Current Drug Safety - Volume 4, Issue 1, 2009

Most researchers and academics in drug safety focus their work on the toxicity and side-effect profiles of pharmacologically active agents. As a professional group, we have become experts at screening drug candidates for potential to cause harm to biological systems or potential to interact adversely with other therapeutic agents. We are vigilant in documenting adverse events through all phases of clinical trials and post-marketing. We constantly refine our screening techniques, making use of the latest available technologies. Consequently, in many fields of medicine the newer drugs have significantly more benign adverse-effect profiles than their predecessors. The public expects safer drugs and new research is delivering them. Nevertheless, maintaining drug safety continues to be a difficult challenge. Discussions about drug safety with our colleagues in the regulatory authorities suggest that most of their time is spent not dealing with issues of drug toxicity but is instead spent dealing with issues of negligence and error. These are issues that we, as researchers and clinicians, rarely consider. From reports to US health authorities in January 2008, one of the most serious recent challenges for drug safety was recognised when some patients undergoing dialysis were found to have acute hypersensitivity reactions, subsequently associated with the contamination of heparin-containing products with oversulfated chondroitin sulphate (OSCS), an impurity that is structurally similar to heparin [1]. Clusters of patients had been having such reactions from November 2007. The symptoms included, lowered blood pressure, facial swelling, tachycardia, urticaria and nausea. By April 2008, 81 deaths associated with contaminated heparin had been reported. Adverse effects of OSCS-contaminated heparin have been demonstrated in rodent and swine models, confirming a reduction in diastolic pressure with administration and that the effect is dependant both on dose and route of administration [2]. Contaminated heparin products have been found in Australia, Canada, China, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand and the United States. The source of the contamination was traced to a manufacturing facility in Changzhou, China, which was inspected by investigators from the US Food and Drug Administration in February 2008. Many inadequacies were reported with the facility itself, as well with suppliers of crude materials to the facility [3]. It is still unclear whether the contamination was accidental or due to replacing the correct raw materials with a cheaper substitute. The impact of the contaminated heparin problem continued throughout 2008. As late as May, new recall notices were being issued for products, including heparin-coated thoracic drainage catheters and some devices used in cardiac surgery. The example of heparin contamination highlights numerous problems for drug safety. The increasingly global nature of the pharmaceutical industry means that errors can be on a larger scale, more difficult to regulate and harder to track to their source. Industry purchases from networks of manufacturers, each of which has a further network of corporations and suppliers. Each supplier and manufacturer has to comply with its own local laws and regulations as well those of the country where its products are used. Then there are language and cultural differences to overcome. This can be a difficult challenge, even for people with the best of intentions. Industries do not exist for altruistic reasons of helping the sick. They are there to make a profit and that brings strong pressures to minimise costs. However, most pharmaceutical companies recognise that it is in their own best interests to comply with safety standards. If they breach standards, not only do they risk expensive legal process but they also lose credibility, which means that they lose business. The manufacturers of contaminated heparin clearly breached regulations. While traditional toxicology and safety monitoring will continue to be core research activities for those interested in drug safety, we should always be prepared to look beyond our traditional horizons. A potential for error and negligence exists which can compromise drug safety throughout the manufacturing, distribution and storage process. Increasing globalisation has heightened the challenge of providing safe drugs. Let us hope that contaminated heparin is no more than a consequence of a world adjusting to new trading relationships and not a sign of things to come.

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The risk of oral NSAID including Cox-2 inhibitors to cause gastrointestinal, renal or cardiovascular adverse events related to systemic drug exposure could be reduced by local application. But only few long-term studies have been published to show safety and efficacy for long-term use of topical NSAID´s. Diractin® (formerly IDEA-033) is a viscous, aqueous formulation for epicutaneous application of ketoprofen based on ultra-deformable, self-regulating carrier (Transfersome ®). This multiple-dose, open label study with treatment periods up to 18 months included 402 patients with joint pain, musculoskeletal pain, stiffness or soft tissue inflammation (age of 61.4 ± 11.5 years). Most of the patients suffered from osteoarthritis (OA) of the knee (68.9%). Diractin® was applied epicutaneously up to twice daily with a maximum dose of 220 mg ketoprofen per a maximum of 2 application sites. The mean pain score at baseline was 5.4 ±1.4 on a 10 point categorical scale. During the study the pain score progressively improved up to week 36 (3.5±1.9) without a substantial further change during the rest of observation period of up to 18 months. The reduction of pain scores between week 0 (baseline) and at all later visits was statistically significant (P < 0.0001). Patients also reported an improvement of quality of life on the EUROQoL. The majority of treatment related adverse events were skin and subcutaneous tissue disorders with the highest frequency reported for erythema (16.7%) and pruritus (2.0%). Systemic ketoprofen exposure remained low throughout the study period with plasma concentrations of less than 1% of what was reported for a single, standard oral dose of 200 mg ketoprofen. There were no occurrences of treatment related serious adverse events and no remarkable changes in laboratory values or vital signs. In summary, Diractin® provided adequate pain relief with a good safety and tolerability profile when used for up to 18 months (72 weeks).

Prolonged exposure to ketamine, a NMDA receptor antagonist, results in accelerated neurodegeneration and attenuated weight gain in neonatal rats. Suppression of the NMDA receptors by non-competitive antagonists has resulted in conflicting reports of both increased and decreased expression of BDNF. To examine the effect of prolonged ketamine exposure on BDNF expression, we administered saline or ketamine (20mg/kg) at 90-minute intervals over 9 hours to postnatal day 7 (P7) rat pups. The ketamine-treated rat pups had increased neurodegeneration, BDNF and TrkB cDNA products and protein levels. This increased expression of BDNF may be a response to ketamine-induced injury.

Twelve cases of Reye's syndrome are presented with different degrees of encephalopathy, hyperammonemia and hypoglycemia; associated to acetyl salicylic acid (ASA) ingestion. The aim of the present retrospective study was to describe our experience in selected patients with Reye's syndrome associated to the ASA ingestion and to underline the influence of hyperammonemia on Reye's encephalopathy. All the cases presented moderate hyperbilirubinemia, elevated alanine aminotransferase, aspartate aminotransferase with an average of 302±205 UI/L and 285±149 UI/L respectively. Arterial blood ammonia averaged 172.4±71.3 μmol/L and glycaemia averaged 35.2±17.0 mg/dl. A high mortality was found in our series (41.7%). Considering that encephalopathy is the leading syndrome in these cases, the influence of ammonia on brain tissue was described. Glutamate is an excitotoxic neurotransmitter, capable to produce neuron and astrocyte damage and apoptosis. The presence of ASA could cause the onset of the mitochondrial permeability transition and the mitochondrial swelling in the astrocyte, leading to hyperammonemia. In Reye's syndrome, hyperammonemia and perhaps the increase of glutamate are the leading factors in the mechanism of brain damage and encephalopathy. Aspirin must be carefully administrated and controlled by professionals. Furthermore, parents must be informed about the risks in the use of this drug in children.

Objective: We present a post-hoc analysis of the safety and efficacy of duloxetine, a selective serotonin/ norepinephrine reuptake inhibitor, for treatment of diabetic peripheral neuropathic pain (DPNP) in older patients. Methods: Data from three double-blind, placebo-controlled trials in adult patients with DPNP were pooled and stratified by age (<65, ≥65 years). Patients were randomized to duloxetine (DLX) 60 mg once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed by a 52-week extension phase (re-randomization to routine care or DLX 120 mg/day). Intent-totreat analyses were used for safety and efficacy assessment. Results: In the acute phase, overall TEAE rates did not differ significantly by age. A greater percentage of older patients discontinued due to TEAEs (P<0.001), regardless of treatment group. Duloxetine improved weekly mean 24-hour average pain scores versus placebo in both age groups (P<0.01). In the extension phase, a significant therapy-by-age interaction (P<0.05) was observed in overall TEAE rate; with routine care, 86.6% of older patients had ≥1 TEAE versus 74.6% of younger patients. Conclusions: Although TEAEs more frequently lead to discontinuation in older patients, duloxetine was well tolerated and efficacious for treatment of DPNP regardless of age. These data suggest duloxetine may be beneficial for treatment of DPNP in patients ≥65.

Carbamazepine is a therapeutic anticonvulsant, used to manage pain. We often use it to treat trigeminal and post-herpes zoster neuralgias. Interstitial pneumonitis (IP) is a known adverse consequence of using carbamazepine, with bronchiolitis obliterans and organizing pneumonitis. (BOOP) drug-induced IP as typical examples. Here we described a patient with post-herpes zoster neuralgia, who suffered from drug-induced acute IP that differed from cases typically induced by carbamazepine.

Mitochondria are recognized as the producers of the majority of energy cells need for their normal activity. After the initial comprehension of how mitochondrial oxidative phosphorylation produces energy, mitochondrial research was not a priority for most cell biologists until novel mitochondrial functions were identified. In fact, it is now known that mitochondria are not only involved in cell calcium homeostasis, intermediate metabolism and free radical generation but are also a crucial crossroad for several cell death pathways. The notion that several clinically used drugs and other xenobiotics induce organ degeneration through damaging mitochondrial bioenergetics led to the use of the organelle as an effective and reliable bio-sensor to predict drug safety. Classic methods used to test the toxicity of a wide range of compounds on isolated mitochondrial fractions were later replaced by novel high-throughput methods to investigate the safety of a very large number of new molecules. Without surprise, the assessment of “mitochondrial safety” for new discovered molecules is of clear interest for pharmaceutical companies which can now select compounds lacking mitochondrial toxicity to undergo further trials, thus avoiding the possibility of later human toxicity due to mitochondrial liabilities.

Hypokalaemia (defined as a plasma potassium concentration <3.5 mEq/L) is a common electrolyte abnormality in clinical practice. Drugs are a common cause of either asymptomatic or symptomatic hypokalaemia. Drug-induced hypokalaemia is an important problem particularly in the elderly and in patients with cardiovascular, renal or hepatic disease. Hypokalaemia can complicate the use of the drug in the therapeutic concentration range, and can also be precipitated with overdose or conditions leading to drug intoxication. Because the etiologies of hypokalaemia are numerous, the diagnosis of drug-induced hypokalaemia may be overlooked. Physicians should always pay close attention to this common side effect. Evaluation and management of a hypokalaemic patient should include a careful review of medications history to determine if a drug capable of causing or aggravating this electrolyte abnormality is present.

Formal retraction notice of article entitled Current Management of Vomiting after Tonsillectomy in Children (Curr Drug Saf. 2009 Jan;4(1):62-73) by Dr Y. Fujii. This article is being retracted as a result of: Failure of Dr. Fijii's institution as well as of himself to rationalize the legitimacy of the study and/or its data as stipulated in request by the Editors-in-Chief of the journals extended on April 9, 2012. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Although increasing use of compliance aids is resulting in improved clinical outcomes for patients, the stability of some drugs being repackaged into these aids is being questioned. This is due to the fact that despite their widespread use, there is limited availability of relevant stability data. This review presents clinical evidence for repackaging into Dose Administration Aids (DAAs), the Australian Pharmaceutical Advisory Committee and other guidelines on general stability issues related to repackaging and a summary of evidence for stability studies conducted in the practice. For frusemide and prochlorperazine chosen as candidates for study because of their light sensitivity, while discoloration on light exposure rendered them unacceptable for patient use, precautions in repackaging and patient counselling can easily overcome this problem. In the case of sodium valproate however, hygroscopicity results in these tablets being unusable after exposure to accelerated storage conditions. In the absence of specific data on the stability of drug products repackaged into compliance aids, the guidelines, practical recommendations for repackaging and the management of compliance aids put forward in this article provide the pharmacist with the tools to make an informed decision on this process.

The delivery of genes and drugs into cells has increasingly attracted attention for the generation of genetically engineered cells. Successful drug delivery will have enormous academic, clinical, and practical impacts on gene therapy, cell and molecular biology, pharmaceutical and food industries, and bio-production. The major aim of gene therapy is to deliver genetic materials into cells effectively, genetically modifying and repairing cell functions with the possibility of inducing therapeutic healing of disease. The genetic material includes DNA, RNA, antisense, decoy DNA, and ribozymes. The aim is that the appropriate transfection would allow diseased cells to return to a healthy condition. The genetic manipulation is often manifested in the mechanisms of intracellular actions of genes and proteins, and may play an important role in making clear the key genes associated with various diseases. Based on fundamental and scientific knowledge, the delivery technology of genetic material should be applicable to producing various proteins of pharmaceutical value (e.g. cytokines, growth factors, and antibodies) and also to producing seeds resistant to harmful insects and cold weather damage. This implies that the cells might be enhanced to produce valuable pharmaceutical and food products. For each approach, it is important, for successful gene expression, to select an appropriate gene to be delivered as well as to develop the gene delivery technology to enhance transfection efficiency. This review will provide an overview of the enhanced gene expression of plasmid DNA complexed with new non-viral gene delivery vehicles by biodegradable biopolymer- metal complex, introducing our recent research data to emphasize the technical feasibility of biopolymer-metal complexes in gene therapy and biotechnology.

Atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) have been prescribed extensively, often in combination with each other. When toxic encephalopathy develops with neuromuscular and autonomic symptoms in a patient taking medication including atypical antipsychotics, it has tended to be diagnosed as neuroleptic malignant syndrome (NMS). However, there have recently been several case reports where the diagnosis of serotonin syndrome is given or raised as a likely differential diagnosis to such cases. In the present review, the author addressed himself to the issues surrounding the neurotoxic reaction to the treatment regimen containing atypical antipsychotics, focusing on the “atypical” forms of NMS and pathophysiological as well as clinical features of serotonin toxicity. Although NMS is idiosyncratic in nature, it appears practically useful to comprehend this syndrome as a spectrum-based concept. Likewise, serotonin toxicity is a broad spectrum of clinical syndromes in close connection with serotomimetic drug use, including varied severity. Some of atypical antipsychotics, i.e., perospirone, aripiprazole, ziprasidone, clozapine, and quetiapine, have been shown to behave as partial agonists at 5-HT1A receptors, providing direct evidence that these atypical antipsychotics are serotomimetic per se. The reciprocal interaction between the dopaminergic and serotonergic systems disturbed by either dopaminergic blockers or serotonergic enhancers leads to the disruption of homeostasis, with typical forms of NMS and serotonin syndrome representing the ends of the common pathophysiological background. The practical and flexible way to consider and manage such cases with updated knowledge derived from basic research should be warranted to be beneficial to our patients.

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