Pharmaceutical Outcomes Programme, Children's and Women's Health Centre of British Columbia, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. email@example.com
Adverse drug reactions (ADRs) rank as the fifth leading cause of death in the western world. The nature and scope of these ADRs in children are not predictable based on post market surveillance reports that rely heavily on adult drug experience. The genotype-specific approaches to therapy in childhood (GATC) national ADR network was established to identify specific ADRs and to improve drug safety through identification of predictive genomic biomarkers of drug risk.
GATC set out to establish a national network of trained surveillance clinicians in pediatric hospitals across Canada. Surveillance clinicians identified, enrolled, and collected clinical data and biological samples from ADR cases and controls. Surveillance was targeted to three ADRs: anthracycline-induced cardiotoxicity, cisplatin-induced hearing impairment, and codeine-induced mortality in breastfed infants.
The initial surveillance site was established in September 2005, with 10 sites fully operational by 2008. In 3 years, GATC enrolled 1836 ADR cases and 13188 controls. Target numbers were achieved for anthracycline-induced cardiotoxicity. Modified target numbers were nearly attained for cisplatin-induced hearing impairment. Codeine-induced infant mortality in a breastfed infant was discovered by GATC investigators. A case-control study was subsequently conducted.
GATC has demonstrated a model of active and targeted surveillance that builds an important step toward the goal of personalized medicine for children. Effective communication, site-specific solutions and long-term sustainability across the network are critical to maintain participation and productivity. GATC may provide a framework of ADR surveillance that can be adapted by other countries and healthcare systems.
Antipsychotic medications have been widely used in elderly patients for treatment of a variety of diagnoses. The aim of our study was to compare the incidence of cerebrovascular and cardiac events as well as mortality in elderly persons treated with second-generation antipsychotics (SGAs) with that of elderly persons treated with conventional first-generation agents (FGAs) in the province of Manitoba.
A population-based retrospective cohort study of all residents of Manitoba aged 65 and older, who were dispensed antipsychotic medications for the first time during the period from April 1, 2000, to March 31, 2007, was conducted using Manitoba Health administrative databases. Cox proportional hazards models were used to compare risks of adverse events in FGA and SGA users.
After controlling for potential confounders (demographics, comorbidity, and medication use), SGA use was not associated with a significantly greater risk of cerebrovascular events, cardiac arrhythmia, and congestive heart failure compared to FGA use (adjusted hazard ratios [HR], respectively: 1.136; 95% CI, 0.961-1.344; 0.865; 95% CI, 0.336-2.232; 1.127, 95% CI, 0.902-1.409). Second-generation antipsychotics users were found to be at a lower risk of mortality (adjusted HR, 0.683; 95% CI, 0.577-0.809), but at a higher risk of myocardial infarction (adjusted HR, 1.614; 95% CI, 1.024-2.543) compared to FGA users.
Among elderly users of antipsychotic medications, the risk of cerebrovascular events, cardiac arrhythmia, and congestive heart failure was similar in FGA and SGA users. Whereas SGA users were at a higher risk of nonfatal myocardial infarction, the use of FGAs was associated with an increased risk of death. Antipsychotic pharmacotherapy in older persons needs to be chosen with careful consideration of all risks and benefits.
The H2-receptor antagonists cimetidine and ranitidine were transferred from prescription only to over-the-counter (OTC) status in Denmark on March 27, 1989. Reports to the Danish Committee on Adverse Drug Reactions, a voluntary reporting system, have been evaluated to detect possible changes in frequency and pattern of adverse drug reactions (ADRs) caused by the altered delivery status. From the introduction of cimetidine in 1977 and until March 31, 1990, the Committee received 494 reports of 612 suspected adverse reactions to anti-ulcer drugs. The H2-receptor antagonists (mainly cimetidine and ranitidine) were responsible for 548 (90%) of the ADRs. The study, which presents experience with these drugs from more than a decade and a total consumption corresponding to 65 million treatment days, confirms their excellent safety record. Serious reactions were rare, and when they occurred, reversible. During the first year with cimetidine and ranitidine available OTC no changes were seen in reporting frequency or ADR pattern which could be ascribed to OTC transfer. Only one ADR report concerning OTC cimetidine was received. This may be caused by several factors: the safety of these drugs, the fact that only very little was actually sold OTC, and a relatively low sensitivity of the voluntary reporting system.
Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.
The association of daily cardiac and respiratory admissions to 168 acute care hospitals in Ontario, Canada, with daily levels of particulate sulfates was examined over the 6-year period 1983-1988. Sulfate levels were recorded at nine monitoring stations in regions of southern and central Ontario spanned by three monitoring networks. A 13-micrograms/m3 increase in sulfates recorded on the day prior to admission (the 95th percentile) was associated with a 3.7% (p
1 During the three years 1978--1980 the Swedish Poison Information Centre received reports of 184 patients hospitalized due to beta-adrenoceptor blocker overdosage. Of the 35 patients who developed signs of severe cardiac dysfunction (HR less than 50 beats/min, systolic blood pressure less than 80 mm Hg), 23 had ingested propranolol, 10 metoprolol and 2 alprenolol. 2 The mean value of the defined daily doses (DDD) per 1000 inhabitants per day in Sweden during these years were 11.97 for propranolol, 8.02 for alprenolol and 7.74 for metoprolol. The incidence of severe poisoning due to alprenolol overdosage is lower than expected according to DDD. 3 During 1979 19 persons died from overdosage with beta-adrenoceptor blockers in Sweden: 15 due to propranolol (non-selective, lacks intrinsic sympathomimetic activity), 2 to metoprolol (cardioselective, lacks intrinsic sympathomimetic activity). These findings indicate that severe and even fatal poisoning may occur regardless of the type of beta-blocking agent. 4 The usefulness of prenalterol, a cardioselective beta-adrenoceptor partial agonist, in reversing unwanted cardiac effects of beta-adrenoceptor blocking agents is illustrated by two cases of massive propranolol intoxication (maximal plasma concentrations of propranolol 7.2 and 7.8 mumol/l respectively). Prenalterol in high doses (130 and 280 mg/24 h respectively) restored cardiac function.