Current Drug Safety - Volume 10, Issue 3, 2015

Calcium channel blockers (CCBs) are a heterogeneous group of drugs often used in the therapy for hypertension and angina. Though CCBs are generally similar in terms of their efficacy yet, they differ in their ability of causing selective inhibition in the contractility of vascular smooth muscle in comparison to cardiac muscle. Felodipine is one of the most vascular selective of the available CCBs and it has no negative inotropic effects at clinically administered doses. Focus of this review is to comprehensively summarize the pharmacokinetics, efficacy, safety and tolerability of felodipine. This review is based on evaluation of relevant literature on felodipine using meta-database PubMed and ScienceDirect and internet search engine (Google Scholar). Clinical studies summarized in this review testify, on technical lines, the clinical efficacy, safety and placebo- like tolerability profile of felodipine, administered alone as well as in combination.

A multidisciplinary approach based on clinical expertise and knowledge of molecular processes involved in hepatocarcinogenesis is needed for the proper management of hepatocellular carcinoma (HCC) patients. Such information must be considered in the context of pathobiology of the underlying liver disease. New drugs targeting specific molecular steps in pathways involved in HCC growth and development bear the promise to radically modify the pharmacological therapies currently in use in hepatooncology. Sorafenib was the first drug approved in the setting of advanced HCC, but although it produces some improvement in survival, the responses are not durable. In addition, there are significant side effects. Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and after progression following sorafenib failure; among them, tivantinib, an inhibitor of cMET receptor, showed interesting results in a recent phase-II study. Additional agents currently studied for the treatment of HCC patients are briefly examined in this review. Aim of this paper is to discuss the state of the art in the management of advanced HCC patients, with a particular interest for the description of their side effects.

The advent of new oral anticoagulants (NOAC) has increased the armamentarium against thromboembolic diseases but has given rise to a conundrum on their reversal. NOAC’s have comparable efficacy to traditional vitamin K antagonists with similar rates of major bleeding. However there is no standardized method for reversal of these agents and no specific antidote. This is of concern not only in acute bleeding episodes but also in clinical scenarios where emergency surgery is required. Recent studies have investigated reversal of dabigatran, rivaroxaban, and apixaban using prothrombin complex concentrates (PCC), recombinant factor VIIa, and in the case of dabigatran, a monoclonal antibody. These studies have been encouraging in showing improvement of bleeding times and blood loss in most models, especially with the use of PCCs and the dabigatran antibody. Of note the majority of common currently used coagulation assays may not correlate with clinical reversal. The management of overt bleeding with NOACs is difficult due to the lack of clinical trials. Current animal trials, case reports and hemostatic testing on human blood have shown some promise; provide guidance but warrant further investigation.

Natalizumab and alemtuzumab are monoclonal antibodies approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). A third monoclonal antibody, daclizumab, should soon become another alternative for RRMS therapy. A group of 26 doctors working at specific MS Units in seven different Latin American countries participated in the present study. All 26 neurologists had experience with natalizumab for the treatment of MS and were willing to discuss strategies for improving this treatment. Most neurologists had no confidence in starting a patient on natalizumab and alemtuzumab, which are new and efficient drugs approved by North American, European and most Latin American health agencies. The Latin American specialists felt they were not properly informed on daclizumab. Specific pharmacovigilance programs for each of these monoclonal antibodies were considered very important by the neurologists, who were also willing to discuss these therapeutic options with peers from other countries.

Introduction: The administration of antibiotics for the treatment of pediatric illnesses is common, reaching one third of pediatric patients. This paper aims to identify the antibiotic prescription practices of pediatricians and to explore the associations between prescribing practices and a series of socio-demographic and professional determinants in Greece. Material and Method: A cross-sectional study was conducted in public hospitals providing secondary and tertiary pediatric care from January to July 2012. A self-administered questionnaire was developed and tested in a pilot study, focusing on respondents’ characteristics, their practices and attitudes related to prescribing antibiotics in common childhood diseases, diagnostic uncertainty, and parental demand. Multivariate regression analysis was performed. Results: In total, 275 physicians responded to the questionnaire (61% response rate). The majority of the physicians prescribed antibiotics empirically in possible group A streptococcus infections (56.9%) and implemented the “watchful waiting” approach in acute otitis media (65.5%); further, they did not feel diagnostic uncertainty (74%) and were not affected by parental demand (81%). Finally, when prescribing, they did not take into consideration the drug cost (64.4%). Gender, physicians’ experience, and the type of hospital (specialized or general hospital) were identified as prognostic factors of prescribing practices. Conclusion: Our findings could provide decision-makers with insights into how to manage physicians’ prescription practices in order to reduce the high rates of antibiotic consumption that Greece is facing nowadays.

Objectives: This study evaluates the impact of carvedilol dose changes on the ventricular arrhythmia event rates for patients > 18 years of age with systolic heart failure and examines dose dependent effects of carvedilol withdrawal in dose reduction and discontinuation subgroups. Methods: This retrospective cohort study included patients with systolic heart failure (EF < 40%) receiving carvedilol. The primary outcome was incidence of ventricular arrhythmia. Ventricular arrhythmia event rates were compared among carvedilol dose continuation, reduction and discontinuation groups. To assess dose dependent effects of beta-blocker withdrawal, dose reduction and discontinuation groups were divided into subgroups. Results: Dose discontinuation (n=64) or reduction group (n=83) had significantly higher ventricular arrhythmia rates compared with dose continuation group (n=262) (65.6 vs 33.7 vs 15.3%, p < 0.001 for both comparisons). Dose discontinuation group also had a significantly higher ventricular arrhythmia event rate compared with dose reduction group (p<0.001). There were no significant differences in ventricular arrhythmia event rates among dose discontinuation or reduction subgroups. Conclusion: Continuation of carvedilol therapy was associated with a substantially lower ventricular arrhythmia event rate compared with reduction or discontinuation of carvedilol therapy. Dose dependent effects of beta-blocker withdrawal in subgroup analyses were not found.

Introduction: Disproportionality analysis (DA) of adverse drug reactions spontaneous reporting (SR) databases is used to identify signals of disproportionate reporting (SDR). The objective of this study was to identify the generation of SDR in the published literature and whether it led to regulatory action. Methods: A systematic literature search in MEDLINE and Cochrane Central Register for Controlled Trials (CENTRAL) in a 10-year period, from 2005 to 2014, was conducted, to identify studies designed to detect drug safety signals through the use of disproportionality measures applied to spontaneous reporting databases of adverse drug reactions. Results: Seventy three studies were included. The number of publications has been rising over the study time period. Forty nine studies focus on drug-event combinations. Large international and smaller national or regional databases were identified. The disproportionality measures applied included frequentist and Bayesian methods and some studies used more than one method. SDRs were identified in more than ninety percent of the studies. Ten studies were found to be confirmatory of previous regulatory decision. Conclusion: It was not found any safety signal issued by drug regulatory agencies exclusively generated by DA. More research devoted to this issue is needed, since the value of these methods on drug safety signaling and their impact on drug regulation actions remains to be established.

Adverse cutaneous reactions are frequently reported to occur with the use of psychotropic medications, which may lead to poor drug compliance. As compared to other groups of psychotropic medication, antipsychotics, both typical and atypical, are less likely to cause adverse cutaneous reactions. The most frequent cutaneous adverse reactions associated with antipsychotics include fixed drug eruptions, exanthematous eruptions, photosensitivity reactions and altered skin pigmentation. Most of these commonly seen cutaneous adverse reactions are benign and easily treatable. Rarely, severe cutaneous adverse reactions such as erythema multiforme, Steven-Johnson syndrome are toxic epidermal necrolysis and have also been associated with antipsychotics. Olanzapine is one of the most commonly prescribed atypical antipsychotic with metabolic complications as most common adverse effects. Dermatological reactions are rarely observed with olanzapine. We report occurrence of pellagroid skin lesions over exposed areas of upper limbs with olanzapine that resolved completely after its discontinuation.

Tacrolimus is a calcineurin inhibitor primarily metabolized by CYP3A4 and secondarily by CYP3A5. Several drugs can modify tacrolimus blood levels as calcium channel blockers (CCBs). Interaction with nicardipine was reported in some cases. A man with a history of malignant arterial hypertension treated with nicardipine, underwent kidney transplantation. After transplantation, he was treated with tacrolimus, mycophenolate mofetil and corticoids. Therapeutic drug monitoring of tacrolimus was done regularly showing a mean trough concentration (C0) of 24.39 ng/mL with some concentrations reaching 52 ng/mL. After changing nicardipine by prazosine, the first tacrolimus C0 after stopping nicardipine was 3.2 ng/mL. Increase of tacrolimus trough concentrations is due to the inhibition of CYP3A4. Very high levels of tacrolimus suggest the non expression of CYP3A5. Thus, because of the possible lack of the secondary pathway, therapeutic drug monitoring of tacrolimus is highly recommended at the introduction of CCBs and also at its stopping.

Sagittal sinus thrombosis (SST) induced by chemotherapy is exceptional. We describe here a new case following the fourth cure of chemotherapy based on cisplatin, bleomycin and etoposide in a 16-year-old patient with no obvious risk factors. Through this uncommon case which forms part of cerebral venous sinus thrombosis (CVST), we propose to study the pathophysiology, the diagnosis and the management of this entity. The exclusion of the other causes of CVST is important not only for the therapeutic implication but also for the prognosis. Then, accurate documentation of each case induced by chemotherapy is needed to further understanding.

We present an 18-month boy with imipramine poisoning to illustrate the neuro-cardiac toxic effects of this potentially deadly poison in children. The toddler ingested an unknown amount of imipramine from a non-childproof bottle which clearly labelled that the drug must be kept out of reach from children. He developed neurologic and cardiac symptoms. Electrocardiography (ECG) showed tachycardia and widened QRS. He was immediately treated with bicarbonate infusion and made an uneventful recovery. This is the youngest and only reported case of symptomatic imipramine ingestion in our locality. Imipramine has been surpassed by newer antidepressants for the treatment of depression in the past decade. Literature is searched to review the mortality rate in young children. Intensive care neuro-cardiac support contributes to the favorable outcome. Despite clear labelling of the bottle, carelessness on the part of the adult and the use of non-childproof bottle are definite preventable factor to such potentially fatal ingestion.

Sweet’s syndrome has been reported in association with inflammatory diseases such as Crohn's disease. It has also been reported in association with several drugs. Here, we report a rare case of Sweet’s syndrome induced by azathioprine in a patient with Crohn's disease.