Current Drug Safety - Volume 1, Issue 2, 2006

All medicines have adverse effects as well as benefits. The aim of pharmacovigilance is to protect public health by monitoring medicines to identify and evaluate issues and ensure that the overall benefits outweigh the potential risks. The tools and processes used in pharmacovigilance are continually evolving. Increasingly sophisticated tools are being designed to evaluate safety data from clinical trials to enhance the likelihood of detecting safety signals ahead of product registration. Methods include integration of safety data throughout development, meta-analytical techniques, quantitative and qualitative methods for evaluation of adverse event data and graphical tools to explore laboratory and biometric data. Electronic data capture facilitates monitoring of ongoing studies so that it is possible to promptly identify potential issues and manage patient safety. In addition, GSK employs a number of proactive methods for post-marketing signal detection and knowledge management using state-of-the-art statistical and analytical tools. Using these tools, together with safety data collected through pharmacoepidemiologic studies, literature and spontaneous reporting, potential adverse drug reactions can be better identified in marketed products. In summary, the information outlined in this paper provides a valuable benchmark for risk management and pharmacovigilance in pharmaceutical development.

The promise of pharmacogenomics lies in the potential to establish a personalized drug therapy with the intent of maximizing effectiveness and minimizing risk, through development of pharmacogenomics biomarkers. However, currently, most pharmacogenomic measurements are not considered valid biomarkers with clear clinical significance, thus this field is in early developmental stages. Recently, the development of comprehensive, high-throughput technologies such as gene expression microarrays has provided powerful new tools for these stages. This technological transformation is, at the same time, generating an increasing demand for statistical analysis of large and complex multivariate datasets from high-throughput assays. This article provides a review of the key features to be observed in statistical analyses of large amounts of data from pharmacogenomic biomarker studies with high-throughput assays. The problem of false positive can be very serious in such studies. The evaluation of stability and reproducibility of the results of statistical analysis are claimed to reduce chance that false positive findings are subject to further investigation in subsequent studies.

Background. Interferons are employed in the management of multiple sclerosis, hepatitis C and certain malignancies. Neuropsychiatric toxicity can interfere with the successful use of these drugs. Methods. This review was based on Medline literature searches, supplemented by bibliographical citations in identified papers. Information uncovered in the literature review was interpreted in light of related pharmacoepidemiological and psychiatric literature. Results. Interferon-associated neurotoxicity does not adhere closely to standard psychiatric syndromal and diagnostic definitions. Delirium, depression, non-specific symptoms related to sickness behavior and, rarely, manic and psychotic syndromes are all potential adverse events during interferon treatment. For depression, the evidence of increased risk is stronger for interferon alpha than for interferon beta. The availability of preventive and treatment interventions suggest that neuropsychiatric toxicity can often be managed without needing to discontinue the treatment. Conclusions. Safety can be maximized by organization of health services in ways that enhance detection and management of neuropsychiatric problems, and which support access to basic and specialized mental health services.

Over the past few years significant steps forward have been made towards the development of insulin formulations suitable for inhalation via several delivery systems. This innovative route of insulin delivery offers the potential of administering pre-meal insulin in a non-invasive way to patients currently receiving multiple daily injections. This article describes the pharmacodynamic and pharmacokinetic profiles and the efficacy and safety data of inhaled insulin preparations. Particular emphasis is placed on Exubera, which currently has the largest pool of efficacy and safety data. In patients with type 1 diabetes 24-week trials have demonstrated that inhaled insulin was equally efficacious to short acting insulin (2-4 daily injections). Results of trials conducted in type 2 diabetes showed inhaled insulin efficacy too, and a potential role for inhaled insulin in patients failing oral medications. Safety data have shown that the most common reported adverse event is mild cough, which appears to be decreasing in frequency during the course of therapy. Higher antibody titers have been observed in patients treated with inhaled insulin compared to subjects treated with subcutaneous insulin. However, the titers do not present any association with clinical correlates. The safety area in need of higher scrutiny is naturally the area of pulmonary function tests (PFTs). A brief synopsis of PFTs is followed by the review of PFTs data following short and long term treatment with inhaled insulin. Two-year data in type 2 diabetes showed a significant change in Forced Expiratory Volume in 1 second (FEV1) after 6 months of treatment, but not after 9, 12,18,24 months of treatment and 6 and 12 months of wash-out. In type 1 diabetes a significant change in Diffusing Lung Capacity of Carbon Monoxide (DLCO) was observed after 24 weeks of inhaled insulin therapy. Long-term data in type 1 diabetes are only available as part of a pooled sample composed of patients with both type 1 and type 2 diabetes. In these patients, who had received inhaled insulin for at least 4 years, annualized changes of FEV1 and DLCO were similar in the group treated with inhaled insulin compared to the group treated with sub-cutaneous insulin.

Natural pulmonary surfactant is a complex mixture of lipids and proteins with many biological functions. Surfactant is responsible for lowering the surface tension within alveoli and maintaining the functional integrity of the distal airways. In addition to this function surfactant components represent important elements of the host defence system of the lung. Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) are syndromes characterised by reduced pulmonary gas exchange due to diffuse injury to the alveolar-capillary barrier. The alveoli fill with proteinaceous fluid, and there is a marked infiltrate of acute inflammatory cells. ARDS and ALI may occur after both direct lung injury such smoke inhalation, and after indirect lung injury such as in sepsis. Qualitative and quantitative surfactant deficiencies are present in individuals suffering from ARDS and ALI, and the role of exogenous surfactant treatment in these conditions has attracted considerable interest. Most clinical studies have shown only improvements in the oxygenation of patients, but a recent study has, for the first time, demonstrated a reduction in the mortality of children with ARDS and ALI treated with exogenous surfactant. Given the differences that exist in surfactant composition, dosing schedules and the pathological processes responsible for ALI, it is clear that considerable work remains to be done in this field.

The New Zealand Intensive Medicines Monitoring Programme (IMMP) was established in 1977 to enhance monitoring for previously unrecognised adverse drug reactions associated with selected new medicines. This involved establishing cohorts from prescription data and collection of event information: thus New Zealand was a pioneer in the development of the methodology now known as Prescription Event Monitoring (PEM). In the IMMP, PEM cohorts are established using information, supplied by pharmacies, from prescriptions for medicines that have been selected for monitoring. Events are identified subsequently from follow-up questionnaires to prescribing physicians and from other sources, including spontaneous reporting of events. The objective of this review is to illustrate how the IMMP methodology enables identification of signals of previously unrecognised adverse reactions. This is enhanced by high response rates from pharmacists and prescribers in providing prescription and event data respectively. In addition, high quality event reports are obtained from multiple sources including follow-up event returns from prescribers, reports received through the national spontaneous reporting programme, prescription returns and from record linkage to other databases. Collaboration with other national centres and with the WHO Collaborating centre for international drug monitoring in Uppsala, Sweden (WHO-UMC) enables information on cases from their databases to be used in validation of IMMP signals. The NZ IMMP methodology and signals of previously unrecognised adverse drug reactions arising from the IMMP databases are reviewed. Recent signals include amnesia and QTc prolongation with sibutramine; pain activation with sumatriptan; epistaxis with risperidone; psychiatric and visual disturbances with the COX-2 inhibitors celecoxib and rofecoxib and psoriasis with rofecoxib. In addition, other types of investigation are discussed along with the importance of rapid communication to prescribers of new information concerning the risks of medications. The IMMP has features that differ from those of other centres that incorporate PEM methodology. New Zealand is a small country (approximately 4 million) and thus communication is relatively easy. This facilitates good rapport with prescribing doctors. However, mainly because of the small population, several years may be required to achieve a large cohort. Although this has drawbacks in terms of rapid results, it enables a longitudinal approach to prescription data analysis, including aspects of prescribing such as reasons for cessation of therapy and changes in prescribing practise. Although not specifically reviewed in this article, the programme has also made significant contributions in determining the incidence of certain adverse drug reactions and in carrying out in-depth epidemiological investigations relating to the safe use of medicines. Through these activities, the New Zealand IMMP provides an ongoing contribution to safety in the use of medicines.

Sirolimus (SRL) is a recently available immunosuppressive agent. SRL, is a macrolide isolated from Streptomyces hydroscopicus that, in complex with its cellular receptor, FK binding protein, potently inhibits downstream signaling by the mammalian target of rapamycin (mTOR). It has been shown to reduce the incidence of acute rejection episode after renal transplantation. SRL by itself does not seem to cause significant nephrotoxicity in most animals and human studies in normal conditions. However, when combined with calcineurin inhibitors, serum creatinine levels often increase. The mechanisms for the synergism of this side-effect are still discussed. Furthermore, recent clinical data have shown that the administration of SRL immediately after renal transplant delay the recovery from delayed graft function. This effect may be secondary to the inhibition of the proliferation of the renal tubular cells which is a normal process for tubular repair. Some experimental data have confirmed this hypothesis. Finally, in the long-term, SRL use has been associated with a significant increase of proteinuria which may in the long-term increase the risk of graft loss of cardio-vascular morbiomortality. For all these reasons, SRL nephrotoxicty has become an important issue after renal transplantation. The review will discuss the clinical and the experimental data regarding this complication, which has been underestimated.

Osteoporosis is characterized by low bone mineral density and deterioration in the microarchitecture of bone that increases its fracture vulnerability. The mainstay of therapy for osteoporosis is anti-resorptive in mechanism. Parathyroid hormone (PTH) is the most recently approved anabolic agent for osteoporosis. The mechanism of PTH's skeleton anabolic action is composite involving pathways linked to common signalling peptides that affect gene osteoblast transcription. A number of animal studies and clinical trials have demonstrated that intermittent PTH administration induces anabolic effects on both cancellous and cortical bone, enhances bone mass and increases mechanical bone strength, increasing spine and hip bone mineral density and reducing fragility fractures. Preclinical studies investigating the effect of PTH on fracture healing show an increase in bone density and strength indicating an enhancement of this biological cascade. Preclinical and clinical safety assessments have revealed little evidence of toxic effects and there have been few reports of adverse events related to their use. An increase in osteosarcoma in rats probably is not prognostic of an equivalent possibility in humans. In summary, parathyroid hormone is a major advance in the treatment of osteoporosis. Additional studies addressing long-term clinical safety are needed. However the current evidence is very promising.

The temozolomide is a promising orally cytotoxic agent used in malignant glioma. The survival curve improvement after drug administration appears to be statistically significant. The review of temozolomide side effects is carried out by search on literature data found on web and is divided on the 4 grades of toxicity according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The adverse effects related with TMZ administration are divided in three categories: myelosuppression, non haematologic toxicity, and infections. The main adverse effect is the myelosuppression that appears to be rather low and reversible as well as the vomiting or nausea. The different schedules of administration are analysed. The frequency of concomitant infections is underlined. In particular, if available, the relationship between temozolomide and other cytotoxic agents or anticonvulsivant drugs is analysed to clarify the possibility of increase of toxicity. The temozolomide is used also in children but the toxicity could be more frequent.