Adverse drug reaction active surveillance: developing a national network in Canada's children's hospitals.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Examination of the kappa agonist and antagonist properties of opioids in the rat drug discrimination procedure: influence of training dose and intrinsic efficacy.

In a two-choice drug discrimination procedure, rats were trained to discriminate either 0.056 (low dose) or 0.17 (high dose) mg/kg of the kappa opioid bremazocine from saline. Substitution and antagonism tests were then conducted with a variety of opioids. The opioids U50, 488, ethylketocyclazocine, spiradoline, enadoline, and U69,593 substituted completely (>/=80% bremazocine-appropriate responding) for the bremazocine stimulus in both training groups, a finding consistent with their high-efficacy kappa profile. In contrast, the other opioids examined could be classified into different subsets on the basis of their patterns of substitution and antagonism: (1) (-)-cyclazocine substituted completely for the low-dose bremazocine stimulus and substituted partially (approximately 50% bremazocine-appropriate responding) for, and antagonized partially, the high-dose bremazocine stimulus; (2) butorphanol, nalorphine and nalbuphine substituted partially for, and antagonized partially, the low- and high-dose bremazocine stimuli; (3) levellorphan did not substitute for either training dose of bremazocine and antagonized the bremazocine stimulus at both training doses; (4) (-)-N-allylnormetazocine [(-)-NANM] substituted partially for the low-dose bremazocine stimulus and substituted completely for the high-dose bremazocine stimuli. Despite the high levels of substitution, (-)-NANM antagonized both the low- and high-dose bremazocine stimuli at doses below those required to produce its maximal agonist effects. The substitution patterns exhibited by (-)-NANM were not antagonized by doses of naloxone that antagonized the stimulus effects of (-)-cyclazocine and bremazocine, suggesting that these substitution patterns were non-opioid mediated. Collectively, these results suggest that the different patterns of substitution and antagonism observed with these opioids were due either to differences in their intrinsic efficacy at the kappa receptor or to a non-opioid component of action.

Effect of Storage Time and Temperature on Fecal Leukocytes and Occult Blood in the Evaluation of Travelers' Diarrhea.

Both the presence of fecal leukocytes and occult blood in stool specimens of travelers with diarrhea have been used as indicators of colonic inflammation due to bacterial infection. This study was conducted to determine if storage temperature of stool specimens can affect the detection of leukocytes and occult blood. Sixteen specimens positive for occult blood and 23 specimens positive for leukocytes were divided into two aliquots. Each aliquot was held at 4 degreesC or 25 degreesC and reexamined daily for fecal leukocytes or occult blood. Four percent of the positive leukocytes specimens and 56% of the occult blood positive specimens were still positive on the fifth day when they were held at 4 degreesC. When the samples were held at 25 degreesC, leukocytes could not be detected after 3 days, but 19% were positive for occult blood on the fifth day. The results indicate that storage temperature of stool specimens was associated with a difference in detection rate.

Assessment of the relative intrinsic efficacy of profadol and meperidine in a pigeon drug discrimination procedure: relevance to partial substitution patterns.

Substitution and antagonism patterns of butorphanol, meperidine and profadol were examined in pigeons trained to discriminate either a 0.056 (low) or 0.18 (high) mg/kg dose of fentanyl from saline. In the low-dose group, fentanyl, meperidine, profadol and butorphanol substituted completely (>/=85% fentanyl-appropriate responding) for the fentanyl stimulus. For fentanyl and butorphanol, complete substitution was obtained at doses that had little effect on rates of responding, whereas profadol substituted at doses that moderately decreased rates and meperidine substituted at doses that markedly decreased rates. Although naloxone antagonized the stimulus effects of meperidine and profadol, it failed to alter their rate-decreasing effects. In the high-dose group, fentanyl and butorphanol substituted completely and meperidine and profadol partially (approximately 50% fentanyl-appropriate responding) for the fentanyl stimulus. During antagonism tests, meperidine and profadol produced only small decreases (less than 15%) in the percentage of fentanyl-appropriate responding produced by the training dose of fentanyl. Analysis of individual data indicated that meperidine and profadol produced three patterns of substitution and antagonism. In one subgroup of pigeons, meperidine and profadol substituted completely for but failed to antagonize the fentanyl stimulus; in another, these opioids failed to substitute for but did antagonize the fentanyl stimulus; and in another, these opioids failed to substitute for or antagonize the fentanyl stimulus. In this latter subgroup, meperidine and profadol produced leftward shifts in the dose-effect function for the stimulus effects of fentanyl and butorphanol. The present findings suggest that the failure of meperidine and profadol to substitute completely for the high-dose fentanyl stimulus was a direct consequence of their rate-decreasing effects rather than low efficacy at the mu receptor.