本文回顾了已故SaulBrusilow博士的科学生涯和成就,约翰霍普金斯大学儿科教授。Brusilow博士的职业生涯专注于涉及高氨血症的疾病。他和他的同事们开发了一套药物,通过提供合成可排泄含氮分子的替代途径,可以降低尿素循环遗传性疾病患者的氨水平。这些药物及其衍生物代表了用于遗传疾病的最早和最成功的药物疗法之一。把注意力转向肝脏疾病引起的脑肿胀,Brusilow博士和他的同事们提出了渗透胶质病假说来帮助解释氨毒性的机制,假设高氨驱动星形胶质细胞中的谷氨酰胺合成酶产生高水平的谷氨酰胺,作为一种有效的渗透压,将水吸入细胞并引起脑水肿。这一假设表明,抑制谷氨酰胺合成酶与其特征明确的抑制剂,甲硫氨酸亚砜胺,在肝性脑病的病例中可能被证明是治疗性的,他们随后的动物研究支持了这一结论。但是,尽管开发的治疗尿素循环障碍引起的高氨血症的药物已被FDA成功开发并批准,该化合物被建议用于治疗肝性脑病,但无法吸引足够的兴趣和投资用于人体试验。
This article reviews the scientific career and accomplishments of the late Dr. Saul Brusilow, Professor of Pediatrics at Johns Hopkins. Dr. Brusilow\'s career was focused on diseases involving hyperammonemia. He and his colleagues developed a set of drugs that could lower ammonia levels in patients with genetic disorders of the urea cycle by providing alternative pathways for the synthesis of excretable nitrogenous molecules. Those drugs and their derivatives represent one of the earliest and most successful drug therapies for genetic diseases. Turning their attention to brain swelling caused by liver disease, Dr. Brusilow and colleagues developed the Osmotic Gliopathy Hypothesis to help explain the mechanism of ammonia toxicity, postulating that high ammonia drives glutamine synthetase in astrocytes to produce elevated levels of glutamine that act as a potent osmolyte, drawing water into the cell and causing cerebral edema. This hypothesis suggests that inhibiting glutamine synthetase with its well-characterized inhibitor, methionine sulfoximine, might prove therapeutic in cases of hepatic encephalopathy, a conclusion supported by their subsequent studies in animals. But although the drugs developed to treat hyperammonemia resulting from urea cycle disorders were successfully developed and approved by the FDA, the compound suggested as a treatment for hepatic encephalopathy was unable to attract sufficient interest and investment to be tested for use in humans.