Outcomes of patients treated through the Canadian Fabry disease initiative.

BACKGROUND: The Canadian Fabry disease initiative (CFDI) tracks outcomes of subjects with Fabry disease treated enzyme replacement therapy (ERT) given to subjects who meet evidence-based treatment guidelines and cardiovascular risk factor modification. METHODS: We report 5 year follow-up data on 362 subjects for a composite endpoint (death, neurologic or cardiovascular events, development of end-stage renal disease or sustained increase in serum creatinine of 50% from baseline). RESULTS: At enrollment, 86 subjects had previously received ERT (Cohort 1a) and 67 subjects were newly started (Cohort 1b) and randomized to agalsidase alfa or agalsidase beta. 209 subjects did not initially meet ERT criteria (Cohort 1c), 25 of whom met ERT criteria in follow-up and were moved to Cohort 1b (total N=178 ERT treated subjects). Use of supportive therapies such as aspirin (78%), renin-angiotensin blockade (59%), and statins (55%) was common in ERT treated subjects. In Cohort 1a, 32 subjects met the composite endpoint with 8 deaths. In Cohort 1b, 16 subjects met the composite endpoint with 1 death. Cohort 1b had fewer clinical events than Cohort 1a (p=0.039) suggesting that the treatment protocol was effective in targeting subjects at an earlier stage. 19.4% of Cohort 1b subjects on agalsidase alfa and 13.3% on agalsidase beta had a clinical event (p=0.57). 10 Cohort 1c subjects had clinical events, none of which would have been prevented by earlier use of ERT. CONCLUSIONS: Cardiovascular risk factor modification and targeted use of ERT reduce the risk of adverse outcomes related to Fabry disease.

Baseline characteristics of patients enrolled in the Canadian Fabry Disease Initiative.

The Canadian Fabry Disease Initiative [CFDI] is a longitudinal study evaluating all Canadians diagnosed with Fabry disease [FD]. The study has 3 cohorts: Cohort 1A which includes 81 subjects who were on enzyme replacement therapy [ERT] prior to October 2006, Cohort 1B which has ongoing enrolment of subjects newly started on ERT who are randomized to agalsidase alfa or agalsidase beta, and Cohort 1C where subjects who do not meet nationally accepted Canadian criteria for ERT are followed to assess the natural history of disease complications. The study currently enrols 244 patients [95 males and 149 females] with a mean age of 41.9+/-14.5years. There is a high prevalence of the c.427G>C mutation. Cohort 1A contains 82 patients [59 males, 23 females] of whom 42% are known to have cardiac complications of FD and 38% renal complications. Cohort 1B at the time of writing contained 37 patients [15 males, 22 females] of whom the indications for ERT were cardiac in 55% and renal in 60%. Cohort 1C at the time of writing contained 125 patients [22 males, 103 females]. Enrolment is ongoing in both Cohorts 1B and 1C. When compared to subjects in the Fabry Outcome Survey and the Fabry Registry, subjects in the CFDI are less likely to be male reflecting less ascertainment bias. The CFDI is a robust national data set that will contribute to available data on the natural history of FD and on the comparative efficacy of the two commercially available ERT products.

Neurotoxic, hemorrhagic and proteolytic activities of Duvernoy's gland secretion from Venezuelan opisthoglyphous colubrid snakes in mice.

Many colubrid snakes produce toxic oral secretions. We studied venom (Duvernoy's gland secretion) collected from Venezuelan opisthoglyphous (rear-fanged) colubrid snakes. Different proteins were present in Thamnodynastes stigilis Duvernoy's gland secretion and were characterized by 20% SDS-PAGE protein electrophoresis. The venom displayed proteolytic (gelatinase) activity that was partially purified on a chromatography ionic exchange mono Q2 column. We demonstrated hemorrhagic activity of Thamnodynastes stigilis Duvernoy's gland secretion on chicken embryos and mouse skin and peritoneum. Mice inoculated with Thamnodynastes stigilis Duvernoy's gland secretion presented signs of neurotoxicity. Thamnodynastes stigilis Duvernoy's gland secretion had proteolytic, hemorrhagic, and neurotoxic activities, not previously described in this species and identifies the presence of a new venomous colubrid in Venezuela.