Current Drug Safety - Volume 7, Issue 2, 2012

Background: In Europe amoxicillin plus clavulanic acid is the most commonly prescribed antibiotic and sodium benzoate is contained in the suspension formulation as a preservative. Objective: We studied the relevance of sodium benzoate as the culprit agent. In a group of children with a history of adverse reactions to amoxicillin plus clavulanic acid suspension. Study Design: A total of 89 children were enrolled over a period of 3 years (2006 - 2009). Single blind oral provocation tests (OPTs) with amoxicillin plus clavulanic acid, sodium benzoate and placebo were performed. 20 children with recurrent idiopathic urticaria were investigated as a control group. Results: according to personal history: 70% of reactions were late in developing while 23% of reactions were immediate and for 5% of the cases it was not possible to define the timing. 8 children (8/89=9%) resulted positive to the provocation tests with amoxicillin plus clavulanic acid; ten children (10/89=11%) had positive results with sodium benzoate; 3% had a double positivity (i.e. excipient and active drug). The timing of reactions significantly differs between the Amoxicillin plus clavulanic acid and sodium benzoate groups (p=0.002). Conclusion: Sodium benzoate probably acts through a non-immunologic mechanism and care should be given to children allergic to sodium benzoate containing pharmaceutical formulations.

Atypical antipsychotic-induced hyperprolactinemia can cause important clinical symptoms, particularly in young women and also in men, such as impotence, loss of libido, gynecomastia, anovulation and galactorrhea. Methods: Observational over one-year follow-up of six patients (four women and two men, mean age of 31.1 years, range 26-37), treated with different atypical antipsychotics in an outpatient psychiatric device, who had clinical complications associated to high prolactin serum levels. All of them were treated with standard doses of cabergoline. Results: Most patients experienced significant clinical improvement after treatment with standard doses of cabergoline (mean dosage 1.08 mg/week), maintained for a mean of 18 month. Normal prolactin levels were achieved after the first months of treatment with cabergoline. No side effects or worsening of psychotic or behavioral symptoms were observed. Conclusions: Long-term treatment with cabergoline seems to be safe in atypical antipsychotic-treated patients.

Introducton: Ticlopidine is an antiplatelet agent available from several decades. Its most important adverse drug reactions (ADRs) involve haematological system. Our aim was to evaluate the safety profile of ticlopidine in the real life, on the basis of spontaneous ADR reporting. Materials and Methods: Spontaneous reports from 8 Italian Regions collected from 1990 to March 2007 were analysed. According to WHO Adverse Reaction Terminology for causality assessment only “certain”, “probable” or “possible” ADRs were included. Association between drugs and any ADR was assessed by using the case/non-case methodoloy. Reporting odds ratio (ROR) was computed as a measure of disproportionality. Results: Overall, 478 reports concerning ticlopidine were analysed. The system organ classes with significant disproportionality for ticlopidine included White Cell Disorders (ROR=22.43, 95% CI 18.54-27.12), Red Cell Disorders (8.22; 6.03-11.18), Liver And Biliary System (6.67; 5.35-8.32), Platelet, Bleeding & Clotting (6.59; 5.16-8.40). Fifteen percent of the ADRs occurred beyond the first three months of ticlopidine therapy. In 386 reports (80.7%), ticlopidine was the only suspected drug. Conclusion: Safety profile of ticlopidine can be considered well-established in terms of ADRs type but their frequency and severity continue to be higher in its current use. Since this drug is still widely used in Italy, both healthcare providers and patients should be aware of its ADRs. More specifically, patients should be regularly monitored during the whole period of use and not only in the first months of treatment.

Ketamine is widely used for anesthesia in pediatric patients. Growing evidence indicates that ketamine causes neurotoxicity in a variety of developing animal models. Our understanding of anesthesia neurotoxicity in humans is currently limited by difficulties in obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. It may be possible to overcome these challenges by obtaining neurons from human embryonic stem cells (hESCs) in vitro. hESCs are able to replicate indefinitely and differentiate into every cell type. In this study, we investigated the toxic effect of ketamine on neurons differentiated from hESCs. Two-week-old neurons were treated with different doses and durations of ketamine with or without the reactive oxygen species (ROS) scavenger, Trolox. Cell viability, ultrastructure, mitochondrial membrane potential (ΔΨm), cytochrome c distribution within cells, apoptosis, and ROS production were evaluated. Here we show that ketamine induced ultrastructural abnormalities and dose- and timedependently caused cell death. In addition, ketamine decreased ΔΨm and increased cytochrome c release from mitochondria. Ketamine also increased ROS production and induced differential expression of oxidative stress-related genes. Specifically, abnormal ultrastructural and ΔΨm changes occurred earlier than cell death in the ketamine-induced toxicity process. Furthermore, Trolox significantly decreased ROS generation and attenuated cell death caused by ketamine in a dose-dependent manner. In conclusion, this study illustrates that ketamine time- and dose-dependently induces human neurotoxicity at supraclinical concentrations via ROS-mediated mitochondrial apoptosis pathway and that these side effects can be prevented by the antioxidant agent Trolox. Thus, hESC-derived neurons might provide a promising tool for studying anesthetic-induced developmental neurotoxicity and prevention strategies.

Traditional herbal remedies have been used to treat many ailments in Nigeria but the safety of herbal remedies has been the major concerns to many people especially when the chemical constituents of the products are not known. This study is therefore designed to evaluate the prevalence of use of complementary drugs with antiretroviral (ARV) therapy and possible treatment outcome of the concurrent utilization of these therapeutic agents. A descriptive crosssectional survey of 354 HIV patients attending APIN clinics in LUTH using a consecutive sampling technique was used. There was also correlation of the data obtained from the patients with their clinical case notes. Results showed that only 8.2 % of the respondents’ used herbal medicine concurrently with ARV therapy. Ninety percent of the participants were on a two nucleoside and one non-nucleoside based ARV therapy. The most common regimen (55%) was Zidovudine/lamivudine/Nevirapine fixed dose combination while 10% use a protease inhibitor based regimen. The commonly herbal drugs used ranges from Jobelyn [Sorghum bicolor plant leaves (13.8%)], Garlic [Allicin, ϒ-glutamyl- (s)-ally-L-Cysteine] (10.3%), Ginger [Essential oil] (17.2%) and Aloe vera [Hydroxyanthracene derivatives expressed as Barbaloin] (10.3%). The major reason for the commencement of herbal medicine is the perception that the medicine will boost their immunity (65.5%). However, there was a marginal improvement though not significant (p ≥ 0.05) in the CD4 counts (489.8 ± 195.2; 419.1 ± 236.2) and viral load (5117.8 ± 26092.0; 31136.7 ± 197954.6) of HIV patients on herbal drugs compared to those who are not on herbal drugs. Herbal medicines have potentials to interact with ARVs and thus result in adverse reactions and possibly therapeutic failure. There is need for thorough investigation of the pharmacological action of these herbal medicines in HIV treatment taking into consideration their pharmacokinetic and toxicological profile.

Mitochondria are considered the powerhouses of the cell playing an important role in energy metabolism. However, they are highly vulnerable to inhibition or uncoupling of the energy harnessing process and run a high risk of causing catastrophic damage to the cell. Several anesthetics or drugs commonly given during anesthesia interact with mitochondria and affect their structure or impair respiratory chain functioning with decreased ATP production. Mitochondria, in fact, are a potential site of action of general and local anesthetics. The purpose of this review is to update present knowledge and describe the effects and molecular mechanisms of the action of the most used drugs of anesthesia on mitochondria.

Drug-induced phototoxicity is elicited after exposure of the skin and/or eyes to topically or systemically administered pharmaceutical substances, followed by exposure to sunlight. This undesirable side effect is one of the impediments in drug discovery and development, and substantial efforts have been made to avoid drug-induced phototoxic reactions. To evaluate the phototoxic potential of compounds, effective methodologies have been developed over the past few years, and screening strategies have also been proposed for predicting in vivo phototoxic reactions. European and American regulatory agencies have published guidelines for predicting and avoiding drug-induced phototoxicity in an early phase of drug discovery. The guidelines have indicated the requirements for assessing the photosafety of chemicals on the basis of their photochemical behaviors and have recommended some phototoxic assessment tools for aiding new drug development. A number of phototoxic screening systems have also been proposed on the basis of the pathogenesis of drug-induced phototoxicity, and some of them have already been applied to the phototoxic evaluation of new drug entities in drug discovery and development. The present review aims to summarize the current status of research tools, screening strategy and regulations for evaluating the photosafety of new drug candidates and to introduce our thoughts on the phototoxic risk assessments of compounds.

Cardiac safety was compared in patients receiving moxifloxacin and other antimicrobials in a large patient population from Phase II–IV randomized active-controlled clinical trials. Moxifloxacin 400 mg once-daily monotherapy was administered orally (PO) or sequentially (intravenous/oral, IV/PO). Across 64 trials, 21,298 patients received PO therapy (10,613 moxifloxacin, 10,685 comparators) while 6846 received sequential IV/PO therapy (3431 moxifloxacin, 3415 comparators). Treatment-emergent cardiac adverse event (AE) rates were similar for moxifloxacin and comparators in PO (6.6% vs 5.8%) and IV/PO (11.0% vs 12.0%) trials. Treatment-emergent cardiac adverse drug reactions were rare in PO (moxifloxacin 3.2% vs comparators 2.4%) and IV/PO (moxifloxacin 1.4% vs comparators 1.5%) patients. There were five (<0.02%) treatment-emergent drug-related deaths due to cardiac events out of 28,144 patients; one PO patient died treated with comparators, one patient died treated with IV/PO moxifloxacin, and three patients died after treatment with IV/PO comparators. Only one case of treatment-related non-fatal torsade de pointes occurred in the comparator arm. Incidence rates of cardiac AEs remained low in populations at elevated risk of cardiac events predisposed to QTc prolongation (i.e. community-acquired pneumonia patients admitted to the intensive care unit and/or mechanical ventilation, patients with documented prolongation of baseline QTc interval, women, and patients ≥ 65 years old). There was no evidence of unexpected cardiac events. After moxifloxacin treatment, an expected small prolongation in QTcB and QTcF was found. This analysis of numerous clinical trials shows the favorable cardiac safety profile of moxifloxacin, when used appropriately and according to its label, versus other antibiotics.

Doping with erythropoietic proteins such as erythropoietin (EPO) is a serious issue in sport. There is little information on the possible ophthalmologic alterations followed by frequent EPO abuse in athletes. EPO is a potent retinal angiogenic factor and is capable of stimulating retinal angiogenesis and neovascularization in the presence of ischemia. Systemic and intravitreal EPO concentrations are highly correlated. A linkage between EPO doping and retinal proliferation is possible and further studies are warranted. Gathering and analyzing data on retinal findings from these athletes, either retrospectively or prospectively might yield preliminary information to support the safety of those athletes. Implications of this hypothesis cover other kinds of neovascularizations and angiogenesis.

Adverse drug reactions' spontaneous reporting systems are an important element in worldwide pharmacovigilance, gathering potentially useful information for post-marketing drug safety surveillance. Data mining and signal management systems, providing the capability of reading and interpreting these systems' raw data (data that has not been subjected to processing or any other manipulation), improve its analysis process. In order for this analysis to be possible, both data mining and signal management systems and raw data should be available to researchers and the scientific community. The purpose of this work was to provide an overview of the spontaneous reporting systems databases reported in literature as having implemented a data mining and signal management system and the implementation itself, evidencing their availability to researchers. A systematic review was carried out, concluding that they are freely provided to researchers within institutions responsible for maintaining the spontaneous reporting systems, but not to most researchers within the scientific community.

Raloxifene is an anti-resorptive agent used in postmenopausal osteoporosis. This is the first report of the occurrence of clinically significant hypocalcemia following raloxifene treatment in a patient with occult vitamin D deficiency. Since vitamin D deficiency is widely prevalent in the community, screening for vitamin D deficiency and its correction is advisable before the initiation of anti-resorptive therapy.

Rapidly developing pulmonary fibrosis associated with the use of the anti-cancer drug oxaliplatin has been reported mainly by Asiatic literature as isolate case reports. This rare but potentially fatal side effect has neither identified risk factors nor established treatment guideline. We report here a new clinical case concerning a patient with advanced gastric cancer treated with the oxaliplatin-based FOLFOX regimen along with a review of the literature as well as a discussion of emerging experimental treatment mainly based on imatinib.

Hypoglycemia is a rare life threatening adverse drug reaction associated with various fluoroquinolones like ciprofloxacin, gatifloxacin and levofloxacin. Moxifloxacin was considered safe in this regard. Only one case has been reported for moxifloxacin-induced hypoglycemia in a renal failure patient. Here, we are reporting the second case of hypoglycemia due to moxifloxacin without any major co-morbid condition.

Introduction: Glatiramer acetate (Copaxone), a polypeptide has been approved for treating patients with active relapsing–remitting multiple sclerosis. Case Presentation: We report the first case of severe acute hepatitis after commencing treatment for multiple sclerosis with glatiramer acetate. A 31-year-old female with multiple sclerosis presented with anorexia, lethargy and jaundice five weeks after commencing glatiramer acetate. She had never received beta-interferon treatment. Investigations revealed a bilirubin of 0.109 mmol/L (0.002-0.02 mmoL/L) and prothrombin time of 21 secs (9-15 secs). Her liver function tests were normal before commencing glatiramer acetate. A liver biopsy performed approximately 6 weeks after commencement of glatiramer acetate showed predominantly centrilobular hepatocyte necrosis with portal-venous bridging, along with mild portal and interface hepatitis. The necrosis was not accompanied by an acute inflammatory or chronic inflammatory infiltrate. The features were not suggestive of autoimmune hepatitis but consistent with drug toxicity. The liver tests returned to normal within 2 months after cessation of glatiramer acetate. Conclusion: Physicians should be aware that glatiramer acetate can be associated with uncommon but yet significantly severe liver toxicity.