CN1090491A - 预防及治疗脓毒症的方法 - Google Patents
预防及治疗脓毒症的方法 Download PDFInfo
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- CN1090491A CN1090491A CN 93118980 CN93118980A CN1090491A CN 1090491 A CN1090491 A CN 1090491A CN 93118980 CN93118980 CN 93118980 CN 93118980 A CN93118980 A CN 93118980A CN 1090491 A CN1090491 A CN 1090491A
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- sodium
- dantrolene sodium
- sepsis
- dantrolene
- pyemic
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
预防和治疗患脓毒症的人或其它哺乳动物的脓
毒症的方法,包括施用安全和有效量的能抑制从肌质
网和/或内质网释放钙的化合物,优选的硝苯呋海因
钠或azuolene sodium。
Description
本发明涉及预防和治疗人类和哺乳动物脓毒症的方法。特别地,本发明涉及预防和治疗脓毒症的方法,该方法包括施用抑制肌质和内质网释放钙的化合物,优选硝苯呋海因钠和/或azumolene sodium。
脓毒症是外科特殊护理和新生儿病房死亡的首要原因。仅在美国,每年就有40万病人患脓毒症。其中,约10万病人最终丧失生命。探讨脓毒症问题严重性的有关多血症的文章表示需要更有效地控制脓毒症参见Glauser,M.P.,et al.,“Septic Shock:pathogenesis”,338 Lancet 732(September 21,1991);Fein,A.M.,et al.,“Sepsis Syndrome”,10(11)Infectious Disease Newsletter 89-96(1991);Parillo,J.E.,“Management of Septic Shock:Present and Future”,115(6)Ann.Intern.Med.491-493(September 15,1991);DiPiro,J.T.,“Pathophysiology and Treatment of gram-negative sepsis”,47(3)American Journal of Hospital Pharmacy S6-S10(November 1990);Bone,R.C.,“The Pathogenesis of Sepsis”,115(6)Ann.Intern.Med.457-469(September 15,1991);Dudley,M.N.,“Overview of Gram Negative Sepsis”,47(3)American Journal of Hospital Pharmacy S3-S6(November 1990);Barriere,S.,et al.,“Gram-negative sepsis,the sepsis syndrome,and the role of antiendotoxin monoclonal antibodies”,11(3)Clin.Pharm.223-235(March 1992)and Murray,M.J.,et al.,“Sepsis and septic shock-Deadly complications that are on the rise”,90(1)Postgraduate Medicine 199-202,205-6,208(July 1991).
外科强化护理和外伤病人最易患脓毒症。脓毒症为一种临床综合症,其特征为白细胞增殖、精神状态改变、呼吸急促、心动过速、代谢性酸中毒、肾及肝功能损伤、低血压和体温过高或体温过低。脓毒症由革兰氏阳性或阴性细菌、病源性病毒、真菌或立克次体或此类感染因子的付产物引起。如果不加以治疗,脓毒症会发展成脓毒性休克,此时病人会表现出脓毒症的全部症状及低血压(收缩压降低到90mmHg以下或降至40mmHg基线收缩压以下)。
在细胞水平上,有证据说明脓毒症导致胞内钙的增加。下述文献描述了维持胞内钙体内平衡的重要性。
Rasmussen,H.,et al.,“Calcium Ion as Intracellular Messenger and Cellular Toxin”,84 Environmental Health Perspective 17-25(1990);Pounds,J.G.,“The Role of Cell Calcium in Current Approaches to Toxicology”,84 Environmental Health Perspectives 7-15(1990);Farber,J.L.,“The Role of Calcium Ions in Toxic Cell Injury”,84 Environmental Health Perspectives 107-111(1990);and Zaloga,G.P.,et al.“Low Dose Calcium Administration Increases Mortality During Septic Peritonitis in Rats”,37 Circul.Shock 226-229(1992).
如果不能维持细胞钙的体内平衡,如在脓毒症中,则胞内钙离子浓度上升可导致酶的激活,所述酶1)水解细胞膜,和2)裂解细胞骨架支柱导致细胞组织的损失,和3)导致控制蛋白合成的细胞DNA裂解。细胞组织的破坏最终导致组织和器官的破坏。见Benson,O.W.等人的“Effect of sppsis on calcium uptake and content in skeletal muscle and regulationin vitro by calcium of total and myofibrillar protei
breakdownoin control and septic muscle:Results from a preliminary study”,106(1)Surgery 87-93。(1989.7)。
目前对脓毒症的治疗包括抗微生物治疗和呼吸及血液动力学维持。然而,尽管运用抗微生物治疗,但仍有许多病人丧失生命。此外,这些病人的验尸检查揭示没有微生物感染的迹象,表明在没有持续感染的情况下,衰弱过程可以持续。由于在脓毒症治疗中维持性及抗微生物疗法仅能提供有限的效用,因此,已经用影响胞内钙体内平衡的化合物进行了研究。
经实验表明电压敏感性钙通道阻滞剂,如异搏停(一种抗高血压剂)能提高诱导狗和小鼠脓毒症的大肠杆菌(E.coli)的存活率。这是以钙通道阻滞剂通过减少从细胞外部进入细胞内部的钙而起作用为前提的。因此,用异搏停治疗阻止了由胞外钙的流入而引起的胞内钙的增加,并且,在异搏停有效地发挥作用的那些细胞中,它可以减少胞内钙超负荷造成的某些有害作用。参见
Bosson,S.,et al.,“Increased Survival with Calcium Antagonists in Antibiotic-Treated Bacteremia”,19 Circulatory Shock 69-74(1986);Bosson,S.,et al.,“Verapamil Improves Cardiac Function and Increases Survival in Canine E.coli Endotoxin Shock”,16 Circulatory Shock 307-316(1985);Lee,H.,et al.,“Protective Action of Calcium Entry Blockers in Endotoxin Shock”,18 Circulatory Shock 193-203(1986).
然而,理论上如异搏停那样,仅能阻断钙进入细胞但它并不能阻止从肌质和内质网释放胞内钙。这样,假定在脓毒症中,从肌质和内质网释放的钙和持续水平的胞内钙激活了导致细胞破坏的酶级联反应。肌肉松弛剂,硝苯呋海因钠和azumolene sodium是已知抑制从肌质网释放胞内钙的化合物。见Physicans Desk Reference,46th Edition(1992)。
利用培养的细胞系的体外研究表明硝苯呋海因钠抑制由肠病源性大肠杆菌(E.coli)引起的胞内游离钙的增加,该大肠杆菌是婴儿期腹泻的致病因素。研究人员认为胞内钙的增加导致了蛋白质的解聚和最终丧失经肠绒毛的吸收能力。见 Baldwin,T.J.等人,“Elevation of Intracellular-Free Calcium Levels in HEp-2 Cell Infected With Enteropathogenic Escherichia coli(E.coli)Infection and Immunity 1599-1604(1991.5)。
相反地,其它研究表明硝苯呋海因对于患脓毒症的大鼠脓毒性肌肉中,全部或肌原纤维蛋白的分解并没有明显影响。参见Benson,O.W.等人的“Effect of sepsis on calcium uptake and content in skeletal muscle and regulation in vitro by calcium of total and myofibribrillar protein breakdown in control and septic muscle:Results from a preliminary study”,106(1)Surgiry 87-93(1987.7)特别是在最近,进行了一项研究以评估将败血症误诊为恶性体温过高时使用硝苯呋海因钠的潜在危险。脓毒症的症状与患恶性体温过高的患者所表现出的症状非常相似。对大鼠和狗进行的研究表明硝苯呋海因钠对患脓毒症的动物并没有不利影响,研究人员得出结论既使在恶性体温过高与脓毒症比较的诊断完全不清楚时,使用该药多半也是安全的。在这些实验中,没有对硝苯呋海因钠治疗脓毒症的效用进行评价。参见Beebe,D.S.等的“Is Dantrolene Safe to Administer in Sepsis”,73 Anesth.Analg.289-294(1991)。
很清楚,硝苯呋海因钠和azumolene sodium用于治疗脓毒症的用途在本领域并未公开。本领域也没有建议将硝苯呋海因钠和azumolene sodium用于治疗脓毒症。另外,使用硝苯呋海因钠和azumolene sodium治疗脓毒症优于使用同样也影响细胞钙的异搏停。异搏停针对在平滑肌、骨胳肌和心肌细胞中占主导地位的电压敏感性钙通道发挥作用。参见Goodman和Gilman的The Pharmacological Basis of Therapeutics,第32章(1990年第8版)。硝苯呋海因钠和azumolene sodium通过肌质和/或内质网直接或间接地进行钙的调节,该肌质网和内质网是细胞内细胞器,钙储存于此,人们发现这类细胞器不仅大量地存在于心肌细胞,平滑肌细胞和骨胳肌细胞,也存在于脑细胞、肝细胞、胰腺细胞和成骨细胞中。这样,化合物例如硝苯呋海因钠和azumolene sodium不仅能在肌肉组织而且能在脓毒症可能损伤的其它主要靶器官中发挥作用。在治疗脓毒症领域中使用硝苯呋海因钠和azumolene sodium是有明显进步性的。
一种预防和治疗患脓毒症的人和其它哺乳动物的脓毒症的方法,包括施用安全及有效量的能抑制从肌质和/或内质网释放钙化合物,优选硝苯呋海因钠和azumolene sodium。
下面为本文中使用的术语定义表:
术语“呼吸急促”,如本文所用,意味着通常以每分钟大于20次呼吸的速率非常快速的呼吸。
术语“肌质网”(复数-sarcoplasmic reticula),如本文所用,意指储存钙的胞内细胞器。肌质网在心肌细胞、平滑肌细胞及骨胳肌细胞中占主要优势。
术语“内质网”(复数-endoplasmic neticula),如本文所用的,意指储存钙的胞内细胞器。内质网在心细胞、肝细胞、肺细胞、胰细胞、脑细胞、肌细胞及成骨细胞中占主要优势。
术语“骨胳肌松驰剂”,如本文所用的,意指通过直接作用于肌肉或作用于神经肌肉接头或作用于中枢神经系统而引起骨胳肌松驰的化合物。硝苯呋海因钠就是通过抑制肌质网和内质网释放钙而直接作用于肌细胞的一个骨胳肌松也剂的例子。氯苯氨丁酸是一种使γ-氨基丁酸(GABA)受体超极化而集中作用的肌松驰剂,琥珀胆碱通过抑制兴奋性突触后电位而作用于神经肌肉接头。胺苯环庚烯(cyclobenzoprine)作用于脑干的中枢神经系统。
术语“败血症”,如本文所用,意指如不加以治疗会导致脓毒症,最终发展为脓毒性休克的一种血液带有的感染。
术语“脓毒性休克”,如本文所用,意指临床症状,其中由脓毒症发展成一种心脏及器官功能明显衰竭的状态。
术语“创伤”,如本文所用,意味着作为,但不局限于汽车事故、飞机坠毁、枪射、航海事故、跌倒、刀伤、刺伤和烧伤的结果而造成的严重的物理伤害。
术语“拟交感神经剂”,如本文所用,意指一种模拟交感神经系统作用的药物。刺激交感神经系统应答身体或心理压力。因此,将模拟交感神经系统活性的药剂用于治疗许多临床疾病,例如体克和心力衰竭。因此,拟交感神经药物,如多巴胺由于刺激心肌β-受体,增加了心脏收缩力。同样地肾上腺素和去氧肾上腺素通过它们对心脏β-受体的作用来刺激心脏。由于脓毒性患者是身体紧张的,并且常伴有心脏功能障碍,可以给这类患者服用拟交感神经剂如多巴胺或去氧肾上腺素。
本文中使用的术语“抗体”,意指应答抗原刺激所形成的并用于中和上述抗原毒性作用的蛋白分子。有五种主要类型的人抗体:IgG、IgA、IgM、IgO和IgE。具体地说,细菌的内毒素是一种可以刺激抗体形成的抗原。可以给脓毒症患者施用应答内毒素抗原所形成的抗体以干扰由内毒素抗原所引起的细胞破坏。
活性物质
本发明的方法中使用的活性物质包括某些骨胳肌松驰剂,最优选的是那些抑制从肌质和/或内质网释放钙的,和那些不一定是骨胳松驰剂,但能抑制经肌质和/或内质网释放钙的化合物。
下列美国专利(引入本文作为参考)描述了用作本文活性物质的一些适宜的化合物:Davis等人的美国专利3,415,821、1968年12.10出版;Conklin等人的美国专利3,689,654,1972年9月5日出版;White的美国专利4,049,650,1977年9月20日出版;和Pong的美国专利4,822,629,1989年4月18日出版。优选的化合物包括硝苯呋海因钠和azumolene sodium。最优选的是硝苯呋海因钠。
硝苯呋海因钠
本发明的方法包括给患脓毒症的人或其它哺乳动物施用安全和有效量的硝苯呋海因钠。硝苯呋海因钠(1-[[5-对-硝基苯基)亚糠基]-氨基]海因钠盐)具有如下结构:
Davis等人的美国专利3,415,821(1968年12月10日出版)描述了硝苯呋海因钠及制备硝苯呋海因钠的方法,在前引入本文作为参考。Conklin等人的美国专利3,689,654(1972年9月5日出版)描述了含硝苯呋海因钠的药物组合物,在前引入本文作为参考。
硝苯呋海因钠是治疗领域中普通专业人员已知的骨胳肌松驰剂。硝苯呋海因钠抑制从肌质网释放钙。参见 Physicans Desk Reference,46th Edition(1992)。硝苯呋海因钠也可用于治疗包括心动过速、呼吸急促和肌肉僵直的恶性体温过高。参见 Physicans Desk Reference,46th Edition(1992)。另外,临床已将它用于治疗包括过度换气、肌肉强直和发烧的强直收缩症状。参见Duce,L.和Vigliette,G.的“The Use of Dantrolene in A case of Severe Tetanic Infection”,51(4)Minerva Anestesiol。147-149(1985);Ortega Cerda,J.J.等人“Dantrolene Sodium in Tetanus Report of a case”,33(1)Rev.Invest.Clin.(Mexico)53-55(Jan-March 1981)和Rocha,H.“MyorelaxantEffect of Dantrolene Sodium in Tetanus”,17 Rev.Inst.Med.Trop.(Sao Paulo)257-262(July-Aug.1975)。
azumolene sodium
本发明的方法包括给患脓毒症的人或其它哺乳动物施用安全和有效量的azumolene sodium。azumolene sodium(1-[[[5-4-溴苯基-2-噁唑基]甲烯基氨基]-2,4-咪唑烷-二酮)具有如下结构:
White的美国专利4,049,650(1977年9月20日出版)描述了azumolene sodium及制备azumolene sodium的方法,在前引入本文作为参考。Pong的美国专利4,822,629(1989年4月18日出版)公开了含azumolene sodium的药物组合物,在前引入本文作为参考。
治疗方法
本发明的方法包括给易感或患有脓毒症的人或其它哺乳动物施安全和有效量的能抑制从肌质和/或内质网释放钙的化合物,优选的是硝苯呋海因钠或azumolene sodium。
短语“安全和有效量的”。如本文所用,意指在合理的医药调节范围内化合物或组合物的量大到足以明显有效地缓解所治疗的症状或病症,但小到足以避免严重的副作用(以合理的有益/危险比率)。本发明的方法所用的药物组合物中的活性成份的安全和有效量随所治疗的特定症状、年龄和所治疗患者的身体状况,疾病的严重性、治疗时间、同期治疗情况、使用的特定活性成份、使用的特定的药物学可接受的赋形剂及包括参与治疗医师的知识和技能在内的这类因素的不同而不同。
脓毒症是与危急护理情形相关的主要问题。当患者的身体异常紧张时产生危急护理情形。具体的危急护理情形包括,但不限于外科手术、创伤及早产。在这些情况下,病人处于异常高度危险的感染中。如果对此类感染不加以控制,则可能导致危胁生命的脓毒症。因此,对脓毒症的治疗通常要求迅速介入。硝苯呋海因钠或azumolene sodium可以0.01mg/Kg至10.0mg/Kg的水平施用。优选的是以0.01mg/Kg/小时至0.5mg/Kg/小时经静脉给患脓毒症的病人施用硝苯呋海因钠或azumolene sodium。更优选地是以0.025mg/Kg/小时至0.35mg/Kg/小时施用。最优选地是以0.05mg/Kg/小时至0.25mg/Kg/小时施用硝苯呋海因钠或azumolene sodium。
也可以通过任何已知的给药方法施用硝苯呋海因钠或azumolene sodium,例如,口服、皮粘膜给药(如表面、舌下、鼻腔内和直肠)非肠道给药(如,经皮下注射、肌内注射、关节内注射、静脉注射)及吸入法给药。因此,具体的给药方式包括,但不限于例如口服、经皮、粘膜、舌下、肌内、静脉、腹膜内、皮下给药及局部用药。
也可以同抗生素共同施用硝苯呋海因钠或azumolene sodium。术语“共同服用”,如本文所用,意指用所有类型的助剂(即,复合)给主体下药:同步地(同时)和继后地(一种药紧随另一种药后(服用)或一种药在另一种药服用片刻后(服用))。例如可以将硝苯呋海因钠或azumolene sodium与某些抗生素药剂包括但不限于青霉素类、头孢菌素类、Ciprofloxacin、红霉素和氨基糖或类抗生素共同服用,Goodman和Gilman的“The Pharmacological Basis of Therapeutics,”第44-49章(1990年第八版)描述了本领域专业人员已知的,并用于本发明方法中的抗生素。另外,喹诺酮内酰胺抗生素也可以与硝苯呋海因钠或azumolene sodium共同服用。用于与硝苯呋海因钠或azumolene sodium共同服用的喹诺酮内酰胺抗生素在下下列文献中得到描述:Demuth等人的世界专利公报WO91/16327和WO91/16310(均于1991年10月31日公开,引入本文作为参考)和EPO公报366,640;366,193;366,189;366,643(均于1990年5月2日公开,一并引入本文作为参考)。
另外,硝苯呋海因钠和azumolene sodium也可以与抗由革兰氏阴性细菌产生的细菌内毒素的抗体共同使用。由革兰氏阴性细菌产生的细菌产生的细菌内毒素为细菌膜脂多糖。脂多糖内毒素触发一系列导致脓毒症,并最终导致脓毒性休克和死亡链锁现象,具体地说,在应答这些脂多糖的存在中,释放出炎症反应介质包括但不限于肿瘤坏死因子、白细胞介素、血小板激活因子、白细胞三烯、前列腺素、干扰素、血小板、舒缓肽。释放炎症反应介质会引起细胞损伤,这种损伤最后导致细胞破坏,并最终导致器官的死亡。参见
Glauser,M.P.,et al.,“Septic Shock:pathogenesis”,338 Lancet 732(September 21,1991);Fein,A.M.,et al.,“Sepsis Syndrome”,10(11)Infectious Disease Newsletter 89-96(1991);Parillo,J.E.,“Management of Septic Shock:Present and Future”,115(6)Ann.Intern.Med.491-493(September 15,1991);DiPiro,J.T.,“Pathophysiology and Treatment of gram-negative sepsis”,47(3)American Journal of Hospital Pharmacy S6-S10(November 1990);Bone,R.C.,“The Pathogenesis of Sepsis”,115(6)Ann.Intern.Med.457-469(September 15,1991);Dudley,M.N.,“Overview of Gram Negative Sepsis”,47(3)American Journal of Hospital Pharmacy S3-S6(November 1990);Barriere,S.,et al.,“Gram-negative sepsis,the sepsis syndrome,and the role of antiendotoxin monoclonal antibodies”,11(3)Clin.Pharm.223-235(March 1992)and Murray,M.J.,et al.,“Sepsis and septic shock-Deadly complications that are on the rise”,90(1)Postgraduate Medicine 199-202,205-6,208(July 1991).
在Barriere等人的“Therapy Reviews Gram Negative Sepsis,the sepsis syndrome the role of antiendotoxin monoclonal antibodies”11(3),Clin.Pharm.223-225(1992年3月)中描述了具体的抗内毒素抗体包括但不限于:HA-IA和E5。HA-IA是由-人细胞系衍生的单克隆IgM抗体。E5为一鼠细胞系衍生的单克隆IgM抗体,参见
Ziegler,E.J.,et al.,“Treatment of gram-negative bacteria and septic shock with HA-IA human monoclonal antibody against endotoxin”,324 N.Engl.J.Med.429-436(1991)and Greenman,R.L.,et al.,“A Controlled Clinical Trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram negative sepsis”,266 JAMA 1097-1102(1991).
另外,也可将抗炎症反应介质的抗体与硝苯呋海因钠或azumolene sodium共同施用。具体地说可以将抗肿瘤坏死因子和白细胞介素的抗体与硝苯呋海因钠或azumolene sodium共同施用。
此外,在患脓毒症期间,因为也可能损害心脏功能,,所以可将硝苯呋海因钠或azumolene sodium与拟产感神经试剂,例如但不限于多巴胺、肾上腺素、去氧肾上腺素共同施用。
Goodman和Gilman的The Pharmacological Basis of Therapeutics,第10章(1990年,第八版)中记述了本领域专业人员已知的并用于本发明方法的拟效感神经药剂。
服用硝苯呋海因钠或azumolene sodium直至消除了脓毒症。为防止脓毒症的有害作用复发,术后脓毒症消退后直至5天应以0.01mg/Kg至10mg/Kg剂量术后施用硝苯呋海因钠或azumolene sodium最好以0.01mg/Kg至0.50mg/Kg的剂量经静脉输注,术后施用硝苯呋海因钠或azumolene sodium。
脓毒症的诊断可以包括,但不限于如下症状;呼吸急促、心动过速、低血压、体温过高、或体温过低、精神状态改变、代谢性酸中毒、(如按通过增高白血及尿氮确定的)肾及肝功能损伤并最终导致丧失肌肉群。用血液培养物来测定感染微生物的存在。已知引起脓毒症的感染微生物包括,但不限于:革兰氏阴性细菌如大肠杆菌(E.coli)、克雷白式杆菌属、绿脓杆菌和肠杆菌;及革兰氏阳性菌如表皮葡萄球菌和粪链球菌。
另外,检测大量的代谢和生理参数以诊断脓毒症。表1列出了这些参数。
表1.诊断脓毒症患者需检测的系列代谢和生理参数
正常范围
1.动脉血气体和血浆电解质
a) 动脉血气体分析包括:
PaO290~100mmHg
PaCO235-40mmHg
PH 7.35~7.42
b) 血浆电解质包括:
Na+135~140mEq/lit
K+3.5~5.0mEq/lit
Ca++9.0~10.6mEq/lit
Mg++1.5~2.5mEq/lit
Cl 95~103mEq/lit
磷、无机 1.8~2.6mEq/lit
2.肾功能
a)24小时尿排出一一可变的,最小尿排出1/2cc/Kg
/hr
b)血清肌酐 0.2~0.6mg/dl
b)血清BUN 8~18mg/dl
c)肌酐清除 120cc/min
3.肝功能
肝细胞损伤的血浆酶表示:
a)SGOT 8~33μ/ml
b)SGPT 1~36μ/ml
c)γGT 2~39μ/ml
4.血液与凝固系统
a)血红蛋白 13~17gm/dl
b)血细胞比容 38~45%
c)白细胞数 4,500~11,000/μl
中性粒细胞 56%
带 3%
嗜酸性细胞 2.7%
淋巴细胞 34%
血小板数 150,000~400,000/μl
5.血浆代谢物
葡萄糖 70~110mg/dl
乳糖 <2.0mg/dl
6.尿氮平衡
-依赖蛋白摄入变化
-病人应处于正性氮平衡
超出所述正常值范围的数据表示是脓毒症。在静脉施用硝苯呋海因钠或azumolene sodium期间,每天检测表1的参数,以确定脓毒症是否在消退。
本发明的方法也包括在患者术前服用硝苯呋海因钠或azumolenesodium。用硝苯呋海因钠术前进行治疗的病人可能是严重外伤的或准备进行会增加感染危险的大手术的患者,例如,但不限于开胸手术或腹腔手术的病人。此类病人以0.01mg/Kg到10.0mg/Kg剂量施用硝苯呋海因钠或azumolene sodium此类患者优选的术前(术前一天)以0.01mg/Kg/小时到0.05mg/Kg/小时的剂量经静脉输注硝苯呋海因钠或azumolene sodium,准备进行大的手术的这类病人也可以术前(术前四小时)在20分钟以上的时间里以2mg/Kg的团块静脉剂量施用硝苯呋海因钠或azumolene sodium。
从外科损伤病人进入急诊室时及治疗创伤的外科手术前,以0.01mg/Kg至10.0mg/Kg的剂量开始给患者,服用硝苯呋海因钠或azumolene sodium,在外伤病人进入急诊室及治疗创伤的外科手术前,优选地以0.01mg/Kg/小时至0.5mg/Kg/小时的剂量静脉施用硝苯呋海因钠或azumolene sodium。
剂量形式
本发明的方法包括静脉服用硝苯呋海因钠或azumolene sodiumo硝苯呋海因钠作为由Procter & Gamble Pharmaceuticals(Norwich,New York)生产的Dantrium
Intravenous可从市场上购买。供应的Dantrium
Intravenous装于70ml小瓶中,该瓶中含有20mg硝苯呋海因钠、3000mg甘露糖醇和足够氢氧化钠,以使当用60ml USP规定的注射用无菌水新配时得到约9.5的PH。
以下非限定实施例描述了本发明方法。
实施例1
一名74岁白种男性患者,因急性腹部疼痛和发烧被收住入医院。该病人被送入手术室,并在术中发现阑尾破裂和肠内容物溢出,且有难闻的感染腹膜腔液。经手术修复,该病人被送入特护病房(S.I.C.U.)。进入S.I.C.U.的重要病征是:
系统性动脉血压-130/70
脉搏-125次/分(窦性心动过速)
温度-39.5℃(直肠)
呼吸-通过机械换气机10次/分。
诊断为腹腔内脓毒症后,开始给病人使用广谱抗生素,并开始静脉输注硝苯呋海因钠(0.025mg/Kg/小时)。
除了测定病人的重要病征(见上文)外,脓毒症期间还要测定一系列实验室参数(见表1)。该患者的症状包括高热、代谢性酸中毒、经升高的血和尿氮确定的肌肉群明显消失、损害的肾功能及异常性出血。
针对该患者恶化的病情,将硝苯呋海因钠的输注剂量提高到0.50mg/Kg/小时。在两至三天后,该病人的临床症状得到改善,表现为发热的消退、酸碱平衡正常、肌肉蛋白裂解的降低(以24小时内尿收集液中的正性氮平衡表示)和血小板数增加及出血减少。继续输注硝苯呋海因钠七天直至脓毒性症状消失。但是在脓毒症症状消退后,仍应继续施用硝苯呋海因钠36小时。他进一步好转并于入院后十天出院。
实施例2
一名因致命疼痛而剖腹产出生的2Kg女婴(早产一个月)。她呈发绀且呼吸异常。给她插入导管,使其复苏并与机械呼吸机相连。两天后,注意到该婴儿呼吸速率加快,血压降低、且体温降低。胸部X-射线表明右下肺叶有一浸润处。开始使用广谱抗生素,并以0.01mg/Kg/小时连续静脉输注硝苯呋海因钠,两天里所取的血液培养物为大肠杆菌阳性。
在脓毒症期间每天进行一组实验室测试(见表1)。在呼吸窘迫和脓毒性症状的消退方面的逐渐改善显示该病人的情况有所好转。代谢性酸中毒消失;肌肉蛋白裂解减少(尿氮排出减少);升高的白血球数恢复到正常。继续输注硝苯呋海因钠五天直至脓毒症消除。无论如何,在脓毒性病程消除后继续施用硝苯呋海因钠24小时。该婴儿在接下来的两周里需呼吸机维持呼吸,但最终能取下导管并完全康复。
实施例3
一名45岁黑人女性患者,她因贫血和粪(便)中带血住入院。检查显示有一大直肠癌肿,该癌肿经手术切除。手术后三天,发现该病人高烧(39.8℃),发冷打战,并且呼吸窘迫。她被转到特护病房(S.I.C.U.),且检查显示手术愈合部位有一渗漏。她被带入手术室进行转移结肠造口术。注意到腹部有明显的感染。术后她又被送回S.I.C.U.,其住院病情显示如下:
1.血液动力学不稳定性-动脉血压降低
2.极度高烧
3.血中葡萄糖浓度升高
4.代谢性乳酸性酸中毒
5.肾功能减低-(肌酐增加和排出尿液减少)。
6.白血球数升高
开始给该病人使用广谱抗生素。由于血液动力学不稳定性和休克期间,给表现出心脏收缩功能降低(心脏射血量4.0升/分)的该病人安插了肺动脉导管,心搏排出量仅为40ml,且肺毛细管边缘压为22mmHg。
该病人开始服用多巴胺5mg/Kg/分钟以提高动脉压改善心脏收缩功能。开始连续静脉输注硝苯呋海因钠(0.025mg/Kg/小时)。输注硝苯呋海因钠30分钟后,心脏输出量和收缩功能得到改善。心脏输出量从4.0升/分提高到5.5升/分,且心搏排出量也从40ml增至60ml。
该病人的病情进一步好转,在以后的两天,血液动力学更加稳定。在她退烧后两天,继续输注硝苯呋海因钠,共计输注了四天硝苯呋海因钠。根据每天对其脓毒症病程的监测,对该病人进行表1中所包括的全面的实验室检测。
实施例4
一名24岁白种男性患者,该病从因长期肾衰,在六个月前进行了死者肾的移植。他因极度高烧并有尿道感染迹象而住入医院。取得血和尿培养物,并开始广谱抗生素治疗。由于血液动力学不稳定性和肾功能减低,开始连续静脉输注硝苯呋海因钠(0.025mg/Kg/小时)。
在特护病房密切监视该患者,并测试一系列代谢和生理参数(见表1)。由血清中肌酐升高和尿排出量的减少表明肾功能减低。血清肌酐稳定在4.0mg/dl,且尿排出量仅达30ml/小时。输注硝苯呋海因钠四天后,该病人的住院病情得到持续改善,且发热和脓毒性症状消退。
Claims (10)
1、一种抑制从肌质网和内质网释放钙的化合物在制备治疗或预防患脓毒症的人或其它哺乳动物的脓毒症的药物中的用途,包括施用安全和有效量的能抑制经肌质网或内质网释放钙的所述化合物。
2、一种抑制从肌质网或内质网释放钙的骨胳肌松驰剂在制备治疗或预防患脓毒症的人或其它哺乳动物的脓毒症的药物中的用途,包括施用安全和有效量的所述骨胳肌松驰剂。
3、硝苯呋海因钠或azumolene sodium,优选硝苯呋海因钠在制备治疗或预防患脓毒症的人或其它哺乳动物的脓毒症的药物中的用途,包括施用安全和有效量的所述硝苯呋海因钠或azumolene sodium。
4、根据权利要求1的化合物的用途,其中所述化合物的安全和有效量为从0.01mg/Kg至10.0mg/Kg。
5、根据权利要求2的骨胳肌松驰剂的用途,其中所述的骨胳肌松驰剂的安全和有效量为从0.01mg/Kg至10.0mg/Kg。
6、根据权利要求3的硝苯呋海因钠的用途,其中所述的硝苯呋海因钠的安全和有效量为从0.01mg/Kg至10.0mg/Kg。
7、根据权利要求1的化合物的用途,其中所述化合物的安全和有效量为从0.01mg/Kg/小时到0.50mg/Kg/小时。
8、根据权利要求3的硝苯呋海因钠的用途,其中硝苯呋海因钠的安全和有效量为从0.01mg/Kg/小时至0.50mg/Kg/小时。
9、根据权利要求1的化合物的用途,其中所述化合物与抗生素经静脉输注同时施用。
10、根据权利要求3的硝苯呋海因钠的用途,其中所述硝苯呋海因钠与抗生素经静脉输注同时施用。
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