HYPOTHERMIA TO PREVENT NEUROTOXIC SIDE EFFECTS OF PEDIATRIC DRUGS

 说明(申请人提供)：儿科药物在新生儿和儿科医学中用作麻醉剂、镇静剂和抗癫痫药，可能对发育中的大脑有害。它们已被证明在啮齿动物和非人类灵长类动物(NHP)的大脑中导致广泛的细胞死亡，损害突触成熟和可塑性，并抑制神经发生(新神经细胞的诞生)。对啮齿动物和NHP的研究提供了令人信服的证据，表明早期接触这些药物也会触发行为毒性，即 会导致长期的行为和认知缺陷，在动物成熟后会持续存在。此外，回溯性临床研究提出了严重的担忧，即人类婴儿接触这些类别的药物可能会导致神经认知和行为障碍。没有麻醉剂、镇静剂和抗癫痫药，行医是不可能的。这些药物必须在手术期间使用，在危重疾病期间延长镇静时间，以及用于癫痫的治疗。因此，关键的问题是，是否可以在临床环境中制定和应用保护措施，以避免这些药物对大脑健康和最脆弱年龄组的随后发育产生潜在的医源性不良影响，特别是在生命第一年的新生儿和婴儿。低温已成功地应用于新生儿和儿科医学，以最大限度地减少围产期窒息、心脏手术和新生儿中风造成的脑损伤。我们建议研究低温作为一种潜在的保护治疗方法来保护发育中的灵长类动物的大脑免受麻醉、镇静和抗惊厥药物的组织学、行为和神经认知毒性的影响。研究将在NHP婴儿身上进行，使用临床相关的药物组合和治疗持续时间。我们计划使用七氟醚(Sevo)，它正在成为儿科药物中最常用的全身麻醉药之一，以及苯巴比妥和咪达唑仑的组合(Pb/M)，这是一种通常用于新生儿和婴儿的镇静或抗癫痫治疗的方案。我们想要检验以下三个假设：(1)NHP婴儿暴露在Sevo麻醉下5小时会导致脑细胞死亡(细胞凋亡)，在整个麻醉过程中和之后1小时应用低温可以防止或减轻这种损害的严重性；(2)NHP婴儿在接受抗癫痫/镇静药物组合苯巴比妥/咪达唑仑(Ph/M)治疗24小时后，在12小时内应用低温可以防止或减轻药物引起的急性细胞死亡(细胞凋亡)反应；(3)NHP婴儿暴露于药物组合铅/M 24小时将导致长期神经行为损害(NBI)，在整个铅/M治疗期间及之后的12小时(药物仍在脑内存在有毒浓度的期间)应用低温可防止或减轻长期NBI。这些问题不能通过对人类对象的研究来回答，但可以通过使用非人类灵长类动物的研究来成功地解决和回答。

 DESCRIPTION (provided by applicant): Pediatric drugs which are used as anesthetics, sedatives and antiepileptics in neonatal and pediatric medicine, can be harmful to the developing brain. They have been shown to cause widespread cell death, impair synaptic maturation and plasticity and inhibit neurogenesis (the birth of new nerve cells) in the brains of rodents and non-human primates (NHP). Studies in rodents and in NHPs have provided compelling evidence that early life exposure to these drugs also triggers behavioral toxicity, i.e. causes long term behavioral and cognitive deficits that persist when the animals mature. Furthermore, retrospective clinical studies raise serious concerns that exposure of human infants to these classes of drugs may lead to neurocognitive and behavioral disorders. Practicing medicine without anesthetics, sedatives and antiepileptics is impossible. These medications must be used during surgeries, prolonged sedation during critical illness, and for the treatment of seizures. Thus, the crucial question arises whether protective measures can be developed and applied in the clinical setting to avoid potential iatrogenic adverse effects of these classes of drugs on brain health and subsequent development in the most vulnerable age groups, specifically neonates and infants during the first year of life. Hypothermia is successfull applied in neonatal and pediatric medicine to minimize brain injury from perinatal asphyxia, cardiac surgery and neonatal stroke. We propose to investigate hypothermia as a potential protective treatment of the developing primate brain against histological, behavioral and neurocognitive toxicity of anesthetic, sedative and anticonvulsant drugs. Research will be conducted in NHP infants using clinically relevant drug combinations and durations of treatment. We plan to use sevoflurane (SEVO), which is becoming one of the most frequently used general anesthetics in pediatric medicine and the combination of phenobarbital and midazolam (Pb/M), a protocol commonly used for sedation or antiepileptic therapy in neonates and infants. We want to test the following three hypotheses: (1) Exposure of NHP infants to SEVO anesthesia for 5 hrs will cause death (apoptosis) of brain cells, and application of hypothermia throughout the duration of anesthesia and for 1 hr thereafter will prevent or reduce the severity of this injuy; (2) Application of hypothermia during and 12 hrs after exposure of NHP infants to a 24 hr long treatment with the antiepileptic/sedative drug combination phenobarbital/midazolam (Pb/M) will prevent or mitigate the acute cell death (apoptosis) response caused by the drugs; (3) Exposure of NHP infants to the drug combination Pb/M for 24 hours will cause long- term neurobehavioral impairment (NBI), and application of hypothermia throughout the duration of Pb/M treatment and for 12 hrs thereafter (the period during which the drugs are still present at toxic concentrations n the brain) will prevent or mitigate the long-term NBI. These questions cannot be answered by research on human subjects, but can be successfully addressed and answered by research using non-human primates.