Current Drug Safety - Volume 1, Issue 3, 2006

Parkinson's disease (PD) is a neurodegenerative disease with limited pharmacologic therapies. Recent animal studies and one large retrospective study have found NSAIDs to be protective against the development of PD. We decided to test this hypothesis by conducting a nested case-control study using the Saskatchewan drug plan database. Entry to the cohort was defined as the first prescription of an antihypertensive agent between 1980 and 1987 and followed until 1999. Cases were defined as those having received three prescriptions for a dopamine agonist within a year. For each case, ten controls were selected matched to the case by age, calendar time and index date. Conditional logistic regression was used to estimate rate ratios adjusting for gender, previous use of arthritis medication and previous antipsychotic use. Current users of NSAIDs had a slightly higher risk of developing PD (RR= 1.49 [95% CI, 1.11-2.01]). This effect was not seen with past users (RR= 1.18 [95% CI, 0.89-1.59]). Based on the results of our study current users of NSAIDs may be at a slightly higher risk of developing PD. More studies are needed to confirm this finding.

Schizophrenia and schizoaffective disorder are prevalent in 1% of the adult population. The condition was thought to predominantly affect the young however recent studies have shown that the condition occurs in individuals throughout the life-span. The aim of this review is to discuss the role of atypical antipsychotics in treating schizoaffective disorder and schizophrenia in the elderly. The advent of atypical antipsychotics has made significant strides in the pharmacotherapy of schizophrenia in the elderly. They are as efficacious as conventional agents in reducing the positive symptoms, possibly some what more efficacious in reducing negative symptoms and appear to have a relatively safer adverse effect profile. However metabolic side affects particularly glucose abnormalities and weight gain, cerebrovascular effects, and mortality risk noted in dementia patients are gaining increasing attention. Appropriate monitoring for the metabolic side effects has been recommended by agencies such as the FDA (United States Food and Drug Administration), ADA (American Diabetic Association) and APA (American Psychiatric Association). Treatment of elderly patients is complicated by age related biological factors affecting drug response and presence of comorbid medical conditions and concomitant medication. Current research supports the role of atypical antipsychotics in the treatment of schizophrenia and schizoaffective disorder in the elderly. Despite advantages compared with conventional agents, challenges to successful therapy remain, even with these better tolerated agents.

All chemotherapy agents can cause hypersensitivity reactions, which have limited the used of critical drugs in very sick patients for fear of inducing a more severe reaction and possibly death. The choice of an alternative chemotherapy regimen is often limited by tumor sensitivity and, because of the increasing number of cancer survivors, exposure to multiple courses of the same or similar chemotherapy agents. Increased exposures lead to sensitization and to hypersensitivity reactions in an increasing patient population. The need to offer first line therapy after cancer recurrence has spurred the clinical development of rapid desensitizations, which allow patients to be treated with medications to which they have presented hypersensitivity reactions. Desensitization protocols are available to treat hypersensitivity reactions to most chemotherapy agents including taxenes, platinums, doxorubicin, monoclonal antibodies and others, by gradual reintroduction of small amounts of drug antigens up to full therapeutic doses. Candidate patients include those who present mild to severe type I hypersensitivity, mast cell/IgE dependent, reactions during the chemotherapy infusion or shortly after. Symptoms include pruritus, flushing, urticaria, angioedema, respiratory and gastrointestinal distress, changes in blood pressure including hypotension, and shock with anaphylaxis. Associated musculoskeletal symptoms and pain can be present in patients reacting to taxenes as in anaphylactoid reactions, in which mast cell/IgE mechanisms cannot be demonstrated. There is now strong evidence that anaphylactoid reactions are amendable to treatment with the same rapid desensitization protocols as for type I hypersensitivity reactions. Initial rapid desensitizations should only be performed in settings with one on one nurse-patient care and where resuscitation personnel and resources are readily available. Temporary tolerization is achieved in a few hours. After the first desensitization, standard protocols are available for safe, repeated desensitizations in outpatient settings with similar conditions, which not only provides flexibility, but allows patients to remain in clinical studies. Breakthrough symptoms are less severe than the initial hypersensitivity reaction in all series reviewed, and deaths have not been reported. The aim of this review is to familiarize the medical community with the type of hypersensitivity reactions amendable to rapid desensitization and to review protocols for chemotherapy desensitization that can be used for most chemotherapy agents. Few studies have measured the cancer response to the chemotherapy agents delivered through rapid desensitizations. One patient population in which 26 patients were desensitized to carboplatin and 16 to paclitaxel had similar rates of remission as for non-desensitized patients. Education of nurses, pharmacists, oncology and allergy specialists will lead to the universal use of rapid desensitization protocols for all cancer patients with hypersensitivity reactions to chemotherapy agents. Basic research is needed to uncover the cellular and molecular mechanisms underlying the temporary tolerization induced by rapid desensitization, so that pharmacological interventions can improve its safety and efficacy.

Despite of more than 500 gene therapy trials worldwide very little systematic safety information is available from gene therapy. Safety information was collected from 146 consecutive patients who participated in three randomized, controlled phase II gene therapy trials in cardiovascular diseases and malignant glioma using adenoviruses, plasmid/ liposomes and retrovirus packaging cells. Total follow-up time of the patients was 78794 days which equals 1.5 years per patient. The main outcome measures were serious adverse events, other adverse events and changes in general laboratory parameters. Except fever and increases in CRP values plasmid/liposomes were safe and well tolerated. The incidence of serious adverse events in adenovirus-treated patients was 0.9 and 4.0/10000 patient days in cardiovascular and malignant glioma trials as compared to 0.5 and 2.1 in randomized control patients, respectively. Transient fever, leukopenia and increases in CRP and liver enzymes were detected in virus-treated patients. No deaths from side effects or no new cancers were associated with gene therapy. It is concluded that gene therapy, like any other therapy, is associated with side effects which depend on the administered vector, dose, and route of delivery and properties of the transgene. However, given the limitations of this study and length of the follow-up, the safety profile of gene therapy seems to be acceptable for the treatment of severe human diseases.

Etanercept is an anti-TNF drug with marked efficacy in inflammatory arthritis. This review addresses dermatological side effects that have been encountered in our 85 patients on the drug for rheumatoid arthritis, and reviews other reported cutaneous adverse events. Injection site reactions are common and usually self-limiting. We and others have encountered patients with recall site reactions where the four rotated injection sites simultaneously develop a hypersensitivity reaction. In all cases, the rash has responded to antihistamines and the etanercept was thereby continued. Other injection site reactions include discoid lupus and cutaneous vasculitis that respond to cessation of treatment and appropriate therapy. Skin reactions more distant from the injection site are also reviewed, with erythema nodosum, widespread lupus rashes, infections and skin tumours summarised. A patient who developed a purpuric rash at the site of last injection with a drug induced worsening of thrombocytopaenia is described. Although the therapeutic advantages of etanercept outweigh the side effects, clinicians need to be aware of the adverse reactions of these drugs with their increasing use.

Inhaled corticosteroids (ICS) are recommended first-line therapy for patients with asthma of all severities. Prolonged exposure to high-dose ICS can cause systemic and oropharyngeal adverse events. Minimizing ICS-related adverse events by selecting an ICS with an improved safety profile may increase patients' adherence to their asthma treatment. Ciclesonide, a novel ICS currently under development, is a parent compound that is converted in the lungs by endogenous esterases to its active metabolite, desisobutyryl-ciclesonide. Reported data suggest that ciclesonide is well tolerated, with no observed effect on hypothalamic-pituitary-adrenal (HPA)-axis function and a low incidence of oropharyngeal adverse events (comparable with placebo). These safety benefits, observed in children and adults with asthma, may be due to ciclesonide's favorable pharmacokinetic/pharmacodynamic properties. The lack of HPA-axis function suppression may be due to the low oral bioavailability, high serum protein binding and rapid apparent systemic clearance reported with desisobutyryl-ciclesonide. The low incidence of oropharyngeal adverse events may be attributed to the low oral deposition of ciclesonide in the oropharynx and its limited conversion to desisobutyryl-ciclesonide. The favorable safety profile of ciclesonide suggests a conferred benefit to asthma patients treated with this novel ICS.

In the last two decades or so the intramuscular administration of botulinum toxin type A, and more recently type B, has become an established first line treatment of many neurological and other medical disorders. So far, the toxin has been used mainly by experienced researchers and clinicians with extensive knowledge of its mode of action and potential adverse effects. However, in the foreseeable future it is likely that this treatment will be provided by more medical practitioners and in different clinical settings, especially as the range of its clinical indications increases. Botulinum toxin, in therapeutic doses, is a remarkably safe drug with relatively few adverse effects. The commonest adverse effects are muscle weakness, fatigue, flu-like symptoms, a dry mouth, dizziness and a skin rash. Nonetheless, serious adverse events may occur, albeit rarely, and it is imperative that prescribers of this treatment are thoroughly familiar with its potential risks. The purpose of this article is to review the possible adverse effects of botulinum toxin intramuscular injections, to describe the factors that might predispose to them and to summarise the strategies for their prevention and treatment.

Introduction: Patients requiring major cardiovascular surgery are likely to be prescribed antiplatelet agents either alone or in combination. By virtue of antiplatelet agent effect, they can potentially increase bleeding complications, especially if used in combination. This article aims to review the evidence and make appropriate recommendations regarding these agents. Aspirin: 16 papers are reviewed which concern surgery whilst taking aspirin. The bulk of the evidence is from the coronary bypass setting. Clopidogrel: 14 papers are reviewed which concern surgery whilst taking clopidogrel. Dipyridamole: 2 papers are reviewed concerning dipyridamole. Cilostazol: No trials are available concerning surgery and cilostazol. Several relevant publications are reviewed. Conclusion: It is the recommendation of the authors that aspirin should usually be continued perioperatively, whilst clopidogrel should be stopped for seven days prior to surgery if at all possible.

Host dependent idiosyncratic drug reactions, otherwise known as unpredictable type B reactions, are of a major concern in clinical practice and drug development. Hypersensitivity syndrome reactions are idiosyncratic in nature and may be induced by a variety of agents including antiepileptic drugs (AEDs). The AEDs hypersensitivity syndrome is a rare but potentially life-threatening syndrome that occurs after exposure to phenytoin, carbamazepine or phenobarbital. Phenobarbital, phenytoin and carbamazepine, have shown cross-reactivity; while, no evidence of cross reactivity between other antiepileptic drugs such as valproic acid, gabapentin or lamotrigine has been observed. True hypersensitivity reaction is a systemic disease defined by the triad of fever, skin eruption and multi-organ involvement that occurs 1-8 weeks after exposure to a drug . Because most reactions occur within two months of treatment initiation, it is likely that the true incidence of the syndrome is underestimated. It was hypothesized that reactive metabolite/s (RM) rather than the parent drug, is/are responsible for initiating the sequence of toxic and immunological events that culminate clinically in a drug hypersensitivity syndrome reaction. Cells that possess surface antigens for which T cells have specific receptors then present this antigen. Exanthemas are related to delayed T- cell hypersensitivity so it has been hypothesized that memory T cells might subsequently increase in number in the most severely affected cutaneous sites. To manage hypersensitivity syndrome successfully, the symptoms must recognized early, the use of the offending drug must be terminated immediately, and alternative antiepileptic medication should be prescribed. Currently, the diagnosis of AEDs-induced hypersensitivity syndromes is based on clinical grounds and on in vitro testing. In the field of pharmacogenetics, we bare witness to how effectively the combination of effective screening methods and understanding of the role of genetic polymorphisms play in the metabolic pathways of AEDs facilitating new therapies that allow scientists and physicians to better diagnose and treat patients.

Drugs may induce hair loss, stimulate hair growth or, more rarely, induce changes in the hair shape and colour. Drug-induced hair loss is usually completely reversible and is, in most cases, a consequence of a toxic effect of the drug on the hair follicle matrix. In rare cases alopecia may be permanent. Depending on type of drug, dosage and patient susceptibility, hair loss presents as telogen effluvium, anagen effluvium or both. Telogen effluvium is also commonly observed after discontinuation of drugs that prolong anagen, such as topical minoxidil and oral contraceptives. Although a large number of drugs have been occasionally reported to produce hair loss, only for a few drugs the relation between drug intake and hair loss has been proven.

The safety of the use of medications in adolescents and children to treat bipolar disorder has not been extensively studied. The prevalence of bipolar disorder in children and adolescents is unknown due to the lack of completed large-scale epidemiological studies. In addition, the diagnosis of this disorder is still questionable in this age group because the same explicit diagnostic criteria used in adults potentially cannot be applied to children and adolescents since the early-onset symptoms often overlap with other disorders such as attention-deficit disorder. The safety of drugs used to treat bipolar disorder is of growing concern, particularly because this population usually requires more than one psychotropic medication to manage the disease. Common side effects seen with several agents, particularly antipsychotics, are somnolence, weight gain, extrapyramidal symptoms, dyslipidemia, type-2 diabetes, and hyperprolactinemia. This review will discuss the most advanced practice guidelines in assessing and treating bipolar disorder in children and adolescents, the safety and effectiveness of the drugs currently used based on clinical trials and post-marketing surveillance, and the risks versus benefits associated with their use.