Prostaglandin metabolism and prostacyclin in cerebral vasospasm

1. Contractions of isolated human pial arteries, induced either by exposition to hemorrhagic cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage and cerebral vasospasm or by exposition to noradrenaline, were markedly augmented after preincubation of the vessel segments with the cyclooxygenase inhibitor indomethacin, while serotonin-induced contractions were unaffected. 2. Prostacyclin relaxed human pial arteries contracted by either PGF2 alpha, noradrenaline, serotonin or hemorrhagic CSF. The same though less marked effects were obtained with 6-keto-PGE1. 3. The results support the contention that an intact vascular prostacyclin synthesis is important for the maintenance of a normal cerebrovascular tone, and that disturbances of the prostaglandin metabolism may be a prerequisite for the development of arterial spasm after aneurysmal subarachnoid hemorrhage. Tentatively. 4. a prostacyclin deficiency may be involved in the pathogenesis of delayed cerebral vasospasm after subarachnoid hemorrhage.     

蛛网膜下腔出血行腰椎穿刺置管持续稳压引流的疗效分析

目的探讨腰椎蛛网膜下腔置管持续引流对蛛网膜下腔出血(SAH)的疗效。方法:对63例SAH患者进行治疗:治疗组(33例)实施腰椎蛛网膜下腔置管持续流脑脊液,对照组(30例)行间断腰椎穿刺放脑脊液。结果:治疗组头痛或轻程度,痊愈率明显优于对照组,脑血管痉挛、脑积水发生率明显低于对照组,未增加再出血、脑疝发生率及病死率。结论:腰椎蛛网膜下腔置管持续稳压引流脑脊液是一种安全、有效的治疗SAH的方法。     

Cerebral Vasospasm and Calcium Channel Blockade. Nimodipine treatment in patients with aneurysmal subarachnoid hemorrhage

Abstract: In patients with aneurysmal subarachnoid hemorrhage (SAH), delayed ischemic cerebral dysfunction (DID or symptomatic vasospasm) with subsequent fixed neurological dysfunction (FND) is a frequent and most feared complication induced by the hemorrhage. Aneurysm operation during the acute stage with intraoperative evacuation of bloodcontaminated cerebrospinal fluid (CSF) from the basal cisterns and subarachnoid spaces has reduced this complication. Nevertheless despite early operation, DID with FND occurs in 13 – 20% or more. In a series of 100 individuals with a ruptured supratentorial aneurysm, who were subjected to aneurysm operation in the acute stage and who subsequently received intravenous treatment with the calcium channel blocker nimodipine, the occurrence of DID with FND was reduced to 5%.     

脑脊液置换及鞘内注射地塞米松治疗蛛网膜下腔出血的疗效分析

目的观察脑脊液(CSF)置换法及鞘内注射地塞米松治疗蛛网膜下腔出血(SAH)的疗效.方法在常规治疗的基础上,行腰椎穿刺,缓慢放出血性脑脊液4～6 ml,再缓慢注入等量生理盐水,如此反复置换后加地塞米松5 mg鞘内注射.结果除2例分别因再出血致脑疝死亡及上消化道大出血死亡外,29例置换后头痛等临床症状能迅速缓解,平均5.3 d.较对照组11.2d明显缩短,死亡率也明显降低.结论脑脊液置换法配合鞘内注射地塞米松的应用可缓解头痛,减轻脑水肿、防止蛛网膜粘连、脑积水和脑血管痉挛,减少并发症,缩短病程,提高治愈率.     

α1-Acid Glycoprotein Concentrations and Cerebrospinal Fluid Drug Distribution after Subarachnoid Hemorrhage

Study Objective . To test the hypothesis that changes in α₁-acid glycoprotein (AAG) concentration alter central nervous system (CNS) drug distribution after subarachnoid hemorrhage. Design . Two-phase, prospective study. Setting . University-associated medical center. Patients . Twenty-one patients with subarachnoid hemorrhage. Intervention . In phase I, serum AAG concentrations of patients with subarachnoid hemorrhage were measured serially and compared with those in 21 controls undergoing elective neurosurgical procedures. In phase II, nimodipine was the pharmacologic probe to determine the relationship between drug distribution into the CNS and changes in AAG concentration. Measurements and Main Results . Serum and cerebrospinal fluid (CSF) samples were collected from patients with subarachnoid hemorrhage treated with nimodipine and used to measure total and unbound drug concentrations. Concentrations of AAG were 39% higher in patients than in controls preoperatively. They decreased significantly by 24 hours after surgery in patients and increased in controls. In both groups the concentrations were higher than reported normal values. During the period of reduced AAG concentration, calculated unbound nimodipine concentrations were 3-fold higher (p<0.05) than at later periods, with a trend toward higher total concentrations. Overall, mean CSF nimodipine concentration was 6.4% of mean serum total concentration. The CSF concentrations decreased as AAG concentrations increased, independent of serum concentrations (r = −0.52, p<0.02). Conclusion . Concentrations of AAG change after subarachnoid hemorrhage and are transiently influenced by surgery. Unbound drug concentration increases when AAG concentrations decrease, whereas CSF concentrations decrease when AAG concentrations increase. These preliminary findings suggest that changes in AAG concentrations can alter unbound serum nimodipine concentrations and may affect CSF drug distribution.     

颈淋巴阻断加重SAH脑脊液对PC12细胞的损伤

目的探讨脑淋巴引流途径在蛛网膜下腔出血(SAH)后神经元损伤中的作用。方法建立兔SAH及脑淋巴引流阻滞(CLB)模型,于SAH模型建立后5d抽取脑脊液加入培养的PC12细胞中,随机将PC12细胞分为空白对照组、正常对照组(正常脑脊液)、SAH脑脊液组,SAH+CLB脑脊液组,分别于培养0.5、1、2、4h后,用比色法测定乳酸脱氢酶(LDH)释放率,采用免疫荧光染色法激光共聚焦显微镜观察PC12细胞细胞骨架。结果与正常对照组比较,SAH脑脊液组PC12细胞LDH释放率增加;SAH+CLB脑脊液组LDH释放率明显高于SAH脑脊液组。正常脑脊液不引起PC12细胞细胞骨架改变,SAH脑脊液组及SAH+CLB脑脊液组PC12细胞胞质着色较弱,突起变短甚至回缩,胞核呈现凋亡特征,上述表现以SAH+CLB组更为明显。结论脑淋巴引流阻滞加重SAH脑脊液对PC12细胞的损伤,提示通过改善脑淋巴引流途径可减轻SAH继发性脑损伤。     

米诺环素对动脉瘤性蛛网膜下腔出血后神经保护作用的研究进展

米诺环素是四环素类广谱抗菌药,临床上用于治疗常见敏感病原菌引起的感染。近期研究发现米诺环素对动脉瘤性蛛网膜下腔出血后损伤体现出神经保护作用。米诺环素主要通过抗炎、抗凋亡、抑制基质金属蛋白酶-9等抗菌外作用减轻动脉瘤性蛛网膜下腔出血引发的早期脑损伤和迟发性脑血,且由于其良好的安全性和耐受性,对动脉瘤性蛛网膜下腔出血的辅助治疗具有一定潜力。本文就米诺环素对动脉瘤性蛛网膜下腔出血的神经保护作用及其可能机制进行综述,为后续深入研究及设计开展临床试验奠定基础。     

Variations between individuals in cerebrovascular responsiveness

1. Despite extensive research no explanation has been put forward to account for the fact that cerebral arterial spasm complicates the course of disease of many but not all patients suffering from rupture of an intracranial aneurysm. Although vasoactive material in hemorrhagic cerebrospinal fluid (CSF) most probably is of major importance in the pathophysiology of delayed cerebral vasospasm, recent studies have failed to demonstrate a correlation between CSF vasoconstrictor activity and the development of delayed cerebral vasospasm. 2. In the present study the reactivity of isolated human pial arteries to various vasoactive agents [prostaglandin F2 alpha, noradrenaline, serotonin, human plasma and CSF from patients with aneurysmal subarachnoid hemorrhage (SAH)] was investigated. 3. There was a very marked variability in the spectrum of responses between arteries from different individuals with regard to the contractile responses to plasma, hemorrhagic CSF and amines. On the other hand, the contractions produced by prostaglandin F2 alpha and potassium were consistent. 4. The markedly individual profile in terms of reactivity toward vasoactive substances emphasizes the importance of a human cerebral vessel wall factor and may explain the capricious occurrence of cerebral vasospasm after aneurysmal SAH.     

Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage

Erythropoietin exerts a neuroprotective effect during cerebral ischemia. We investigated the effect of systemic administration of recombinant human erythropoietin in a rabbit model of subarachnoid hemorrhage-induced acute cerebral ischemia. The animals were divided into three groups: group 1, subarachnoid hemorrhage; group 2, subarachnoid hemorrhage plus placebo; group 3, subarachnoid hemorrhage plus recombinant human erythropoietin (each group, n=8). Experimental subarachnoid hemorrhage was produced by injecting autologous blood into the cisterna magna. Treatment with recombinant human erythropoietin and placebo was started 5 min after subarachnoid hemorrhage and was continued every 8 h for 24 h. Before the animals were killed, erythropoietin concentration was measured in the cerebrospinal fluid. The rabbits were killed 24 h after subarachnoid hemorrhage and ischemic brain injury was histologically evaluated. In group 3, the concentration of erythropoietin in the cerebrospinal fluid was significantly increased and a significant reduction in cortical necrotic neuron count was also observed. These findings may encourage the use of erythropoietin in the treatment of cerebral ischemia that often occurs in the early stage of subarachnoid hemorrhage.     

西洛他唑治疗动脉瘤性蛛网膜下腔出血的作用机制和临床研究进展

动脉瘤性蛛网膜下腔出血后的迟发性脑缺血是患者严重残疾甚至死亡的主要原因，迟发性脑缺血形成的主要危险因素是脑血管痉挛。西洛他唑是磷酸二酯酶Ⅲ的选择性抑制剂，可舒张血管、抗脂质过氧化、抗血管炎症因子、抑制基底动脉的表型转化和内皮损伤以及抑制腱糖蛋白-C。近年来一系列临床试验表明西洛他唑单用或者联合使用可有效治疗动脉瘤性蛛网膜下腔出血后的脑血管痉挛，进而改善迟发性脑缺血。回顾了西洛他唑在动脉瘤性蛛网膜下腔出血中的作用机制和临床研究，为进一步研究西洛他唑在动脉瘤性蛛网膜下腔出血中的应用提供参考。     

Safe and efficient drug delivery system with liposomes for intrathecal application of an antivasospastic drug, fasudil

Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents.     

Clinical evaluation of cefotiam in the cerebrospinal fluid of patients with ruptured cerebral aneurysms in the acute stage

The treatment of the patients with ruptured cerebral aneurysm in acute stage is performed by direct neck clipping and cisternal drainages for preventing vasospasm. The cisternal drainage is carried out for 1 to 2 weeks' duration. The cisternal drainage has higher risk for bacterial infections in the cerebrospinal fluid (CSF). In this paper, penetration characteristics of cefotiam (CTM) in CSF were studied. CTM concentrations in CSF were measured at 1, 3 and 6 hours after intravenous drip infusion of CTM (2 g). CTM concentration in cisternal CSF was higher than that of ventricular CSF. The peak concentration in CSF was higher than 0.78 micrograms/ml and obtained at 3 hours after intravenous drip infusion. Our data suggest that CTM is a useful cephalosporin for treatment of meningitis (Staphylococcus aureus, Streptococcus pneumoniae et al.). Apart from meningitis, the higher concentration of CTM in CSF was obtained in the cases with the vasospasm. The result may support that the breakdown of blood brain barrier is induced by the peroxidative substance from the cisternal subarachnoid clots which has the vasospastic activity.     

Transfer of cefotaxime to the pelvic organs (author's transl)

The new antibiotic cefotaxime (HR 756, CTX) has been proved to be clinically effective against infections observed in the field of obstetrics and gynecology. The present study was intended to investigate the transfer of CTX to the internal genital organs and the dead pelvic space. The results were obtained as follows: 1. The concentrations of CTX transferred to the uteri and its appendages after CTX 1 g intravenous injection were sufficiently effective against the major pathogens (Gram-negative and anaerobic bacteria) demonstrated in the field of obstetrics and gynecology. 2. The concentrations of CTX transferred to the dead space of the pelvis were effective against almost all of the Gram-negative bacteria for 6 to 12 hours after CTX 1 g or 2 g intravenous injection. CTX was thus proved to be very effective for the prevention and treatment of infections of the dead pelvic space.     

Alpha-adrenoceptors in human and animal cerebral arteries: alterations after sympathetic denervation and subarachnoid hemorrhage

Vasospasm of cerebral arteries in patients with subarachnoid hemorrhage frequently presents severe clinical problems resulting from cerebral ischemia, but the pathogenesis of vasospasm is still poorly understood. The contractile response of human cerebral arteries to noradrenaline is larger than the responses in other species. Neurogenic factors controlling brain circulation may play an important role in pathological conditions such as subarachnoid hemorrhage. Motohatsu Fujiwara and colleagues review species variations of alpha-adrenoceptors in cerebral arteries and their alterations after surgical sympathectomy. They compare these changes to those occurring in human cerebral arteries following subarachnoid hemorrhage and discuss their relationship to vasospasm.     

Use of nimodipine for prevention and treatment of cerebral arterial spasm in patients with subarachnoid hemorrhage

The chemistry, pharmacology, pharmacokinetics, adverse effects, dosage, and availability of nimodipine are discussed, and the clinical use of nimodipine in preventing and treating cerebral arterial spasm in patients with subarachnoid hemorrhage is reviewed. Nimodipine is a highly lipid-soluble dihydropyridine derivative that readily crosses the blood-brain barrier. In animal studies, nimodipine has been shown to be effective in increasing cerebral blood flow; preventing vasoconstriction attributable to sympathetic stimulation, hypocapnia, and hypertension; and improving neurological outcome after cerebral ischemia. Nimodipine is reported to be 90% protein bound; its half-life is approximately 13 hours, with substantial interpatient variability. Nimodipine has been studied in the prevention and treatment of cerebral arterial spasm in patients with subarachnoid hemorrhage. In four open trials, in which nimodipine was administered orally, intravenously, topically during surgery, or by intracarotid injection, and in two double-blind, placebo-controlled trials, neurological outcomes were improved in patients receiving the drug. However, in both sets of trials nimodipine had limited effects on cerebral arterial spasm. Although nimodipine can cause hypotension, no serious adverse reactions to the drug were reported in clinical trials in patients with subarachnoid hemorrhage. Based on limited data currently available, nimodipine appears to improve neurological outcome in patients with subarachnoid hemorrhage. However, its efficacy in preventing or treating cerebral arterial spasm in these patients seems to be limited.     

腰穿置管稳压引流治疗蛛网膜下腔出血后脑积水

目的探讨蛛网膜下腔出血(SAH)后脑积水简便、安全、有效的治疗方法。方法所收治的283例SAH病人中有90例发生了急性脑积水,在内科治疗基础上,其中46例进行了腰穿置管稳压引流治疗结果与无脑积水者对照比较。结果上法治疗后32例(32/46,70%)意识水平均有所改善;所有受治病人12d内再出血和脑缺血的发生率与无脑积水的病人组无显著性差异〔5/46(11%),24/193(12%);16/46(35%)60/193(31%)。P>0.05〕。治疗组未发生脑室炎或脑膜炎。结论腰穿置管稳压引流是一种治疗SAH后脑积水简便、安全、有效的方法。     

Nitric Oxide Concentrations and Cerebrospinal Fluid Parameters in an Experimental Animal Model of Streptococcus pneumoniae Meningitis

Streptococcus pneumoniae is a common cause of meningitis. Nitric oxide (NO) has been implicated in causing cerebral edema. Modulating NO production in cerebrospinal fluid (CSF) may have a role in the treatment of bacterial meningitis. Experimental S. pneumoniae meningitis was induced in a rabbit model to determine CSF parameters and NO concentrations. An electrochemical probe in the CSF throughout the 7-hour experiment monitored NO concentrations. The animals had S. pneumoniae (10⁵) injected intracisternally and incubated for 1 hour. Cerebrospinal fluid 200–300 μl was obtained by intracisternal puncture at zero, 2, 4, and 7 hours after drug administration to measure glucose, protein, and lactic acid by standard chemical methods. White blood cell count was measured by hemocytometry. Three groups of five animals were used—control (C), ceftriaxone (CTX), and ceftriaxone plus dexamethasone (CTX+D). Ceftriaxone concentrations in CSF were obtained by microdialysis and analyzed by high-performance liquid chromatography. Mean (± SEM) CSF white blood cell count was significantly higher at 2 hours in the C group than in the other two groups (C 7307 ± 1302, CTX 605 ± 345, CTX+D 730 ± 43/mm³, p<0.002). Ceftriaxone induced a significant rise in protein at 4 hours compared with the other groups (C 364 ± 107, CTX 1158 ± 797, CTX+D 365 ± 100 mg/dl, p<0.02). Cerebrospinal fluid lactic acid was significantly different at 4 and 7 hours between C and CTX+D groups (4-hr C 8.0 ± 2.2, CTX+D 2.0 ± 0.4 mmol/L, p<0.05; 7-hr C 10.2 ± 2.4, CTX+D 2.8 ± 0.8 mmol/L, p<0.01). Median NO concentrations were significantly elevated in the control group compared with the other two groups (C 11.7, CTX 6.8, CTX+D 6.5 μM, p<0.02 C vs CTX, p<0.01 C vs CTX+D). Average (± SEM) NO concentrations were significantly higher in the C group at 4 hours (18.1 ± 0.4, CTX 5.8 ± 1.8 μM, p<0.05; CTX+D 11.5 ± 4.0 μM, p>0.05), whereas they did not rise significantly until 7 hours in the CTX group (CTX 18.7 ± 0.7, C 8.9 ± 0.4 μM, p=0.055; CTX+D 8.1 ± 2.2 μM, p<0.05). These results indicate that ceftriaxone with or without dexamethasone significantly decreases lactic acid concentrations and white cell penetration into the CSF in an experimental model of S. pneumoniae meningitis. In addition, ceftriaxone induced a significant elevation in CSF protein. Median NO production in the CSF was significantly attenuated by ceftriaxone.     

The penetration of cefotaxime into the cerebrospinal fluid. Comparison between acute and chronic stages in intracranial diseases

Two grams of cefotaxime (CTX) were administrated by drip infusion to 10 patients (11 material) with acute or chronic stage of intracranial diseases. Concentrations of CTX in the serum and the cerebrospinal fluid (CSF) were determined at 15, 30, 60, 120, 240 and 300 minutes after injection. The results obtained were summarized as follows: Serum levels: Peak levels of CTX in sera were 66.2 +/- 10.23 (S.E.) micrograms/ml in the acute stage group (ASG), and 75.7 +/- 31.39 (S.E.) micrograms/ml at 15 minutes after injection in the chronic stage group (CSG). There were no significant difference between the 2 groups. CSF levels: Peak levels of the drug in CSF were 1.35-4.32 micrograms/ml in ASG and 0.18-0.7 microgram/ml in CSG. Average concentration at 60 minutes after injection was 1.11 +/- 0.09 (S.E.) micrograms/ml in ASG and 0.30 +/- 0.08 (S.E.) micrograms/ml in CSG. The value in ASG was significantly higher than the value in CSG by t-test. The ratio between CSF and serum levels: The levels increased as time passed in both groups and the values in ASG were higher than those in CSG at all time points. Average ratios at 60 minutes after injection were 3.85 +/- 0.29 (S.E.)% in ASG and 1.12 +/- 0.50 (S.E.)% in CSG. The value in ASG was significantly higher than that in CSG by t-test. From the above results, it is considered that CTX is useful for the prophylaxis of postoperative infections in intracranial diseases.     

尼莫地平对蛛网膜下腔出血后脑血管痉挛模型兔血浆BNP和ET-1表达水平的影响

目的探讨尼莫地平（ND）对蛛网膜下腔出血（SAH）后脑血管痉挛（CVS）兔血浆脑利钠肽（BNP）和内皮素-1（ET-1）含量的影响。方法采用枕大池二次注血法建立兔CVS模型。将40只成年日本大耳白兔随机均分为单纯SAH组（SAH组）和ND治疗组（ND组）。观察两组实验动物的食量及神经功能评分,分别采用酶联免疫吸附测定法（ELISA）和放射免疫法（R IA）检测血浆BNP、ET-1含量,并用经颅多普勒超声（TCD）动态观察两组家兔术前1天和术后第1、4、7、10、14天的基底动脉（BA）血流速度。结果两组家兔注血后第1天血浆BNP水平开始升高（P〈0.05）,ET-1虽较术前有所升高但无统计学意义（P〉0.05）,4-7 d BNP、ET-1均达到高峰（P〈0.05-0.01）,且随着时间的推移有逐渐降低的趋势;ND组BNP及ET-1含量增加的程度明显低于SAH组（P〈0.05-0.01）,但仍显著高于术前对照组（P〈0.05）;两组家兔术后BA血流速度的动态变化趋势与其血浆BNP、ET-1的变化基本一致。结论 SAH后血浆BNP、ET-1含量增多参与了CVS的过程,与CVS的发生、发展密切相关;ND可降低SAH后CVS时血浆BNP、ET-1的水平。