Current Drug Safety - Volume 2, Issue 3, 2007

Aging is one of the most significant risk factors for neurological disorders including Alzheimer's Disease (lateonset AD and sporadic AD), the most common form of dementia. AD is characterized by progressive atrophy and loss of neurons resulting in cognitive deficits, confusion and dementia, culminating in childlike helplessness and death. One of the major pathological hallmarks of the disease are amyloid plaques, composed primarly of insoluble fibrils of Aβ peptide: this molecule derives from the processing of the transmembrane amyloid precursor protein (APP) by different secretases and its production is a physiological event, but the anormal increase in Aβ levels appears to be toxic both in vitro and in vivo. Being APP cleavage a membrane event the involvement of lipids in alterations of this cleavage is assumable. Cholesterol is the most abundant lipid in cellular membranes and is an essential component of them, determining the fluidity and biophysical properties. In fact, genetic studies of the risk of AD have reported association with polymorphism in some cholesterol related genes like the allele η4 of the apolipoprotein E, cholesterol 24-hydroxylase (CYP46A1), ATP-binding cassette transporter a1 (ABCA1) and the lipoprotein receptor-related protein (LRP). Moreover a recent publication shows a downregulation of Seladin-1 (which catalyze the last step of cholesterol biosynthesis) in affected neurons in Alzheimer's Disease. Post-mortem analysis of AD brains reveal a loss in cholesterol content and this make the therapeutical use of statin-like drugs quite a lot controversial. Taking together their clinical trials results and the large body of literature regarding lipid profile alterations in AD, it is actually unclear how much these agents can be helpful or not for affected patients.

There have been a number of highly publicized safety-based drug withdrawals in the United States in recent years. We conducted a review of drugs withdrawn since 1993 and examined trends in drug withdrawals. Our objective was to determine the frequency and characteristics of withdrawn drugs and trends since 1993, and to discuss the implications of the findings. We found that a mean of 1.5 drugs per year have been withdrawn since 1993, and that the number of withdrawals has not increased over time. However, some recent drug withdrawals have impacted large numbers of people. The rate of withdrawals alone is not an adequate measure of the status of drug safety in the US, and there is a serious dearth of data that can be used to examine the impact of drug withdrawals. Although drug withdrawals are an important issue to address, drug safety policies need to be developed within the broader context of drug safety and effectiveness. A comprehensive approach will be needed to address the improvement of drug safety. We propose improvements to the evidence base to increase drug safety and assess how new scientific evidence can be incorporated into drug safety efforts.

Allergy and immune diseases including asthma, atopic dermatitis, rhinitis, and autoimmune diseases have been treated mainly with steroid based therapy that has multiple side effects. Even then, these allergic diseases are sometimes still not easy to control. Therefore, new effective treatments with fewer side effects are expected to be developed. Prostanoids consisting of prostaglandins and thromboxane are cyclooxygenase metabolites of arachidonic acid. They exert a range of actions mediated through their respective receptors expressed in target cells. In the skin, a wide variety of prostanoids and their receptors are highly expressed under pathophysiological conditions. However, their roles have not been well clarified. Recent developments in molecular biology have enabled us to investigate the physiological roles for each receptor via the disruption of the respective gene in combination with receptor selective compounds. It has been demonstrated that each prostanoid receptor has multiple functions whose expression is regulated in a context dependent manner, sometimes resulting in opposite, excitatory and inhibitory, outcomes. The balance of prostanoid production and receptor expression is important for homeostasis of the human body. Here, we review new findings on the roles of prostanoids in allergy and immune diseases, focusing on skin disorders as a representative, and discuss the clinical potentials of receptorselective drugs.

Accurate prediction of human drug safety remains a major challenge for drug development. Species-difference in drug toxicity represents a main reason for the difficulty in the prediction of human drug toxicity with nonhuman animal models. A combined in vitro-in vivo strategy (IVIVS), using human-based in vitro experimental systems to derive humanspecific information, and animal systems for in vivo variables, may lead to a more accurate prediction of human in vivo drug toxicity. The success of IVIVS requires in vitro models with human-specific drug metabolism, appropriate target cell populations, and relevant endpoints. A novel theory, the Target Cell Initiation Theory for drug-induced organ failure (TACIT), is proposed to support the IVIVS. Based on TACIT, toxicity that requires chronic administration and multiple secondary changes may be defined by the evaluation of changes in target cells that initiate the cascade of secondary events. A novel in vitro experimental system, the Integrated Discrete Multiple Organ Co-culture (IdMOC) system, which allows the evaluation of multiple organ toxicity under conditions allowing multiple organ interactions, is described as a promising technology.

The QT interval in electrocardiogram (ECG) reflects the total duration of ventricular myocardial depolarization and repolarization. It has been well recognized that many condition may cause QT interval prolongation. Unfortunately, numbers of cardiac and non-cardiac drug prolong the QT interval and cause a distinctive polymorphic ventricular tachycardia termed torsade de pointes (TdP). TdP can degenerate into ventricular fibrillation, which leads to sudden cardiac death. Recently various regulatory and clinical bodies of Europe, USA, Canada and Australia have made their focus on the drugs that induce prolongation of QT interval. Committee for Proprietary Medicinal Products (CPMP) of the European Agency issued a document entitled ‘Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products’ [1, 2]. In addition, USFDA adopted the guideline ‘Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-anti arrhythmic drugs’ [3]. These documents and guidelines are primarily concern with development of novel agents and the new use or new dose of already approved drugs. The scope of this guideline is to study the effect of drugs on QT prolongation and give idea of evaluation of drug's effects on QT prolongation. Today more than 50 available drugs (both old and new) have been identify, which prolong the QT interval [1]. Several drugs have been withdrawn from many countries on this basis but many of these drugs are still available in Indian market and potentially creating life-threatening arrhythmias. This article will focus on recommendation of study on the normal limits of QT interval in Indian population and preparation of the database, which can be helpful in withdrawal of drugs from the market that produces QT prolongation.

Despite considerable research, metastasis remains a major challenge in the clinical management of cancer. Recent reports show that abnormally augmented expression of Cx26 is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells. The function of Cx26 appears to be responsible for this phenotype since exogenous expression of a dominant-negative form of Cx26 and oleamide derivatives called MI-18 and MI-22 that specifically inhibit Cx26-mediated gap junction-mediated intercellular communications (GJIC) prevent the spontaneous metastasis of BL6 cells. As expected from their structural similarity to oleic acid (the major component of olive oil), both MI-18 and MI-22 are safe drugs; nonetheless, they are potent inhibitors of the spontaneous metastasis of BL6 mouse melanoma cells. Thus, they are a novel prototype of an anti-metastasis drug that has minimal side effects. While the primary tumors do not necessarily show strong Cx26-immunostaining signals, pronounced Cx26 expression is detected in the highly invasive tumor regions; it is also more frequently observed in metastasized tumors. Thus, Cx26 expression may be useful as a prognostic tool that can predict the existence of highly metastatic cancer cells in clinical samples.

Coronary artery stenting is currently the most frequently performed percutaneous coronary intervention for the treatment of coronary artery disease. Recently, drug- eluting stents, loaded with anti-inflammatory, anti-migratory, antiproliferative or pro-healing drugs, have revolutionized the management of coronary artery disease by markedly reducing in-stent restenosis. Despite the excellent short- and mid-term results of randomized controlled trials observed with drugeluting stents, there remain a number of unresolved issues and valid concerns about long-term safety and efficacy of this revolutionary technology. Important safety issues such as thrombosis, late stent malapposition, aneurysm formation, edge effect, late inflammation due to choice of polymer used to bind the drug, the release of toxins, and potential interactions with brachytherapy and drugs have not been completely addressed. This review article evaluates current available scientific evidence on the various safety issues related to the use of drug-eluting stents.

Zolpidem is among the most frequently prescribed hypnotic drugs for those who suffer from insomnia. Recent media reports drew attention to driving impairment after zolpidem misuse. This review summarizes the available data on the effects of recommended use and misuse of zolpidem on driving ability and traffic safety. Both experimental studies and roadside evidence were taken into account. From these studies it must be concluded that patients should fully comply with the prescription instructions of zolpidem, i.e. to take the medication just prior to a full 8 hours of uninterrupted sleep. If this strategy is adopted, zolpidem is a safe alternative to benzodiazpine hypnotics and zopiclone who do show significant driving impairment the morning following bedtime administration. However, to ensure traffic safety higher dosages than recommended (10 mg) or allowing less than 8 hours between zolpidem intake and actual operation of a motor vehicle should be avoided.

Severe sepsis and septic shock are common in the critically ill patient and account for considerable morbidity and mortality not to mention the high associated costs. Advances in our understanding of sepsis pathophysiology and in the important link between the inflammatory response to sepsis and activation of coagulation led to the development and licensing of the first ever, specific, immunomodulatory anti-sepsis drug. Drotrecogin alfa (activated), a recombinant version of activated protein C, was shown in a large randomized controlled clinical trial to reduce mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Vasopressor requirements and duration of mechanical ventilation were also reduced. Apart from an expected increased risk of severe bleeding, mostly associated with interventions, drotrecogin alfa (activated) was not associated with any other adverse reactions. In this article, I will briefly summarize the events leading to the development of drotrecogin alfa (activated) including aspects of sepsis epidemiology and pathophysiology and the results of early animal and clinical studies. The results of the large multicenter phase III PROWESS study will then be reviewed, along with results from subsequent open-label studies. Finally, I will focus on the key side effect issue with drotrecogin alfa (activated), that of increased bleeding, drawing data from the available clinical studies, and highlighting the contraindications and precautions when prescribing this drug.

Desmopressin acetate is the synthetic analogue of the antidiuretic hormone arginine vasopressin. It has been employed clinically for >30 years in a range of formulations: intranasal solution (since 1972), injectable solution (since 1981), tablets (since 1987), and most recently, an oral lyophilisate (since 2005). The antidiuretic properties of desmopressin have led to its use in polyuric conditions including primary nocturnal enuresis, nocturia, and diabetes insipidus. While a large body of clinical data is available for desmopressin, and despite its widespread use, comprehensive reviews of the safety of desmopressin are lacking (although some case series have attempted to correlate patient and/or dosing characteristics with the occurrence of adverse reactions). The purpose of this paper is to review the safety of desmopressin, based on analyses of both published data (MedLine) and of adverse reactions reported to Ferring Pharmaceuticals, the major manufacturer of desmopressin. Based on the findings, suggested strategies to reduce the risk of adverse reactions are proposed. Treatment with intranasal and oral formulations of desmopressin is generally well tolerated, and side effects are usually minor. The risk of hyponatraemia, although small, can be reduced by adhering to the indications, dosing recommendations and precautions when prescribing desmopressin.