WO2022111543A1 - 扎那米韦在制备治疗或预防先兆子痫的药物中的用途 - Google Patents

扎那米韦在制备治疗或预防先兆子痫的药物中的用途 Download PDF

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WO2022111543A1
WO2022111543A1 PCT/CN2021/132895 CN2021132895W WO2022111543A1 WO 2022111543 A1 WO2022111543 A1 WO 2022111543A1 CN 2021132895 W CN2021132895 W CN 2021132895W WO 2022111543 A1 WO2022111543 A1 WO 2022111543A1
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injection
zanamivir
preeclampsia
administration
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杜涛
胡涛
杜新
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深圳埃格林医药有限公司
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Priority to US18/254,319 priority Critical patent/US20240009166A1/en
Priority to EP21897043.2A priority patent/EP4238561A4/en
Priority to JP2023531118A priority patent/JP2023551455A/ja
Publication of WO2022111543A1 publication Critical patent/WO2022111543A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present application provides the use of zanamivir in the preparation of a medicine for treating or preventing preeclampsia, as well as the corresponding medicine and treatment method.
  • Preeclampsia also known as preeclampsia or toxemia of pregnancy, refers to the clinical symptoms of hypertension, proteinuria and edema that appear after 20 weeks of pregnancy, accompanied by headache, vertigo, nausea, vomiting, abdominal discomfort, etc. syndrome.
  • Preeclampsia not only affects the development of the fetus, but often endangers the life of the mother. According to statistics, preeclampsia affects about 8.5 million pregnant women worldwide every year, and causes about 63,000 pregnant women and about 500,000 perinatal deaths. It is one of the important factors that cause maternal and perinatal morbidity and mortality. . There is also evidence that preeclampsia has a higher incidence in developing countries, about 9.4% in China.
  • the pathophysiological process of the disease is roughly divided into two stages: 1) Abnormal placenta formation, especially uterine spiral arteriole diastolic disorder, which affects the blood supply from the mother to the fetus. Reduced placental perfusion activates placental release of associated cytokines and causes systemic hemodynamic changes. 2) Clinical symptoms in pregnant and lying-in women are mainly caused by circulatory system disorders caused by dysfunction of maternal vascular endothelial cells, including changes in vascular reactivity, activation of coagulation cascades, and destruction of vascular integrity. Preeclampsia affects most organs of the mother, but mainly the kidneys, liver and brain.
  • preeclampsia Although there are a large number of preclinical and clinical studies on preeclampsia, its pathogenesis is currently known to be complex but not clear, and the corresponding treatment methods are also quite lacking, generally only symptomatic hypotensive, diuretic, sedative treatment, etc. Magnesium sulfate can be used to relieve spasticity, and termination of pregnancy is still the most effective clinical treatment.
  • the etiology of preeclampsia may be based on polygenic genetic factors. Predisposing factors lead to abnormal cellular immunity, placental and trophoblastic ischemia and hypoxia, abnormal oxidative stress response, and secondary systemic vascular endothelial cell damage. cause the disease to occur.
  • VEGF vascular endothelial growth factor
  • sFlt-1 soluble vascular endothelial growth factor-1
  • angiotensin II receptor 1 The autoantibodies and tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin 1 (IL-1) and IL-6, pentraxin 3 (PTX3), etc. can cause the damage of maternal vascular endothelial function through different ways.
  • vasodilators and vasoconstrictors in the blood of patients with preeclampsia is imbalanced, and the damage to the vascular endothelium increases the sensitivity of blood vessels to vasoconstrictor factors, but decreases the sensitivity to vasodilator factors, resulting in systemic arteriolar spasm .
  • Patients with existing hypertension, diabetes, obesity and hyperlipidemia may have oxidative stress and abnormal vascular endothelial function before pregnancy, and are more likely to develop preeclampsia after pregnancy.
  • Vascular endothelial cells lay flat on the lumen surface of blood vessels and are direct receptors and responders of flow shear force. Endothelial cells convert extracellular mechanical signals into intracellular signals through various pathways, thereby triggering downstream biochemical reactions.
  • Vascular endothelial cell glycocalyx is a layer of villous polysaccharide protein complex structure located in the apical membrane of endothelial cells, between the vessel wall and blood, it is a dynamic natural barrier on the surface of endothelial cells, and mediates the mechanotransduction function of endothelial cells.
  • Vascular endothelial cell glycocalyx is a highly negatively charged endothelial cell surface layer composed of oligosaccharide chain glycoproteins containing sialic acid residues and proteoglycans containing glycosaminoglycan side chains.
  • endothelial cell glycocalyx is also involved in the process of flow shear force perception and transmission.
  • vascular endothelial glycocalyx The degradation of the vascular endothelial glycocalyx is usually mediated by a variety of specific enzymes.
  • Neuraminidase also known as sialidase, can act on the oligosaccharide chain glycoproteins containing sialic acid residues at the end of the glycocalyx to hydrolyze the ketoglycosidic bonds to release sialic acid, and finally cause the degradation of the glycocalyx and the release of sialic acid.
  • Corresponding vascular endothelial function is impaired. It has been shown in the literature that elevated levels of neuraminidase can be detected in the blood of patients with some cardiovascular system-related diseases such as type II diabetes, and inhibition of neuraminidase can correspondingly improve by inhibiting glycocalyx degradation.
  • the present application provides the use of zanamivir in the manufacture of a medicament for the treatment or prevention of preeclampsia.
  • the zanamivir includes the compound zanamivir and its pharmaceutically or pharmaceutically acceptable derivatives or salts.
  • the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
  • injections include injections, powder injections; oral preparations include tablets, capsules, oral liquids, throat or nasal sprays, and external preparations include ointments, sprays, and patches.
  • preeclampsia is improvement of headache, vertigo, nausea, vomiting, abdominal discomfort, hypertension, proteinuria, edema, liver and kidney function, thrombocytopenia and/or abnormal blood coagulation system; creatinine, neuraminic acid Increased glucosidase and sialic acid, decreased blood NO levels; and improved pregnancy outcomes.
  • the application provides a method of treating or preventing preeclampsia comprising administering zanamivir to a patient at risk for or suffering from preeclampsia.
  • the zanamivir dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
  • the injections include injections and powders; oral preparations include tablets, capsules, oral liquids, throat or nasal sprays, and external preparations include ointments, sprays, and patches.
  • preeclampsia is improvement of headache, vertigo, nausea, vomiting, abdominal discomfort, hypertension, proteinuria, edema, liver and kidney function, thrombocytopenia and/or abnormal blood coagulation system; creatinine, neuraminic acid Increased glucosidase and sialic acid, decreased blood NO levels; and improved pregnancy outcomes.
  • the administration method of zanamivir can be selected from intramuscular injection, intravenous injection, intravenous infusion, preferably intramuscular injection; administration 1-7 times per week, preferably 1-4 times; more preferably 1-2 times; The duration of the drug is 1-30 days, preferably 1-7 days, more preferably 1-7 days.
  • the present application provides a medicament for the treatment or prevention of preeclampsia.
  • the pharmaceutical dosage forms are injections, oral preparations or external preparations; preferably injections, oral preparations; particularly preferably injections; further preferably intramuscular injections. .
  • the medicament includes instructions, and the instructions describe that the administration method of zanamivir is 1-7 times per week, preferably 1-4 times; more preferably 1-2 times; the administration duration is 1-30 days , preferably 1-7 days, more preferably 1-7 days.
  • preeclampsia is improvement of headache, vertigo, nausea, vomiting, abdominal discomfort, hypertension, proteinuria, edema, liver and kidney function, thrombocytopenia and/or abnormal blood coagulation system; creatinine, neuraminic acid Increased glucosidase and sialic acid, decreased blood NO levels; and improved pregnancy outcomes.
  • the dosage is 20-40 mg/day, 90 mg/kg or 120 mg/kg, preferably 20 mg/day.
  • the medicine also includes pharmaceutically acceptable adjuvants, which include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, Adhesive, gas generating agent.
  • pharmaceutically acceptable adjuvants include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, Adhesive, gas generating agent.
  • zanamivir is the only active ingredient in the method or the medicine; or the method also includes administering other active ingredients or the medicine also includes other active ingredients; the other active ingredients include but are not limited to hypotensive drugs, protein Supplements, anti-vertigo drugs, cardiovascular drugs.
  • the present application provides the use of a neuraminidase inhibitor in the manufacture of a medicament for the treatment or prevention of preeclampsia.
  • the neuraminidase inhibitors include compounds neuraminidase inhibitors and their pharmaceutically or pharmaceutically acceptable derivatives or salts.
  • the pharmaceutical dosage forms are injections, oral preparations or external preparations; preferably injections, oral preparations; particularly preferably injections.
  • injections include injections, powder injections; oral preparations include tablets, capsules, oral liquids, throat or nasal sprays, and external preparations include ointments, sprays, and patches.
  • preeclampsia is improvement of headache, vertigo, nausea, vomiting, abdominal discomfort, hypertension, proteinuria, edema, liver and kidney function, thrombocytopenia and/or abnormal blood coagulation system; creatinine, neuraminic acid Increased glucosidase and sialic acid, decreased blood NO levels; and improved pregnancy outcomes.
  • the application provides a method of treating or preventing preeclampsia comprising administering a neuraminidase inhibitor to a patient at risk for or suffering from preeclampsia.
  • the dosage forms of the neuraminidase inhibitor are injections, oral preparations or external preparations; preferably injections, oral preparations; particularly preferably injections.
  • the injections include injections and powders; oral preparations include tablets, capsules, oral liquids, throat or nasal sprays, and external preparations include ointments, sprays, and patches.
  • preeclampsia is improvement of headache, vertigo, nausea, vomiting, abdominal discomfort, hypertension, proteinuria, edema, liver and kidney function, thrombocytopenia and/or abnormal blood coagulation system; creatinine, neuraminic acid Increased glucosidase and sialic acid, decreased blood NO levels; and improved pregnancy outcomes.
  • the administration method of the neuraminidase inhibitor can be selected from intramuscular injection, intravenous injection, intravenous infusion, preferably intramuscular injection; weekly administration 1-7 times, preferably 1-4 times; more preferably 1-2 times ; The duration of administration is 1-30 days, preferably 1-7 days, more preferably 1-7 days.
  • the present application provides a medicament for the treatment or prevention of preeclampsia.
  • the pharmaceutical dosage forms are injections, oral preparations or external preparations; preferably injections, oral preparations; particularly preferably injections; further preferably intramuscular injections. .
  • the medicament includes instructions, and the instructions describe the administration method of the neuraminidase inhibitor as 1-7 times per week, preferably 1-4 times; more preferably 1-2 times; the administration duration is 1- 30 days, preferably 1-7 days, more preferably 1-7 days.
  • preeclampsia is improvement of headache, vertigo, nausea, vomiting, abdominal discomfort, hypertension, proteinuria, edema, liver and kidney function, thrombocytopenia and/or abnormal blood coagulation system; creatinine, neuraminic acid Increased glucosidase and sialic acid, decreased blood NO levels; and improved pregnancy outcomes.
  • the dosage is 20-40 mg/day, 90 mg/kg or 120 mg/kg, preferably 20 mg/day.
  • the medicine also includes pharmaceutically acceptable adjuvants, which include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, Adhesive, gas generating agent.
  • pharmaceutically acceptable adjuvants include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, Adhesive, gas generating agent.
  • the neuraminidase inhibitor is the only active ingredient in the method or the medicine; or the method also includes administering other active ingredients or the medicine also includes other active ingredients; the other active ingredients include but are not limited to antihypertensive drugs , protein supplements, anti-vertigo drugs, cardiovascular disease drugs.
  • zanamivir described in this application is not limited to the chemical structure of CAS No. 139110-90-8 (ie, 5-acetamido-4-[(aminoiminomethyl)-amino]-2,6-hydrogen -3,4,5-Trideoxy-D-glyceryl-D-galactose-2-enolic acid, or 4-guanidino-2-deoxy-2,3-didehydro-N-acetyl neuraminic acid), also including its pharmaceutically or pharmaceutically acceptable derivatives or salts.
  • Neuraminidase inhibitors in this application refer to compounds or compositions that inhibit neuraminidase, including various neuraminidase inhibitors known and studied in the art, including but not limited to Zanadase miwe.
  • hydroxyprogesterone caproate is also referred to as 17-alpha hydroxyprogesterone caproate, 17-HPC, 17-hydroxyprogesterone caproate, 17-hydroxyprogesterone caproate, and the CAS number is 630-56-8.
  • Pre-eclampsia as described in this application refers to a clinical syndrome with hypertension, proteinuria and edema as the main symptoms during pregnancy, accompanied by headache, vertigo, malignant, vomiting, abdominal discomfort, etc.
  • the main symptoms also include creatinine, neuramine
  • Specific symptoms of elevated nuclease and sialic acid and reduced blood NO levels include, but are not limited to, the above.
  • zanamivir can be administered as the only active ingredient for the treatment of pre-eclampsia or prepared as a corresponding drug, or it can be administered or prepared into a drug in combination with a known or under-studied drug for the treatment of pre-eclampsia or pre-eclampsia-related symptoms Combination or pharmaceutical composition.
  • drugs include, but are not limited to, blood pressure lowering drugs, protein supplements, anti-vertigo drugs, cardiovascular disease drugs, etc.
  • the administration mode of zanamivir in the present application can be intramuscular injection, intravenous injection, intravenous infusion, etc., preferably intramuscular injection.
  • the frequency of administration of zanamivir in this application can be 1-7 times a week, preferably 1-4 times, more preferably 1-2 times; the duration of administration can be 1-30 days , preferably 1-14 days, more preferably 1-7 days.
  • zanamivir in the present application is not limited to the range described in the description and claims, and clinicians can adjust the dosage according to factors such as patient conditions and drug dosage forms.
  • zanamivir in this application include but are not limited to injections such as injections, powder injections, etc., oral preparations such as tablets, capsules, oral liquids, etc., throat or nasal sprays, external preparations such as ointments, sprays, Patches, etc.; injection preparations, oral preparations are preferred; injection preparations are particularly preferred.
  • Described in this application and improving pregnancy outcomes include, but are not limited to, miscarriage and fetal/infant health problems associated with pre-eclampsia or blood pressure.
  • excipients for the drugs involved in this application according to the general knowledge in the field of pharmacy.
  • the types of excipients that can be used include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners Flavoring agents, adhesives, gas generating agents, etc.
  • the dose of neuraminidase inhibitor such as zanamivir may be 90 mg/kg-120 mg/kg; preferably 120 mg/kg.
  • zanamivir can improve the symptoms of hypertension and proteinuria in pre-eclampsia, and reduce the level of creatinine in urine; zanamivir can reduce the level of neuraminidase and sialic acid in the blood, and increase the level of NO in the blood. Level. Zanamivir combined with hydroxyprogesterone caproate showed superior preventive and therapeutic effects on preeclampsia. It provides new ideas and means for the development of drugs for the prevention and treatment of preeclampsia.
  • mice (aged 8-10 weeks) were randomly divided into control group and preeclampsia model group. On days 7-16 of the gestational cycle, the mice in the model group were subcutaneously injected with 50 mg/kg of N-nitro-L-arginine methyl ester (L-NAME) to induce pre-eclampsia every day. In the control group, an equal volume of solvent was injected subcutaneously.
  • L-NAME N-nitro-L-arginine methyl ester
  • zanamivir can significantly improve the symptoms of hypertension and proteinuria in pregnant mice with L-NAME-induced preeclampsia, and increase the litter size of pregnant mice.

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Abstract

提供了扎那米韦在制备治疗或预防先兆子痫的药物中的用途以及相应药物和治疗方法；扎那米韦可以有效改善先兆子痫的高血压，蛋白尿，肌酐、神经氨酸苷酶和唾液酸升高症状，增加NO水平；改善妊娠结局。扎那米韦和己酸羟孕酮联用显示出更优的效果。

Description

扎那米韦在制备治疗或预防先兆子痫的药物中的用途
交叉引用
本申请要求在2020年11月24日提交中国专利局、申请号为202011331782.9、发明名称为“先兆子痫的治疗方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
本申请要求在2020年12月01日提交中国专利局、申请号为202011388482.4、发明名称为“先兆子痫的治疗方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
本申请要求在2021年11月24日提交中国专利局、申请号为202111400709.7、发明名称为“扎那米韦在制备治疗或预防先兆子痫的药物中的用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请提供了扎那米韦在制备治疗或预防先兆子痫的药物中的用途以及相应药物和治疗方法。
背景技术
先兆子痫，又称子痫前期或妊娠毒血症，是指妊娠20周后出现的以高血压，蛋白尿和水肿为主要症状，并伴随头痛、眼花、恶性、呕吐、腹部不适等的临床综合征。先兆子痫不仅影响胎儿的发育，而且经常危及孕产妇的生命安全。据统计，先兆子痫每年在世界范围内影响到约850万怀孕女性，并造成约63000孕产妇和约50万围生儿的死亡，是引起孕产妇和围生儿发病以及死亡的重要因素之一。亦有证据表明，先兆子痫在发展中国家有更高的发病率，在中国大约为9.4％。该疾病的病生理过程大致分为2个阶段：1)异常的胎盘形成，尤其是子宫螺旋小动脉舒张障碍，并影响到母体向胎儿的血流供应。减少的胎盘血流灌注则会激活胎盘释放相关的细胞因子并引起全身性的血液动力学的改变。2)孕产妇出现临床症状，主要是由母体血管内皮细胞功能障碍引起的循环系统紊乱，包括血管反应性的改变，凝血级联反应的激活和血管完整性的破坏等。先兆子痫对孕产妇的大部 分器官都会产生影响，但主要是肾脏，肝脏和大脑。
尽管对于先兆子痫有大量临床前和临床研究，其发病机制目前已知复杂但尚不明确，相应治疗手段也相当匮乏，一般仅为对症的降血压、利尿、镇静治疗等，重度子痫出现时可使用硫酸镁解除痉挛症状，目前终止妊娠仍是最有效的临床治疗措施。先兆子痫的病因可能是在多基因遗传因素的基础上，易感因素导致细胞免疫异常，胎盘和滋养细胞缺血缺氧，氧化应激反应异常，引起继发性全身血管内皮细胞受损而导致该病的发生。鉴于此，科学界提出了一系列的机制学说包括胎盘或滋养细胞缺血学说，氧化应激学说，免疫调节异常学说，遗传学说以及血管内皮损伤学说等来阐释先兆子痫的发病机制。胎盘螺旋小动脉重铸障碍和胎盘浅着床，滋养细胞缺血缺氧以及血管内皮细胞损伤通常被认为是先兆子痫发病的病理生理基础。大量研究表明，由于缺血缺氧引起的胎盘及血管源性循环因子的释放,包括血管内皮生长因子(VEGF)、可溶性血管内皮生长因子-1(sFlt-1)、血管紧张素II受体1的自身抗体及肿瘤坏死因子-α(TNF-α)、白细胞介素1(IL-1)和IL-6、正五聚蛋白3(PTX3)等可通过不同途径引起母体血管内皮功能损伤。此外，先兆子痫患者血液中的血管舒张因子和血管收缩因子比例失调，血管内皮受损使血管对血管收缩因子的敏感性增加，而对血管舒张因子的敏感性下降，从而导致全身小动脉痉挛。原有高血压，糖尿病，肥胖以及高脂血症的患者，在妊娠前即可能存在氧化应激和血管内皮功能异常，妊娠后更易于发生先兆子痫。
血管内皮细胞平铺于血管内腔面，是流动剪切力的直接感受者与响应者，内皮细胞通过各种途径将胞外力学信号转化为胞内信号，进而引发下游生化反应。血管内皮细胞糖萼是位于内皮细胞顶膜的一层绒毛状多糖蛋白复合结构，介于管壁与血液之间，是内皮细胞表面的动态天然屏障，并介导内皮细胞的力传导功能。血管内皮细胞糖萼是由末端含唾液酸残基的寡糖链糖蛋白与包含糖胺聚糖侧链的蛋白聚糖所组成的带高度负电荷的内皮细胞表面层。除了作为血管壁的选择性通透屏障，调节微循环流变性质，参与血管保护和信号传递之外，大量的证据表明内皮细胞糖萼也介入了流动剪切力的感受与传导过程。采用选择性酶降解的方法，Manolis等通过同时选择性降解糖萼中的唾液酸，硫酸肝素，硫酸软骨素，透明质酸来对牛胸主动脉内皮细胞进行处理，结果发现流动剪切力诱导的一氧化氮(NO)合成受阻，表明完整无损的糖萼在剪切力诱导的NO合成中发挥了重要作用。研究亦证实，当糖萼完整无损时，流动剪切力可以通过核心蛋白传递到肌动蛋白细胞骨架， 或者通过核心蛋白直接传递到细胞膜上，从而介导细胞下游的信号传导，如NO的生成，细胞骨架的重组等。而当糖萼受损时，血管内皮细胞的正常功能则受到影响。最近的一项临床研究发现在早发型先兆子痫患者中可以检测到更多的糖萼降解，并且伴随着血液中糖萼成分硫酸肝素蛋白聚糖和透明质酸水平的升高，从而表明血管内皮糖萼降解与早发型先兆子痫发病密切相关。
血管内皮糖萼的降解通常由多种特异性的酶介导。神经氨酸苷酶，亦称为唾液酸酶，可以作用于糖萼末端含有唾液酸残基的寡糖链糖蛋白，使其酮糖苷键发生水解而放出唾液酸，并最终引起糖萼降解和相应的血管内皮功能受损。有文献表明，在一些心血管系统相关疾病如II型糖尿病的患者血液中可以检测到神经氨酸苷酶水平的升高，而抑制神经氨酸苷酶则可以通过抑制糖萼降解来相应地改善血管内皮功能以及整个心血管系统的功能。鉴于目前临床上并无有效预防和治疗先兆子痫的药物，在本领域中存在对用于预防和治疗该疾病药物的极大需要，抑制神经氨酸苷酶的药物则为预防和治疗先兆子痫的药物开发提供了全新的思路和手段。
发明内容
一方面，本申请提供了扎那米韦在制备治疗或预防先兆子痫的药物中的用途。
所述扎那米韦包括化合物扎那米韦及其医学或药学上可接受衍生物或盐。
进一步地，所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂。
进一步地，所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
进一步地，所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
另一方面，本申请提供了治疗或预防先兆子痫的方法，包括向有先兆子痫风险或患有先兆子痫的患者施用扎那米韦。
进一步地，所述扎那米韦剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂。
所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷 剂，外用制剂包括软膏剂、喷剂、贴剂。
进一步地，所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
进一步地，所述扎那米韦的施用方法可选肌肉注射、静脉注射、静脉输液，优选肌肉注射；每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
另一方面，本申请提供了治疗或预防先兆子痫的药物。
进一步地，所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂；进一步优选肌肉注射剂。。
进一步地，所述药物包含说明书，说明书中记载扎那米韦的施用方法为每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
进一步地，所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
进一步地，本申请的方法或药物在施用时，剂量为20-40mg/天,90mg/kg或者120mg/kg，优选20mg/天。
进一步地，所述药物中还包括药学上可接受的辅料，所述药学上可接受的辅料包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂。
进一步地，扎那米韦为方法或药物中的唯一有效成分；或者在方法中还包括施用其他有效成分或药物中还包含其他有效成分；所述其他有效成分包括但不限于降血压药，蛋白质补充剂，抗眩晕药，心血管疾病药物。
另一方面，本申请提供了神经氨酸酶抑制剂在制备治疗或预防先兆子痫的药物中的用途。
所述神经氨酸酶抑制剂包括化合物神经氨酸酶抑制剂及其医学或药学上可接受衍生物或盐。
进一步地，所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂； 特别优选注射剂。
进一步地，所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
进一步地，所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
另一方面，本申请提供了治疗或预防先兆子痫的方法，包括向有先兆子痫风险或患有先兆子痫的患者施用神经氨酸酶抑制剂。
进一步地，所述神经氨酸酶抑制剂剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂。
所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
进一步地，所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
进一步地，所述神经氨酸酶抑制剂的施用方法可选肌肉注射、静脉注射、静脉输液，优选肌肉注射；每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
另一方面，本申请提供了治疗或预防先兆子痫的药物。
进一步地，所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂；进一步优选肌肉注射剂。。
进一步地，所述药物包含说明书，说明书中记载神经氨酸酶抑制剂的施用方法为每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
进一步地，所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
进一步地，本申请的方法或药物在施用时，剂量为20-40mg/天,90mg/kg或者120mg/kg， 优选20mg/天。
进一步地，所述药物中还包括药学上可接受的辅料，所述药学上可接受的辅料包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂。
进一步地，神经氨酸酶抑制剂为方法或药物中的唯一有效成分；或者在方法中还包括施用其他有效成分或药物中还包含其他有效成分；所述其他有效成分包括但不限于降血压药，蛋白质补充剂，抗眩晕药，心血管疾病药物。
本申请的所述的扎那米韦不限为CAS号139110-90-8的化学结构(即，5-乙酰氨基-4-[(氨基亚氨基甲基)-氨基]-2,6-氢-3,4,5-三去氧-D-丙三醇基-D-半乳糖-2-烯醇酸，或4-胍基-2-脱氧-2，3-二脱氢-N-乙酰神经氨酸)，也包含其医学或药学上可接受衍生物或盐。本申请中的神经氨酸酶抑制剂是指对神经氨酸酶起抑制作用的化合物或组合物，包括本领域已知和研究中的各种神经氨酸酶抑制剂，包括但不限于扎那米韦。
本申请中己酸羟孕酮也被称为17-α己酸羟孕酮、17-HPC、17-己酸羟孕酮、17-羟己孕酮，CAS编号为630-56-8。
本申请所述的先兆子痫指妊娠过程中以高血压，蛋白尿和水肿为主要症状，并伴随头痛、眼花、恶性、呕吐、腹部不适等的临床综合征，主要症状还包括肌酐、神经氨酸苷酶和唾液酸升高以及血液NO水平降低，其具体症状包含但不限于上述。
本申请中扎那米韦可以作为治疗先兆子痫的唯一有效成分施用或制备相应药物，也可以与治疗先兆子痫或先兆子痫相关症状的已知或研究中的药物联合施用或制备成药物组合或药物组合物。这些药物包括但不限于降血压药，蛋白质补充剂，抗眩晕药，心血管疾病药物等。
本申请中的扎那米韦注射给药方式可以为肌肉注射、静脉注射、静脉输液等，优选肌肉注射。
依据剂型和病情不同，区别本申请中的扎那米韦给药频率可以为每周1-7次，优选1-4次，更优选1-2次；给药持续时间可以为1-30日，优选1-14日，更优选1-7日。
本申请中扎那米韦施用量不局限与说明书和权利要求中所记载的范围，临床医师可以根据患者情况和药物剂型等因素调整用量。
本申请的扎那米韦可用剂型包括但不限于注射剂如注射液、粉针剂等，口服制剂如片 剂、胶囊剂、口服液等，咽喉或鼻喷剂，外用制剂如软膏剂、喷剂、贴剂等；优选注射剂，口服制剂；特别优选注射剂。
本申请中所述的以及改善妊娠结局包括但不限于与先兆子痫或血压相关的流产和胎儿/婴儿健康问题。
本领域技术人员可以根据药学领域一般知识为为本申请所涉及的药物选择适合的辅料，可用的辅料种类包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂等。
本发明中，神经氨酸酶抑制剂如扎那米韦施用量可为90mg/kg-120mg/kg；优选120mg/kg。
实验结果表明，扎那米韦可以改善先兆子痫的高血压以及蛋白尿症状，降低尿液中肌酐水平；扎那米韦可以降低血液中神经氨酸苷酶和唾液酸水平，增加血液中NO水平。扎那米韦与己酸羟孕酮联用对先兆子痫显示出更优的预防和治疗作用。为预防和治疗先兆子痫的药物开发提供了全新的思路和手段。
附图说明
图1为各组孕鼠妊娠第12天平均动脉压情况图；其显示扎那米韦(120mg/kg)可以显著降低L-NAME引起的孕鼠平均动脉压升高(数据为平均值±标准误，N＝9-22,*p<0.05)；
图2为各组孕鼠妊娠第12天舒张压情况图；其显示扎那米韦(120mg/kg)可以显著降低L-NAME引起的孕鼠舒张压升高(数据为平均值±标准误，N＝9-22,*p<0.05)；
图3为各组孕鼠妊娠第12天收缩压情况图；其显示扎那米韦(120mg/kg)可以显著降低L-NAME引起的孕鼠收缩压升高(数据为平均值±标准误，N＝9-22,**p<0.01)；
图4为各组孕鼠妊娠第17-18天24小时尿蛋白情况图；其显示扎那米韦可以显著降低L-NAME引起的孕鼠24小时尿蛋白升高(数据为平均值±标准误，N＝5-22，**p<0.01，***p<0.001)；
图5为各组孕鼠产仔数量情况图；扎那米韦可以显著改善L-NAME引起的孕鼠产仔数量减少(数据为平均值±标准误，N＝9-16，*p<0.05)。
具体实施方式
实施例1先兆子痫动物模型的建立
将怀孕的CD-1小鼠(年龄8-10周)随机分为对照组和先兆子痫模型组。在妊娠周期的第7-16天，模型组小鼠每天通过皮下注射50mg/kg的N-硝基-L-精氨酸甲酯(L-NAME)诱导先兆子痫。对照组则皮下注射等体积的溶剂。
实施例2实验分组
Figure PCTCN2021132895-appb-000001
实施例3治疗效果评估
L-NAME诱导的先兆子痫动物模型，根据文献报道，在首次给予L-NAME的两天后即会出现高血压症状，并至少持续到首次给予L-NAME的五天后。蛋白尿症状的出现则相对较晚。因此，在本实验中，我们重点监测孕鼠妊娠第12天(即L-NAME首次给予的五天后)的血压变化，以及收集妊娠第17-18天的24小时尿液并测定总蛋白的水平。同时，我们也记录了各组孕鼠生产的幼仔数量。
实施例4实验结果
孕鼠妊娠第12天的血压检测结果表明(图1-3)，和怀孕对照组相比，怀孕模型组小鼠的平均动脉压、收缩压以及舒张压均有显著的升高，预示本动物模型成功显示出先兆子痫的高血压症状。其中，90mg/kg扎那米韦对血压没有明显改变。但是，120mg/kg扎那米韦给药后可以显著降低L-NAME引起的孕鼠平均动脉压、收缩压以及舒张压的升高,且均 具有统计学显著性差异。
妊娠第17-18天的24小时尿液中总蛋白测定结果表明(图4)，和怀孕对照组相比，怀孕模型组小鼠的24小时尿蛋白有显著的升高，预示本动物模型成功显示出先兆子痫的蛋白尿症状。扎那米韦在90mg/kg和120mg/kg给药后可以显著降低L-NAME引起的孕鼠尿蛋白升高，且均具有统计学显著性差异。
本实验中，我们也记录了各组孕鼠生产的幼仔数量。如图5所示，和怀孕对照组相比，怀孕模型组的孕鼠产仔数量明显减少。扎那米韦在90mg/kg和120mg/kg给药后可以显著改善L-NAME引起的孕鼠产仔数量减少，其中120mg/kg给药组的幼仔数量恢复到和怀孕对照组相当的水平，且具有统计学显著性差异。
综上所述，扎那米韦可以显著改善L-NAME诱导的先兆子痫孕鼠的高血压和蛋白尿症状，并增加孕鼠产仔数量。结果提示扎那米韦对先兆子痫有预防和治疗作用，可以改善母体的高血压和蛋白尿症状，同时也有保护胎儿发育的潜力。

Claims (37)

  1. 扎那米韦在制备治疗或预防先兆子痫的药物中的用途，其中所述扎那米韦包括化合物扎那米韦及其医学或药学上可接受衍生物或盐。
  2. 根据权利要求1所述的用途，其中所述药物剂型为注射剂，口服制剂或外用制剂。
  3. 根据权利要求2所述的用途，其中所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
  4. 根据权利要求1-3任一项所述的用途，其中所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
  5. 治疗或预防先兆子痫的方法，其特征在于，包括向有先兆子痫风险或患有先兆子痫的患者施用扎那米韦。
  6. 根据权利要求5所述的方法，其中所述扎那米韦剂型为注射剂，口服制剂或外用制剂；。
  7. 根据权利要求6所述的方法，其中所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
  8. 根据权利要求5-7任一项所述的方法，其中所述扎那米韦的施用方法可选肌肉注射、静脉注射、静脉输液，优选肌肉注射；每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
  9. 根据权利要求5-8任一项所述的方法，其中所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
  10. 治疗或预防先兆子痫的药物，其特征在于，其中包含扎那米韦。
  11. 根据权利要求10所述的药物，其中所述药物剂型为注射剂，口服制剂。。
  12. 根据权利要求11所述的药物，其中所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂；进一步优选肌肉注射剂。
  13. 根据权利要求10-12任一项所述的药物，其中所述药物包含说明书，说明书中记载扎那米韦的施用方法为每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
  14. 根据权利要求10-13任一项所述的药物，其中所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝 血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
  15. 根据权利要求5-9任一项所述的方法或根据权利要求10-14任一项所述的药物，其中扎那米韦施用量或者说明书中标注扎那米韦施用量为20-40mg/天。
  16. 根据权利要求15所述的方法或者药物，其中扎那米韦施用量或者说明书中标注扎那米韦施用量为20mg/天。
  17. 根据权利要求10-16任一项的药物，还包括药学上可接受的辅料，所述药学上可接受的辅料包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂。
  18. 根据权利要求5-9任一项所述的方法或根据权利要求10-17任一项所述的药物，其中扎那米韦为方法或药物中的唯一有效成分；或者在方法中还包括施用其他有效成分或药物中还包含其他有效成分；所述其他有效成分包括但不限于降血压药，蛋白质补充剂，抗眩晕药，心血管疾病药物。
  19. 神经氨酸酶抑制剂在制备治疗或预防先兆子痫的药物中的用途，其中所述神经氨酸酶抑制剂包括神经氨酸酶抑制剂及其医学或药学上可接受衍生物或盐。
  20. 根据权利要求19所述的用途，其中所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂。
  21. 根据权利要求20所述的用途，其中所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
  22. 根据权利要求19-21任一项所述的用途，其中所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
  23. 治疗或预防先兆子痫的方法，其特征在于，包括向有先兆子痫风险或患有先兆子痫的患者施用神经氨酸酶抑制剂。
  24. 根据权利要求23所述的方法，其中所述神经氨酸酶抑制剂剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂。
  25. 根据权利要求24所述的方法，其中所述注射剂包括注射液、粉针剂；口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂，外用制剂包括软膏剂、喷剂、贴剂。
  26. 根据权利要求23-25任一项所述的方法，其中所述神经氨酸酶抑制剂的施用方法可选 肌肉注射、静脉注射、静脉输液，优选肌肉注射；每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
  27. 根据权利要求25-26任一项所述的方法，其中所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
  28. 治疗或预防先兆子痫的药物，其特征在于，其中包含神经氨酸酶抑制剂。
  29. 根据权利要求28所述的药物，其中所述药物剂型为注射剂，口服制剂。。
  30. 根据权利要求29所述的药物，其中所述药物剂型为注射剂，口服制剂或外用制剂；优选注射剂，口服制剂；特别优选注射剂；进一步优选肌肉注射剂。
  31. 根据权利要求28-30任一项所述的药物，其中所述药物包含说明书，说明书中记载神经氨酸酶抑制剂的施用方法为每周给药1-7次，优选1-4次；更优选1-2次；给药持续时间1-30日，优选1-7日，更优选1-7日。
  32. 根据权利要求28-31任一项所述的药物，其中所述治疗或预防先兆子痫为改善头痛、眼花、恶性、呕吐、腹部不适、高血压，蛋白尿，水肿，肝肾功能，血小板减少和/或凝血系统异常；肌酐、神经氨酸苷酶和唾液酸升高，血液NO水平降低；以及改善妊娠结局。
  33. 根据权利要求23-27项所述的方法或根据权利要求28-32任一项所述的药物，其中神经氨酸酶抑制剂施用量或者说明书中神经氨酸酶抑制剂施用量为20-40mg/天。
  34. 根据权利要求15所述的方法或者药物，其中神经氨酸酶抑制剂用量或者说明书中标注神经氨酸酶抑制剂用量为20mg/天。
  35. 根据权利要求28-34任一项的药物，还包括药学上可接受的辅料，所述药学上可接受的辅料包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂。
  36. 根据权利要求23-27任一项所述的方法或根据权利要求28-35任一项所述的药物，其中神经氨酸酶抑制剂为方法或药物中的唯一有效成分；或者在方法中还包括施用其他有效成分或药物中还包含其他有效成分；所述其他有效成分包括但不限于降血压药，蛋白质补充剂，抗眩晕药，心血管疾病药物。
  37. 根据上述任一权利要求所述的用途、方法或药物，其特征在于，神经氨酸酶抑制剂如扎那米韦施用量为90mg/kg-120mg/kg；优选120mg/kg。
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