Current Drug Safety - Volume 5, Issue 3, 2010

As is the case for most drugs, vigabatrin (VGB) has major advantages and also has significant adverse effects. However, the situation for VGB is somewhat unusual. The drug was prescribed for many years before Eke et al. [1] reported peripheral visual field defects (VFDs) in three adult patients. Other adverse effects [2], including psychiatric changes and transient MRI abnormalities have been reported but will not be discussed here. VFDs appear to be common, having been found in 25% to 50% of adult patients taking VGB [2]. Although the VFDs are asymptomatic in most patients [3, 4], this must be viewed as a serious adverse effect. For example, those with horizontal visual fields less than 120° are not permitted to hold a driving licence. Visual acuity is not usually affected and, although those with VFDs retain an average lateral visual field of 65° [5] (i.e., 130° horizontal), sometimes the visual field constriction may be severe [3]. There is debate about whether the VFDs are reversible [6, 7] but a number of reports have suggested that they are not [8, 9]. Does the emergence of this frequent, serious, and possibly irreversible adverse effect imply that VGB should no longer be prescribed or should be withdrawn from the market? The recent FDA approval would suggest that this is certainly not the case. What is the justification for the availability of this drug? VGB is almost unique in having an apparently single, intended mode of action, namely inhibition of GABA-transaminase, the enzyme that breaks down the inhibitory neurotransmitter GABA, with result that GABA concentrations in the brain are increased. It can be of benefit in treating partial-onset seizures in some patients for whom no other drug has been effective. VGB also has a major role to play in the treatment of infantile spasms, a very severe form of epilepsy with a high risk of poor outcome, both in terms of ongoing seizures and in terms of significant cognitive impairment [10]. If the infantile spasms are secondary to tuberous sclerosis, VGB appears to be particularly effective; in the initial studies 100% of the babies became spasm free [11]. In subsequent studies the response rate has been less but has remained very high. The other effective treatment for infantile spasms is ACTH or steroids, which can be also associated with serious adverse effects [10]. How is the clinician to weigh the risk of the serious adverse effect of VFDs against the possible advantage of good seizure control? In the case of partial-onset seizures, the decision-making process might be easier because the advantages and disadvantages can usually be discussed directly with the patient, who can then make an informed decision. However, this is not always the case. One of my patients was a wheelchair-bound teenager with severe learning disability (mental retardation) and severe epilepsy, in whom good seizure control had been achieved with VGB. Another clinician stopped the VGB because of concerns about the possibility of VFDs. If this patient had developed visual field constriction, it would almost certainly not affected his quality of life, which was much more severely impaired by his other problems and which was certainly very severely decreased when the uncontrolled seizures returned. After consultation with his carers, the VGB was re-instituted, with a good response. The remainder of the discussion will concentrate on infantile spasms because the situation with this severe form of epilepsy is very different. Because the onset is typically around 4 to 9 months of age, it is up to the parents or carers to decide on treatment, in discussion with the clinician. Concerns about possible VFDs may weigh heavily with parents. They might also have difficulty in appreciating what the implications of this possible adverse effect could be for their child. What guidance can be given? To answer this question, further information is required. Perhaps the best way of considering this situation is to ask a series of additional questions. Several of these issues are discussed in the excellent review by Willmore et al. [2]. Have visual field defects been described in children who took VGB for infantile spasms as infants? What is the minimum period or minimum dose of VGB that has resulted in apparently permanent visual field defects? If the VGB is stopped at the first sign of VFDs, will this adverse effect be less than it would have been if the VGB had been continued? Is there any evidence that treating infantile spasms promptly and effectively changes prognosis, particularly with regard to cognitive outcome? Which is superior in treating infantile spasms, VGB or ACTH/steroids; should different treatments be favoured in different circumstances?

Purpose: This study was designed to delineate the relative frequency of CYP2C9 and VKORC1 polymorphisms known to affect warfarin response in the highly heterogeneous Israeli population. Methods: Frequencies of CYP2C9 allelic variants CYP2C9*2, CYP2C9*3 and of VKORC1 single nucleotide polymorphisms (snps)- 1639G>A and D36Y were determined in genomic DNA of 438 healthy unrelated Israeli volunteers of Jewish, Druze and Arab Moslem descent, using allele specific PCR-RFLP. Genotyping results obtained were confirmed by probe free High Resolution Melt (HRM) Technology. Results: Arab Moslems had a higher frequency of warfarin “sensitive” CYP2C9*2, CYP2C9*3 and VKROC1-1639G>A alleles (0.21, 0.07 and 0.58, respectively) than both Jews (0.13, 0.11 and 0.57, respectively) and Druze (0.12, 0.06 and 0.53, respectively). Statistically significant differences were found in CYP2C9*2 between Druze and Moslems (p=0.01) and between Jews and Moslems (p=0.016) and in CYP2C9*3 between Druze and Jews (p=0.0086). VKORC1(-1639G>A) was the major gene polymorphism associated with warfarin sensitivity in all 3 subpopulations. In contrast, the warfarin “resistant” VKORC1 D36Y allele was very rare in the Israeli population (0- 0.015). The results presented demonstrate that allelic variants in CYP2C9 and VKORC1 are very common in Israel with ∼95% of Jews, ∼84% of Druze and ∼91% of Arab Moslems manifesting at least one known warfarin “sensitive” or “resistant” allele. Conclusions: Individualized genotype based warfarin therapy is highly relevant in the Israeli population due to the high incidence of genetic variations associated with warfarin sensitivity in all 3 non-mixing subpopulations tested.

This study analyzes prospectively the antibiotic prescription habits in terms of appropriateness of use and cost pattern effects in the paediatric wards of two different university hospital patient set-ups. Data on demographics, discharge diagnosis, antibiotic utilization and costs were collected prospectively from the children's individual electronic charts at Rambam Health Care Campus (R) and Kaplan Medical Centre (K) in Israel. A total of 505 and 497 children from R and K units, respectively, were screened. Of the surveyed population, 239 and 330 children in the R and K units were hospitalized due to infectious diseases. The antibiotic appropriateness for the R and K units were 84% and 91%, respectively (p>0.5). Total antibiotics Defined Daily Dose (DDD) and Drug Utilization 90% (DU90%) index were 241.7 and 217.5 for the R unit and 388 and 349.2 for the K unit, (p<0.001). Drug Cost 90% indices (DC90%) for the two units were NIS 6,023.5 and NIS 5,955.8; respectively. This study generates up-to-date information on the antimicrobial prescription habits in two different hospitals and suggests that antibiotic treatment in both hospitals appears to be appropriate. Significant lower median antibiotic cost was depicted in the K admission unit in comparison to the R admission unit (11.3 NIS - 40.0 NIS; p<0.01), respectively. Drug use evaluations are useful indicators for following trends of drug prescription, optimizing antibiotic usage and controlling expenditure.

Mortality rates across matched cohorts of hospitalized patients treated with IM olanzapine, haloperidol, and/or ziprasidone in a hospital database were compared. Using propensity score matching, matched cohorts of IM olanzapine- (N=2,984) and IM haloperidol-treated patients (N=2,984) and IM olanzapine- (N=2,876) and IM ziprasidone-treated patients (N=2,876) were obtained. The study outcome was in-hospital death within 2 days of administering IM antipsychotic. Incidence of death was not statistically different between olanzapine-ziprasidone cohorts (OR=1.21, 95% CI 0.92-1.59). The olanzapine cohort demonstrated a significantly lower death incidence than the haloperidol cohort (OR=0.73, 95% CI 0.57-0.93; p=.011). The results suggest that patients treated with IM olanzapine do not have a significantly greater risk of death than patients treated with IM haloperidol or IM ziprasidone.

Antibiotics are the therapeutic agents most often associated with hepatotoxicity. However, this is mainly due to the widespread prescription of these drugs. The relative risk of antibiotic-related hepatotoxicity is low. Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult, particularly because some cases occur long after the drug has been stopped. Among the penicillins, amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations. Flucloxacillin ranks as the second highest cause of DILI in many countries. The severity of antibiotic-induced DILI varies widely, with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestatic/mixed type. The pattern is strongly influenced by age. Recently telithromycin (a new generation macrolide) has been linked with DILI, with a typical pattern, which includes abrupt commencement of fever, abdominal pain, jaundice and, in some cases, ascites. Antibiotic-induced DILI appears, in most instances, to be idiosyncratic. Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity.

Background: Oral anticoagulation (OAC) is the most effective treatment to prevent strokes in patients with atrial fibrillation (AF). Many older patients are not prescribed OAC. Objective: To explore which co-morbid conditions in older patients with AF have been associated with under-treatment with OAC, or were used as exclusion criteria for trials, or have been associated with increased risk of bleeding. Methods: A Pubmed search was conducted with the terms elderly, atrial fibrillation, stroke risk, bleeding risk, intracranial haemorrhage, cognition, fall risk, renal dysfunction, alcohol abuse, malignancy, polypharmacy, NSAID, under-treatment, under-use and under-prescription. Results: Higher age is associated with under-treatment. Patients with a higher risk of stroke show higher rates of bleeding complications. The associations of bleeding rates with possible contraindications are inconsistent. Discussion: Published bleeding rates reflect selection bias, describing mainly relatively healthy older patients. The use of stratification schemes for stroke risk and for bleeding risk will have to be implemented. Conclusion: The decision to prescribe OAC in older patients with AF remains a challenging task since bleeding risk is difficult to estimate reliably. Stratification schemes may be helpful.

Cardiovascular disease remains the primary cause of mortality for patients with type 2 diabetes, which is characterized by insulin resistance. The thiazolidinediones (TZDs), also known as glitazones, are one of the pharmacological approaches to improve insulin sensitivity. At present, there are two available TZDs: pioglitazone and rosiglitazone. The common target of action for TZDs is the nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ) that regulates the gene transcription involved in adipocyte differentiation and glucose and lipid metabolism. TZDs have shown similar effects on glycemic control, as well as on weight gain, fluid retention, increased risk of heart failure, and leg and forearm fractures. However, TZDs have differential effects on cardiovascular disease. This article will review the differential effects of pioglitazone and rosiglitazone on cardiovascular risk factors and outcomes, as well as the potential differences between them. Based upon available evidence, pioglitazone has a beneficial effect on cardiovascular disease. By contrast, it seems that rosiglitazone increases cardiovascular risk. The difference in lipid profile may be the main factor accounting for the superiority of pioglitazone in reducing cardiovascular risk.

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life. However, the use of LABAs has raised safety concerns, such as their potential to provoke severe asthma exacerbations (SAEs) and death. This systematic review of major findings discusses the safety controversy surrounding LABA therapy and provides background for the U.S. Food and Drug Administration's warnings concerning LABA use. Findings from large clinical trials and several meta-analyses are described and compared in terms of their implications for the safety of LABAs. Monotherapy LABA therapy in the treatment of asthma remains controversial and is not recommended by the most recent asthma management guidelines. Despite the existence of numerous published studies, we conclude that more well-designed research on this topic --- to determine whether LABAs are associated with SAEs, such as asthma-related hospitalizations, intubations, and emergency room visits, or death --- is required. Particularly needed is research that makes use of large, secondary longitudinal databases.

Dronedarone is an oral Class III antiarrhythmic agent which was recently approved by the US Food and Drug Administration for use in nonpermanent atrial fibrillation. Structurally similar to amiodarone, dronedarone is a benzofuran derivative but it lacks the iodine moiety attached to amiodarone. Based upon the investigational clinical trials to date, it appears that dronedarone has an established efficacy when compared to placebo along with exhibiting a minimal adverse effect profile. The efficacy of dronedarone will need to be further evaluated in comparison trials with established antiarrhythmics for atrial fibrillation. The adverse profile of dronedarone appears to be substantially safer in comparison to amiodarone, although there is still little data available. The adverse effect profile of amiodarone necessitates close and extensive monitoring. Although a risk of pulmonary toxicity was identified in animals, long term studies in humans are needed to determine the significance of this adverse effect with dronedarone. One noted effect of dronedarone is an isolated increase in serum creatinine levels, and the clinical relevance of this effect needs further evaluation. Based on supporting evidence, the use of dronedarone is contraindicated in advanced or decompensated heart failure. Some clinically significant dronedarone drug interactions have been identified. Although the potential differences between dronedarone and amiodarone have been evaluated there have been no direct comparison trials published to date. This article reviews the chemistry, antiarrhythmic effects, pharmacokinetics, efficacy, adverse effects and drug interactions of dronedarone.

Domperidone is a prokinetic agent widely prescribed in adults and children with gastrointestinal disorders. Recently several Regulatory Agencies published safety information on the risk of long QT syndrome associated with the use of domperidone. We conducted a literature review using PubMed (1966 - Jan 2010) with the aim to locate articles on ventricular arrhytmias, Sudden Cardiac Death (SCD), long QT syndrome and Torsade de Pointes (TdP) following domperidone administration. Twenty-two papers were included in the review: three studies in in vitro models, one animal study, five case reports/series, twelve clinical studies and one editorial. In vitro studies demonstrated cardiac electrophysiological effects of domperidone on the rapid component of the cardiac delayed rectifier K+ current (IKr) through the blockade of channels encoded by the Human Ether-a-go-go Related Gene (HERG). A total of fourteen cases of cardiotoxicity following intravenous (12 cases) or oral (2 cases) domperidone administration from case reports/series were identified. A case - control study, performed on a general practice observational database reported an OR: 3.8 (95% CI: 1.5-9.7) for SCD after domperidone exposure. Prescribers and other healthcare professionals should take into account the risk of QT syndrome in domperidone users and avoid administering domperidone in patients concomitantly taking strong CYP3A4 inhibitors or other QT prolonging drugs.

Second generation antipsychotics (SGAs) are increasingly employed in the treatment of depression. Adjunctive aripiprizole and olanzapine/fluoxetine combination (OFC) have been approved in the US in the treatment of depression. Quetiapine also appears to be poised for an FDA approval as an adjunctive treatment for resistant depression. Historically, first generation antipsychotics were thought to carry an enhanced risk of certain side effects in the treatment of mood disorders, including an enhanced risk of extrapyramidal symptoms (EPS). The second generation antipsychotics are also known to be associated with a variety of metabolic side effects. The use of SGA in a depressed population may pose risks that differ from use in other conditions such as bipolar disorder and schizophrenia. In this paper, the risk of extrapyramidal and metabolic side effects is reviewed in depressed patients treated with second generation antipsychotics.

In the treatment of pain management, physicians employ a variety of drugs, ranging from low-impact to highly potent, and to maximize patient health, urine toxicology analyses can significantly improve the delivery of pain treatment. Drugs such as opioids that are used for pain management are peculiar in that they provide effective pain relief and have a high risk of addiction. The use of illicit drugs in the general population has been on the rise; however, self-reporting and close monitoring of patient behavior are insufficient means to detect drug abuse and confirm compliance. Therefore, in order to create more effective drug treatment plans, physicians must understand and account for the implications of patient drug use history. Urine toxicology analysis is an important tool for pain physicians because it is more sensitive than most alternative blood tests, more efficient and cost-effective. Urine testing in addition to improving patient pain management also has forensic and legal implications. There are however limitations to urine toxicology methods as they can produce false-positive and false-negative results and are prone to human error and sample contamination There is also a need for more specific and rapid urine drug testing. Healthcare professionals should therefore be familiar with the limitations of various urine drug testing methods, and possess skills necessary to properly interpret these results. This review suggests that the overall benefits incurred by both the patient's short-term and long-term health support the routine integration of urine toxicology analysis in routine clinical care. In addition to improving health care and patient health, it has a strong potential to improve patient-physician relationships and protects the interest of involved healthcare practitioners.

Due to an oversight on the part of the author, incorrect author's name (Biondi Elisa) was published in the article entitled “Statin-Like Drugs for the Treatment of Brain Cholesterol Loss in Alzheimer's Disease”, in Current Drug Safety, 2007, Vol. 2(3), pp. 173-176. PMID: 18690964. [PubMed - indexed for MEDLINE]. The correct author's name is Elisa Biondi.