Current Drug Safety - Volume 7, Issue 3, 2012

The signal transduction of tumor necrosis factor-alpha (TNF-alpha) is complex and regulated via a vast number of interconnecting pathways. The TNF-alpha signaling pathway plays a major role in the pathogenesis of subarachnoid hemorrhage (SAH). The advent of molecular mimicry has provided a number of opportunities to tackle disease with improved specificity. Here we review the mechanisms of their action and the potential for TNF-alpha inhibitors as a treatment for subarachnoid hemorrhage. Searches were performed using PubMed with the search terms “subarachnoid haemorrhage”, “TNF alpha”, “novel drugs” TNF alpha inhibition”, “management”, “cerebral aneurysm”, and “vasospasm” from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed. In conclusion, there is considerable theoretical evidence for the potential of TNF-alpha inhibitors to impact on the pathogenesis of aneurismal SAH. Such indications demonstrate the potential for specific targeting of molecular signaling pathways to prevent the growth and rupture of cerebral aneurysm.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed therapies worldwide. Meta-analysis data indicate the potential for myocardial infarction, cerebrovascular incident, heart failure, renal failure and arterial hypertension. Here we review the mechanisms of their actions and the potential for therapeutic use in subarachnoid hemorrhage. Searches were performed using PubMed with the search terms “subarachnoid hemorrhage”, “NSAID”, “treatment”, “management”, “cerebral aneurysm”, and “vasospasm” from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed.There are considerably mixed views on the potential impact of NSAIDs on the treatment and prevention of SAH. Whilst theoretically, the potential for positive intervention in the condition is huge, little effect appears to be measurable in clinical practice.

The hypothesis that alterations in hormone levels can impact on subarachnoid hemorrhage (SAH) is rapidly gaining momentum. Specifically, the concept that post-menopausal women are more susceptible to the condition has convinced many of the protective roles of estrogen and progesterone. Here we review the mechanisms of their actions and the potential for estrogen and progesterone replacement therapy in subarachnoid hemorrhage. Searches were performed using PubMed with the search terms “subarachnoid hemorrhage”, “estrogen”, “progesterone ”treatment”, “management”, “cerebral aneurysm”, and “vasospasm” from 1970 to February, 2012. Articles were also identified through searches of the Cochrane library and searches of the authors' own files. Only papers published in English were reviewed. In conclusion, there is significant theoretical evidence for the potential role of estrogen and progesterone use in altering the pathogenesis of SAH. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature.

Background: Antidepressants, more specifically SSRIs, represent one example of a widely prescribed class of medications in pregnant women for which less than adequate pregnancy data have been available since the first drug in this class was marketed 20 years ago. Moreover, findings from studies performed after 2005, when health governmental authorities issued warnings regarding first trimester exposure to paroxetine and the risk of cardiac malformations, may be the result of detection bias if physicians were investigating more their pregnant patients that used paroxetine than the others. Objectives: To estimate the prevalence of 1) paroxetine use during pregnancy, and 2) diagnosed cardiac malformations in the Quebec and France populations. Methods: Two distinct pregnancy databases were used for this ecologic study: the Quebec Pregnancy Registry and the French EFEMERIS database. Results: In Quebec, among the 109,344 eligible pregnancies, 1,612 (1.5%) were exposed to paroxetine. Prevalence of paroxetine use during pregnancy increased from 0.7% to 1.2% between 1998 and 2003, simultaneously to the increase of the prevalence of cardiac malformation diagnoses. In France, among 40,317 eligible pregnancies, 173 (0.4%) were exposed to paroxetine; between 2004 and 2008 the number of paroxetine fillings and cardiac malformation diagnoses remained constant. Conclusions: Despite differences in the Quebec and French healthcare systems, increase in paroxetine prevalence use during pregnancy was already consistent with an increase in the prevalence of cardiac malformations, even before the warning on the risk of cardiac malformations in newborns in 2005-2006, limiting the possibility of detection bias.

High dose busulfan (BU) has become a mainstay in conditioning regimens for hematopoietic stem cell transplantation (HSCT), despite its unpredictable response, narrow therapeutic index and severe toxicity. The present study provides an integration of pharmacokinetic and genetic data of 63 adults with acute myeloid leukemia (AML) preconditioned for HSCT with high dose oral BU, with the aim of defining biomarkers predictive of poor BU metabolism. BU area under the concentration time curve (AUC) demonstrated that 76% of the patients achieved target AUC; 24% required dose modification. The main findings of this study were: (1) AML patients carrying the GSTP1 rs1695 variant allele were at risk of developing supra-therapeutic BU-AUC due to reduced BU clearance. (2) Combined polymorphisms in GSTM1 and ABCB1 were associated with BU clearance and AUC rates. In conclusion, GST and ABCB1 genotyping may assist care-givers in personalizing BU dosage with less trial-and-error and may enable preemptive identification of patients at risk for BU toxicity.

It is common for injecting drug users (IDU) to prepare injections by crushing tablets which are not designed for parental administration. The injection of insoluble tablet excipients can lead to serious local and systemic medical complications. The aim of the study was to investigate the effectiveness of various types of filters in removing harmful insoluble particles from the injections prepared using crushed oxycodone tablets. Injections were prepared from a sustained-release oxycodone tablet formulation. The filtration of tablet extracts was carried out following procedures used by IDU using makeshift filter and commercially available filters. Particulate contamination and oxycodone content were analysed using light microscopy and spectrophotometer. Unfiltered extracts contained hundreds of thousands of particles of sufficient size to cause harms. Cigarette filters removed large particles but failed to remove small particles. The combination of cigarette filter and syringe filter (0.45 μm or 0.22 μm) reduced the particle count by 90 – 95%. A double membrane syringe filter (0.8/0.2 μm) removed more than 99% of the particles. Recovery of oxycodone was more than 95% with the tested syringe filters. Particulate contamination in injections prepared from crushed tablets can be effectively removed using a combination process of cigarette filter and syringe filters, or a 0.8/0.2 μm syringe filter. Compared to other filters, the 0.8/0.2 μm syringe filter did not block, the filtration was quick and easy to perform, and did not retain oxycodone. The use of a 0.8/0.2 μm syringe filter can provide an important harm reduction measure for IDU.

Drug adverse effects (ADEs) and toxicities have been extensively studied from chemical structure, genetic, biological systems and clinical perspectives. The rapid accumulation of chemical, biological and clinical data are highly useful for characterizing and predicting ADEs, and have enabled increasing exploration of computational methods as low cost tools for predicting various ADEs and toxicities. This article reviews the strategies, current progresses, underlying difficulties and future prospects in using computational methods for predicting ADEs and toxicities.

Purpose: To categorize and synthesize medication safety event detection methods in the critically ill in order to provide clinicians and administrators with approaches to event detection that are intended to expand and complement traditional voluntary reporting systems. Methods: A literature search of OvidMEDLINE was performed to identify articles related to medication safety involving critically ill patients in the intensive care unit setting. The inclusion of articles was restricted to comparative studies. The bibliographies of all retrieved articles were reviewed to obtain additional articles of relevance. The various event detection methods were compared by: evidence supporting their use; number, type and severity of events detected; phase of the medication use process in which events were detected; and ease and cost of implementation. Major limitations of each method were also collated. Results: There are a number of methods that can be used to identify medication safety events in the critically ill. These can broadly be categorized as: 1) voluntary reporting, 2) record review, 3) rules/triggers and 4) direct observation and 5) interviews/surveys. Relatively few studies have directly compared these assessment methods in the ICU setting, although the limitations of the traditional voluntary reporting system as the sole method of event detection are well established. Although not truly dichotomous, these methods can be broken down into more proactive and reactive approaches. Rules/triggers and direct observation of the medication use process in the ICU are examples of proactive approaches to event detection, while the traditional unsolicited voluntary reporting is typically reactive. However, each of the event detection methods has advantages and disadvantages, so the methods should not be considered mutually exclusive with respect to obtaining information about medication safety. Conclusions: Given the limitations of traditional voluntary reporting systems, a multimodal approach used to identify medication safety events is most likely to capture the largest number and type of events. We would advise not trying to implement additional approaches beyond voluntary reporting systems all at once. This would be difficult and costly. Rather, we suggest a systematic implementation of additional event detection approaches that takes into account hospitalspecific considerations.

Introduction: Docetaxel belongs to the taxane group of chemotherapeutic agents used in the management of various malignant diseases. Nail changes as a complication of such treatment are observed in about 44%. Subungual haemorrhages (SH), are very rare following docetaxel therapy and only a few cases have been previously reported. Observation: An 80-year-old man suffering from prostate adenocarcinoma was treated with a 3-weekely cure of docetaxel started 3 months earlier. Nail changes occurred after the 5th cycle of docetaxel. Clinical examination revealed orange discoloration of the nail plates, subungueal haemorrhages (SH) and onycholysis involving nails of all the digits and toenails of both hands and feet. These features were highly suggestive of nail toxicity following docetaxel therapy. Discussion: Nail changes secondary to Taxane chemotherapy includes nail bed dyschromia, onycholysis, red or orange Beau's lines and subungueal hyperkeratosis. SH, as reported in this case, is related to the cumulative dose of docetaxel and should not be attributed to other systemic diseases. Clinicians should recognize this complication to avoid abusive treatment or investigations and inform the patients about the possibility of nail changes secondary to taxane drugs.

Objectives: The 5-HT2 antagonistic action of quetiapine may disinhibit the dopaminergic system enhancing dopaminergic activity in the forebrain and influencing the mood state. Our objective is to investigate the possible induction of manic symptoms by quetiapine through a case report and a review of the literature. Method: We report the case of a 54 year old woman suffering from bipolar depression who developed hypomania seven weeks after the initiation of 300 mg/d of quetiapine. A literature review concerning the induction of hypomania or mania by quetiapine have retrieved the presence of seven similar case reports or series. Results: Available literature points toward an early induction of hypomania or mania with low dosage of quetiapine treatment (between 100 and 400 mg/day never exceeding 600 mg/day). Hypomania or mania are possible short term complications that can be present few days to few weeks of treatment initiation. The discontinuation of the drug or the increase of its dose seems to reverse the hypomanic or manic symptoms. Patients described in the literature suffer mostly from schizophrenia. Conclusion: The atypical antipsychotic drug quetiapine, which have antidepressant properties at low doses via its indirect dopamine enhancing activity due its serotoninergic antagonism, appears to be involved in the induction of rare hypomanic or manic state in patients suffering from bipolar disorders and to have mood stabilizing properties at higher doses when its dopamine antagonist activity becomes more prominent. Its manic/hypomanic induction properties should not prevent its administration to patients suffering from bipolar disorder.