. MDR-1 gene encoded P-glycoprotein (P-gp), is constitutively expressed in excretory tissues, including vascular endothelial cells (VEC) of the blood-brain-barrier. Here, we describe several MDR proteins over-expressed in VEC, astrocytes and neurons from adults and pediatric RE patients. Surgically treated cases showed brain P-gp over-expression with persistent plasmatic low levels of AEDs, and/or accelerated 99mTc-MIBI hepatic-clearance. Experimentally, we observed that a sequential and progressive seizures-induced P-gp over-expression from VEC → astrocytes → neurons correlated with increasing refractoriness to phenytoin treatment. Clinically and experimentally, we observed that nimodipine reverts RE phenotype. Because P-gp depolarizes potential membrane of P-gp-expressing tumor-cells, we hypothesized that weaker glutamic stimulation may totally depolarizes to P-gp-expressing neurons, inducing persistent low convulsive-threshold and playing a role in epileptogenesis mechanisms Pharmacological control of ABC-transporters could avoid the current invasive surgical treatments for Refractory Epilepsy.

Update on Anti-TNF-Alpha Treatment in Rheumatic Diseases by Marco Massarotti, Antonella Ferrara, Bianca Marasini (pp. 311-318).
The development of inhibitors of Tumor Necrosis Factor (TNF)α ro-inflammatory cytokine playing a pivotal role in chronic inflammatory diseases, represents a milestone in the therapy of several rheumatic diseases. Currently, three TNFα -blo drugs are available for clinical use in rheumatic diseases: infliximab, etanercept and adalimumab. These drugs rapidly reduce disease activity and probably change the poor outcome of several chronic rheumatic diseases, by preventing the development of bone erosions, joint deformity and disability. Although these drugs have proved to be effective and well tolerated in the short period, some concerns exist about long-term safety and efficacy. In fact, the longterm use of inhibitors of TNFα,a pivota okine in host defense, might result in the development of infections and neoplasms, therefore the long-term safety has to be defined. The most frightening infection to date is tuberculosis, and guidelines for the screening of patient candidates to biological treatment has significantly reduced the risk. Parasitic and viral infections do not contraindicate biological therapy. Lymphoma has been reported in association with TNFα antagonists, h ether or not there is a causal relationship is still debated. The use of biological agents in other rheumatic inflammatory conditions is rapidly increasing, but their cost poses a considerable financial burden on healthcare systems and a careful economic evaluation is needed. /abs >

Colloidal and Pharmacological Activity of Albumin in Clinical Fluid Management:Recent Developments by Christian Wiedermann (pp. 319-328).
Human albumin is extensively used and investigated in clinical fluid management. Whether albumin confers sufficient benefit to justify its cost has been a subject of enduring controversy. A 2003 systematic review assembled evidence of benefit, but uncertainty has persisted. Abundant additional data have been newly reported, and this review provides an update. Major recent developments include the largest ever single randomized trial in the field of fluid management as well as the largest ever meta-analysis of randomized trials in the field. The randomized trial confirmed the safety of albumin in intensive care unit patients, while the meta-analysis demonstrated that albumin administration reduces morbidity in broad populations of acutely ill hospitalized patients. In liver disease, new randomized trials have shown that albumin can reduce morbidity as an adjunct to paracentesis and improve circulatory function in spontaneous bacterial peritonitis. Large observational studies have provided evidence of a survival advantage among cardiac surgery patients receiving albumin rather than artificial colloids. For extracorporeal circuit priming during cardiopulmonary bypass, albumin was found in a meta-analysis to maintain platelet counts and fluid balance more effectively than crystalloid. Randomized trials in both cardiac and noncardiac surgery indicated less impairment of coagulation by albumin than hydroxyethyl starch. Improved oxygenation, augmented loss of excess fluid and reduced morbidity after albumin supplementation were demonstrated in a randomized trial of hypoalbuminemic patients. A large-scale pharmacovigilance study showed serious adverse events in albumin recipients to be rare. Emerging evidence has further supported many of the current uses of albumin in fluid management.
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