Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
Drowning is a leading cause of injury-related death in children. In 2017, drowning claimed the lives of almost 1000 US children younger than 20 years. A number of strategies are available to prevent these tragedies. As educators and advocates, pediatricians can play an important role in the prevention of drowning. BACKGROUND Drowning is the leading cause of injury death in US children 1 to 4 years of age and the third leading cause of unintentional injury death among US children and adolescents 5 to 19 years of age. 1 In 2017, drowning claimed the lives of almost 1000 US children. Fortunately, childhood unintentional drowning fatality rates have decreased steadily from 2.68 per 100 000 in 1985 to 1.11 per 100 000 in 2017. Rates of drowning death vary with age, sex, and race and/or ethnicity, with toddlers and male adolescents at highest risk. After 1 year of age, male children of all ages are at greater risk of drowning than female children. Overall, African American children have the highest drowning fatality rates, followed in order by American Indian and/or Alaskan native, white, Asian American and/or Pacific Islander, and Hispanic children. For the period 2013-2017, the highest drowning death rates were seen in white male children 0 to 4 years of age (3.44 per 100 000), American Indian and/or Alaskan native children 0 through 4 years (3.58), and African American male adolescents 15 to 19 years of age (4.06 per 100 000). 1 Drowning is also a significant source of morbidity for children. In 2017, an estimated 8700 children younger than 20 years of age visited a hospital emergency department for a drowning event, and 25% of those children were hospitalized or transferred for further care. 1 Most victims of nonfatal drowning recover fully with no neurologic deficits, but severe long-term neurologic deficits are seen with extended submersion times (.6 minutes), prolonged resuscitation efforts, and lack of early bystander-initiated cardiopulmonary resuscitation (CPR). 2-4 The American Academy of Pediatrics issues this revised policy statement because of new information and research regarding (1) populations at
Drowning is a leading cause of injury-related death in children. In 2018, almost 900 US children younger than 20 years died of drowning. A number of strategies are available to prevent these tragedies. As educators and advocates, pediatricians can play an important role in prevention of drowning.
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