HYPOTHERMIA TO PREVENT NEUROTOXIC SIDE EFFECTS OF PEDIATRIC DRUGS

 描述（由申请人提供）：在新生儿和儿科医学中用作麻醉剂、镇静剂和抗癫痫药的儿科药物可能对发育中的大脑有害。它们已被证明会导致啮齿动物和非人类灵长类动物（NHP）大脑中广泛的细胞死亡，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引发行为毒性，即 会导致长期的行为和认知缺陷，这些缺陷在动物成熟后仍然存在。此外，回顾性临床研究提出了严重的问题，即人类婴儿暴露于这些类别的药物可能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，在危重病期间延长镇静，并用于治疗癫痫发作。因此，出现了一个关键问题，即是否可以在临床环境中制定和应用保护措施，以避免这类药物对最脆弱年龄组（特别是新生儿和一岁以内的婴儿）的大脑健康和随后发育的潜在医源性不良影响。低温已成功地应用于新生儿和儿科医学，以减少围产期窒息、心脏手术和新生儿卒中引起的脑损伤。我们建议研究低温作为一种潜在的保护性治疗的发展中的灵长类动物的大脑对麻醉，镇静和抗惊厥药物的组织学，行为和神经认知毒性。将使用临床相关药物组合和治疗持续时间在NHP婴儿中进行研究。我们计划使用七氟烷（SEVO），这是儿科医学中最常用的全身麻醉药之一，以及苯巴比妥和咪达唑仑（Pb/M）的组合，这是一种常用于新生儿和婴儿镇静或抗癫痫治疗的方案。我们想检验以下三个假设：（1）NHP婴儿暴露于SEVO麻醉5小时会导致死亡（细胞凋亡），并且在整个麻醉期间和之后1小时应用低温将防止或减轻这种损伤的严重性;（2）在NHP婴儿暴露于抗癫痫/镇静药物组合苯巴比妥/咪达唑仑（Pb/M）的24小时长的治疗期间和之后12小时应用低温会阻止或减轻急性细胞死亡（凋亡）反应;（3）NHP婴儿暴露于药物组合Pb/M 24小时将导致长期神经行为损害（NBI），并在整个Pb/M治疗期间和此后12小时内应用低温（在此期间药物仍然以毒性浓度存在于大脑中）将预防或减轻长期NBI。这些问题无法通过对人类受试者的研究来回答，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.