Clinical trial of nicardipine prolonged-release implants for preventing cerebral vasospasm: multicenter cooperative study in Tokyo.

BACKGROUND: since October 1999, nicardipine pellets (NP) have been used to prevent vasospasm in patients with subarachnoid hemorrhage (SAH). We started a multicenter cooperative study on Jan 1, 2007, and 136 patients in six hospitals were enrolled to this trial in 2 years. The incidence of cerebral vasospasm and outcome were examined in these patients. METHODS: the patients with SAH were treated with NP during surgery after clipping of their aneurysms. FINDINGS: the study included 87 female patients, 38 over 70 years old, 34 in grades 4 and 5, and 46 of Fisher group 2 or 4. Aneurysms were located on anterior circulation in 133, posterior in 3. All patients were treated with Fasudil hydrochloride except for 3. Two to twelve pellets were implanted in the cistern where thick clots existed and vasospasm was highly likely. Delayed ischemic neurological deficits (DIND), angiographical vasospasm and cerebral infarctions were seen in 11 of 134 (8.2%), 32 of 130 patients (24.6%), and 16 of 129 (12.4%), respectively. No complications were experienced. Independent rate at 3 months was 78%. CONCLUSIONS: the incidence of cerebral vasospasm in this multicenter trial is similar to that of our first trial performed in a single center.

Risk factors for regrowth of intracranial meningiomas after gamma knife radiosurgery: importance of the histopathological grade and MIB-1 index.

INTRODUCTION: The influence of histopathological grade and MIB-1 index of intracranial meningioma on the results of its radiosurgical management is not clear. The objective of the present retrospective study was to make an evaluation of these factors along with an analysis of other variables associated with progression-free survival after gamma knife radiosurgery (GKR). PATIENTS AND METHODS: Thirty-four intracranial meningiomas with known detailed histopathological diagnosis were analyzed. Tumors of WHO histopathological grades I, II, and III were diagnosed in 24, 3, and 7 cases, respectively. The median MIB-1 index was 1.3% (range: 0-31.9%). In 14 cases the MIB-1 index was 3.0% and more. In 26 cases the treatment was done at the time of tumor recurrence. Median volume of the neoplasm at the time of GKR was 4.1 mL (range: 0.4-43.1 mL). Median marginal dose was 12 Gy (range: 8-19 Gy). Median length of follow-up constituted 63 months (range: 19-132 months). RESULTS: Actuarial progression-free survival at 1, 3, 5, and 10 years constituted 100, 94, 83, and 58%, respectively. Histopathological grade II or III (p<0.0001), MIB-1 index 3% and more (p=0.0004), and non-skull base location (p=0.0026) of the tumor showed negative associations with progression-free survival in multivariate analyses. Actuarial progression-free survival at 5 years after GKR for benign and non-benign meningiomas constituted 100 and 45%, respectively (p<0.0001). CONCLUSION: Radiosurgery is a highly effective management option for benign intracranial meningiomas, but growth control of non-benign ones is significantly worse. It requires close neuroradiological follow-up and necessitates the search for modified treatment strategies.

Suitability of a US3-inactivated HSV mutant (L1BR1) as an oncolytic virus for pancreatic cancer therapy.

Recently, the use of oncolytic viruses against cancer has attracted considerable attention. We studied the potential of the US3 locus-deficient herpes simplex virus (HSV), L1BR1, for oncolytic virus therapy. Its high specificity and potency indicate that L1BR1 is a promising candidate as a new oncolytic virus against pancreatic cancer. Moreover, the virus exhibited the unique characteristic of increasing apoptosis when used in combination with anticancer drugs. We assessed the feasibility of using the US3 locus-deficient HSV named L1BR1 as a new replication-competent oncolytic virus for the treatment of pancreatic cancer. The US3 locus of HSV has been shown to be a key gene in producing a multifunctional protein kinase that inhibits apoptosis induced by viral infections, chemicals and ultraviolet (UV) light. L1BR1 has been reported to be more than 10 000-fold less virulent than the parental virus in mice. In this study, we examined the tumor specificity and oncolytic effect of this attenuated replication-competent virus, L1BR1, in pancreatic cancers derived from SW1990, Capan2 and Bxpc-3cells compared with the parent virus and other well-known oncolytic herpes viruses (R3616 and hrR3). We also studied the efficacy of L1BR1 for the induction of apoptosis as an attribute of this virus in combination with the anticancer drugs 5FU and cisplatin. The combined treatment of the pancreatic cancer cells with L1BR1 and these anticancer drugs enhanced apoptosis significantly. More importantly, L1BR1 showed the lowest replication capacity in normal human hepatocytes, but the highest tumor-reducing effect in vivo among the oncolytic herpes viruses tested. In addition, L1BR1 significantly increased the induction of apoptosis of cancer cells when treated in combination with anticancer drugs although the parental virus inhibited the induction of apoptosis. These results suggest that L1BR1 is promising as a new anticancer oncolytic virus.

Enhanced efficacy of herpes simplex virus mutant HF10 combined with paclitaxel in peritoneal cancer dissemination models.

BACKGROUND/AIMS: Oncolytic viral therapy is used worldwide. Many genetically engineered viruses have been evaluated for their potential as a new therapeutic agent for cancer. HF10, herpes simplex virus (HSV) type-1 clone, has remarkable anti-tumor effects, based on our previous research. In this study, we investigated the ability of HF10 to infect and lyse murine colon cancer cells, CT26, in vitro, and tested its efficacy in an immuno-competent animal model of colorectal cancer. Further, we attempted to evaluate HF10/paclitaxel combination therapy. METHODOLOGY: In vitro, viral replication and cytotoxicity of HF10 against CT26 was observed. In vivo, BALB/c mice harboring carcinomatous peritonitis of CT26 cells were treated with HF10, paclitaxel or HF10 combined with paclitaxel. RESULTS: HF10 is effective for peritoneal dissemination without ascites. The combination of HF10 and paclitaxel prolonged survival of mice bearing carcinomatous dissemination of CT26 compared with the controls, HF10 alone and paclitaxel alone. Paclitaxel did not suppress viral replication and cytotoxicity of HF10. CONCLUSIONS: These results indicate that the combination of HF10 and paclitaxel had a remarkable effect as a cancer therapy and this method is applicable to almost all advanced cancers. This new combination therapy is a potentially epoch-making cancer therapy.

Endothelin-1 is not involved in serotonin-induced coronary spasm in a swine model.

OBJECTIVES: The role of endothelin-1 (ET-1) in the pathogenesis of coronary artery spasm is not well understood. We aimed to determine if ET-1 is involved in serotonin-induced coronary spasm in the swine model. METHODS: In 10 miniature pigs, a segment of the left anterior descending coronary artery was denuded and irradiated with X-ray. Three months after endothelial denudation, coronary vasomotion was assessed in vivo by quantitative arteriography. RESULTS: Intracoronary serotonin at 10 micrograms/kg provoked coronary spasm (augmented narrowing of the luminal diameter) at the denuded site (diameter reduction 93 +/- 4%) but not at the non-denuded control site (19 +/- 4%, P < 0.01) associated with ST segment elevation in the region perfused by the denuded artery. Intracoronary administration of ET-1 at 25 ng/kg caused mild vasoconstriction of the denuded (26 +/- 4) and non-denuded site (16 +/- 3%, n.s.), but provoked ST segment elevation in the regions perfused by both the denuded and non-denuded arteries. The treatment with an endothelin antagonist (BQ123 0.1 mg/kg) significantly attenuated coronary vasoconstriction and ST segment elevation evoked with ET-1, but did not alter serotonin-induced vasoconstriction either at the denuded or control site. CONCLUSIONS: The results of this study suggest that endogenous ET-1 may not be involved in the pathogenesis of serotonin-induced coronary spasm in our swine model.

Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The possible role of inflammatory reaction of the cerebral artery in the pathogenesis of cerebral vasospasm has been noted in recent studies. We quantitatively measured the levels of expression of genes related to inflammation in the spastic artery in a canine double-hemorrhage model. METHODS: Twenty dogs were assigned to 4 groups: group D0, control; group D2, dogs killed 2 days after cisternal injection of blood; group D7, dogs given double cisternal injections of blood and killed 7 days after the first injection; and group D14. Angiography was performed twice: on the first day and before the animals were killed. Total RNA was extracted from the basilar artery. The expressions of interleukin (IL)-1alpha, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, E-secretin, fibronectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, transforming growth factor-ss, basic fibroblast growth factor, and collagen types I, III, and IV were examined with TaqMan real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Prolonged arterial narrowing peaking on 7 day was observed. There was a significant difference in vessel caliber between D0, D2, D7, and D14 groups (P:<0.0001). There were significant differences in mRNA expression in the basilar artery for IL-1alpha, IL-6, IL-8, ICAM-1, and collagen type I between D0, D2, D7, and D14 groups (P:=0.0079, 0. 0196, 0.0040, 0.0017, and <0.0001, respectively). The average level of mRNA was highest in D7 for IL-1alpha, IL-6, IL-8, and ICAM-1 (17-, 16-, 131-, and 1.7-fold compared with those of D0, respectively) and in D14 for collagen type I (10.9-fold). CONCLUSIONS: Increased expression of genes related to inflammation in the spastic artery suggests that inflammatory reaction of the cerebral artery is associated with sustained contraction.

Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage.

To understand the molecular processes of continuous vasospasm of cerebral arteries after subarachnoid hemorrhage, mRNA differential display and screening of cDNA expression array were performed to identify genes that are differentially expressed in vasospastic arteries of canine two-hemorrhage models. The expression levels of 18 genes were found to be upregulated, and those of two genes to be downregulated. Of these, 12 represent known genes or homologues of genes characterized previously, and the other eight genes are not related to any sequences in the databases. The known genes include five upregulated inflammation-related genes encoding monocyte chemotactic protein-1, cystatin B, inter-alpha-trypsin inhibitor family heavy chain-related protein, serum amyloid A protein, and glycoprotein 130, suggesting that inflammatory reaction may be involved in the development of cerebral vasospasm. The upregulation of three known genes encoding stress-related proteins of vascular endothelial growth factor, BiP protein, and growth-arrest and DNA-damage-inducible protein may be involved in possible cell survival in the damaged arteries. A full-length cDNA for the unknown clone DVS 27, whose expression was most highly upregulated, was isolated from the cerebral artery cDNA library by hybridization. Characterization of these genes should help to clarify the molecular mechanism of continuous cerebral vasospasm after subarachnoid hemorrhage.

Familial neuronal migration disorder: subcortical laminar heterotopia in a mother and pachygyria in the son.

We describe clinical manifestations and magnetic resonance imaging (MRI) findings in a man and his mother who were diagnosed as having a neuronal migration disorder. The son had severe psychomotor retardation and the mother had intractable seizures and mild psychomotor retardation. MRI demonstrated moderate pachygyria in the son and subcortical heterotopia in the mother. In both patients, the frontal parts of the brain were characteristically more affected than any other areas. A dominant pattern of inheritance in the family suggests a genetic role in the underlying cause of the migration disorder. The difference in severity between the two patients also suggests an X-linked dominant inheritance. Our family fits the condition of X-linked lissencephaly.

Using hydroxylapatite ceramic buttons covered with periosteum to prevent cerebrospinal fluid leakage: technical note.

BACKGROUND: Many attempts have been made to prevent cerebrospinal fluid (CSF) leakage, but the procedures proposed to date are troublesome and not promising. We describe a method of completely preventing CSF leakage using hydroxylapatite ceramics. METHODS: Exposed frontal sinus, mastoid air cells, and frontal base defects caused by fracture are covered with periosteum or fascia and plugged with a trimmed hydroxylapatite ceramic button. RESULTS: There was no CSF leakage, postoperative meningitis, or other complication related to the technique in a consecutive series of 25 patients treated using this procedure. CONCLUSION: The use of this easy and quick technique may prevent CSF leakage completely.

The effect of continuous drainage of cerebrospinal fluid in patients with subarachnoid hemorrhage: a retrospective analysis of 108 patients.

The effects of continuous drainage of cerebrospinal fluid (CSF) on vasospasm and hydrocephalus were analyzed retrospectively in 108 patients with subarachnoid hemorrhage (SAH) who were operated on for ruptured aneurysms within 48 hours of their onset. Ninety-two of these patients underwent a procedure for CSF drainage (cisternal drainage, ventricular drainage, lumbar drainage, or a combination of these). The duration, the total volume, and the average daily volume of CSF drainage were 10.4 +/- 7.0 days (mean +/- SD). 2034 +/- 1566 ml, and 190 +/- 65.3 ml, respectively. Patients with a greater drainage volume at a lower height of drainage in the early period after SAH developed more cerebral infarctions later (P less than 0.025). The relationship between the total volume of CSF removed and shunt-dependent hydrocephalus was determined to be statistically significant (P less than 0.005). Cerebral infarction and hydrocephalus after SAH were also found to be statistically associated (P less than 0.001). Thus, continuous cerebrospinal fluid drainage should not be performed too readily in patients with SAH, because the removal of a large amount of CSF can induce cerebral vasospasm as well as hydrocephalus.

Clinical features of intracranial aneurysms in siblings.

OBJECTIVE: Among the family members of patients with aneurysmal subarachnoid hemorrhage (SAH), siblings have been documented to be at high risk of SAH and to have a high prevalence of unruptured aneurysms. We studied the distinctive features of aneurysms in siblings and attempted to determine the risk of rupture. METHODS: We analyzed detailed data on 159 patients with siblings who had ruptured and unruptured aneurysms in 77 families from throughout Japan. RESULTS: Seventy-three percent of the patients were female, and the mean age at the time of rupture was 55.6 years. In 39 families, two or more siblings had SAH. Eighty of 107 patients with ruptured aneurysms and 28 of 52 with unruptured aneurysms had a family history of SAH in siblings (P = 0.0082). Multiple and mirror-image aneurysms were found in 42 and 21 patients, respectively. Among 218 aneurysms, middle cerebral artery aneurysms were the most common type (43%). Anterior communicating artery aneurysms were underrepresented (15%). There were significantly more ruptured than unruptured anterior communicating artery aneurysms, compared with other aneurysms (P = 0.01). CONCLUSION: The clinical features of aneurysms in siblings in this population agreed well with those reported for familial intracranial aneurysms and SAH, except for the age at the time of rupture. It is suggested that the risk of rupture is greater when patients with unruptured aneurysms have siblings with aneurysmal SAH and/or anterior communicating artery aneurysms.

Metabolic profiles of patients with subarachnoid hemorrhage treated by early surgery.

OBJECTIVE: This study was conducted to evaluate the metabolic response of patients with subarachnoid hemorrhage (SAH) and to determine whether the severity of hemorrhage influenced the response. METHODS: Resting energy expenditure, nitrogen balance, and serum rapid-turnover proteins were studied for 3-day periods at Day 4, Day 10, and before discharge in patients with SAH who underwent surgical clipping within 2 days after the onset. The patients were divided into two groups according to the Hunt and Hess classification system; there were 17 patients with Grade I or II (mild group) and 19 patients with Grade III, IV, or V (severe group). RESULTS: The mean resting energy expenditures (mean+/-standard deviation) were highest on Day 10, which were 146+/-24% and 198+/-78% of basal energy expenditure in the mild and severe groups, respectively. The nitrogen balance levels of the mild group on Days 4 and 10 were -3.0+/-3.5 g per day and -4.5+/-2.9 g per day, and those of the severe group were -7.5+/-3.2 g per day and -9.2+/-4.1 g per day, respectively. There was a significant difference in the nitrogen balance over time between the two groups (P=0.0037). Serum transferrin, prealbumin, and retinol-binding protein levels were lowest on Day 4 and gradually increased. There were no significant differences in these parameters between the two groups. CONCLUSION: SAH treated by surgery induces a profound stress response. A significant difference of increased catabolism but not decreased anabolism between the mild and severe groups was noted.

Prophylactic effect of papaverine prolonged-release pellets on cerebral vasospasm in dogs.

OBJECTIVE: A drug delivery system using copoly(lactic/glycolic acid) was developed for the intracranial administration of papaverine. A rod-shaped implant prepared by a heat compression method was tested to determine its efficacy in preventing cerebral vasospasm in dogs. METHODS: Sixteen dogs were randomly assigned to one of two groups, i.e., placebo or papaverine. Control angiography was performed, followed by right craniectomy and the induction of subarachnoid hemorrhage by the placement of a clot in the Sylvian fissure. Two pellets, containing either 25 mg of papaverine or no papaverine, were placed in the cistern. In in vitro studies, 56% of the actual papaverine loading was released in the first 4 days and 78% within 8 days. On Day 7, angiography was repeated and the animals were killed. A similar experiment using low-dose pellets containing 5 mg of papaverine, half of which was released within 7 days, was performed with 16 mongrel dogs. RESULTS: There were significant differences between the papaverine- and placebo-treated groups in the reductions of vessel diameters of the internal carotid, middle cerebral, and anterior cerebral arteries on the clot side. The mean concentration of papaverine in the clot was 4.5 x 10(-4) mol/L. The low-dose pellet failed to prevent cerebral vasospasm, although the mean concentration of papaverine in the clot was 2.3 x 10(-5) mol/L. CONCLUSION: A prolonged-release preparation of papaverine that could be implanted intracranially at the time of surgery prevented vasospasm significantly while maintaining an appropriate concentration of papaverine in the cistern.

Insulin-like growth factor-1 in the arterial wall after exposure to periarterial blood.

Intimal proliferation is thought to be initiated by the migration and proliferation of smooth muscle cells after endothelial damage. These changes may be induced, in part, by mitogenic growth factors such as insulin-like growth factor-1 (IGF-1). This study was designed to investigate the role of locally synthesized IGF-1 and its receptor in the arterial wall in response to the exposure to periarterial blood. Rat femoral arteries were exposed to periarterial blood for various time periods (control, 1, 3, 7, 14, and 21 d). Total ribonucleic acid was extracted from the arteries of 10 to 15 animals, and the expression of IGF-1 messenger ribonucleic acid in treated and untreated arteries was analyzed using dot blot analysis. To identify and localize IGF-1 receptors on the arterial walls, an in situ ligand binding of IGF-1 to the arterial sections was utilized using [125I]IGF-1 as a tracer. Our results revealed that luminal narrowing was maximum at 7 days posttreatment. Intimal proliferation occurred at 14 and 21 days. The results of dot blot analysis showed that the expression of IGF-1 messenger ribonucleic acid was increased four-fold by Day 3 and remained elevated up to 7 days, then gradually decreased. In situ [125I]IGF-1 binding to the normal rat femoral artery localized IGF-1 receptors to the arterial wall. There was a marked increase in the number of receptors at 3 and 7 days after treatment with periarterial blood. These results suggest that locally synthesized IGF-1 and its receptor may function in an autocrine and/or paracrine loop as part of the response of the arterial wall to periarterial blood, resulting in intimal proliferation.

Procollagen types I and III and transforming growth factor-beta gene expression in the arterial wall after exposure to periarterial blood.

The stiffening and thickening of the arterial wall after subarachnoid hemorrhage may reflect increased connective tissue. The purpose of this study was to examine the nature of collagen synthesis in response to periarterial blood. Rat femoral arteries were exposed to periarterial blood for varying lengths of time (control, 1, 3, 7, and 14 d). Dot-blot analysis of total ribonucleic acid extracted from the arteries (n = 10 to 15 animals each) demonstrated that the expression of procollagen Types I and III messenger ribonucleic acid increased at 7 (threefold) and 14 days. The expression of transforming growth factor-beta (TGF-beta), an important regulator of collagen synthesis, was markedly increased by 3 days (threefold), followed by a gradual decline. There were marked differences in procollagen Types I and III and TGF-beta gene expression between arteries exposed to blood and sham-operated arteries for a period of 7 days (n = 25 animals). Northern blot analysis of total ribonucleic acid extracted from cultured vascular smooth muscle cells showed that the treatment with a higher concentration of serum for 48 hours increased the expression of procollagen Types I and III and TGF-beta, whereas exposure to oxyhemoglobin did not. After exposure to periarterial blood, arterial walls show increased synthesis of procollagen Types I and III, perhaps a response to the increased secretion of TGF-beta, which in turn could be the result of exposure to serum factors.

Time course of changes in concentration of intracellular free calcium in cultured cerebrovascular smooth muscle cells exposed to oxyhemoglobin.

A culture of smooth muscle cells obtained from monkey middle cerebral arteries was developed to allow quantitative assessment of intracellular calcium and immunofluorescence analysis after various periods of exposure to oxyhemoglobin. Intracellular calcium concentration was examined for up to 7 days after a single exposure to oxyhemoglobin. Intracellular calcium concentrations were measured with the fluorescent dye fura-2 and were significantly elevated for 7 days after exposure to oxyhemoglobin (P less than 0.01). Less than 2 minutes after application of oxyhemoglobin, there was marked elevation of intracellular calcium from the control value of 75 +/- 2 nmol/L to 240 +/- 28 nmol/L (P less than 0.01 by analysis of variance). Intracellular calcium concentration of cells exposed for 24 hours to oxyhemoglobin and then grown in normal oxyhemoglobin-free medium fell close to normal levels on Days 3 and 7. On Day 3, the increase in intracellular calcium that followed repeated daily exposure to oxyhemoglobin was greater than that resulting from a single application of oxyhemoglobin (P less than 0.01 by Student's t test), but by Day 7 the elevation produced by these different approaches was similar. Smooth muscle cells exposed to oxyhemoglobin showed a reduction in immunoreactivity to alpha-actin. These data support the hypothesis that disruption of intracellular calcium regulation and calcium overloading may be important in the process of cell injury, which results in vasoconstriction and sometimes cell death, after exposure to oxyhemoglobin.

Angles between A1 and A2 segments of the anterior cerebral artery visualized by three-dimensional computed tomographic angiography and association of anterior communicating artery aneurysms.

OBJECTIVE: The angle of arteries at bifurcations, as well as the blood flow, are factors of hemodynamic stress on the apical region, where aneurysms often develop. Using images obtained with three-dimensional computed tomographic angiography, we sought to determine the angles between the A1 and A2 segments of the anterior cerebral artery of the anterior communicating artery (ACoA) complex associated with aneurysms. These angles cannot be detected by conventional cerebral angiography. METHODS: The course of the anterior cerebral artery was studied using three-dimensional computed tomographic angiography in 42 consecutive patients with ACoA aneurysms. Twenty-one other subjects, randomly chosen from patients without aneurysms, served as controls. Bilateral A1-A2 angles of the contrast-opacified anterior cerebral artery were measured by three-dimensional computed tomographic angiography in patients with normoplastic A1 segments, and the relationship between the angle and the association of aneurysms was analyzed using cerebral angiography. RESULTS: Of the 42 patients with ACoA aneurysms, 19 patients showed hypo- or aplastic A1 segments, as did only 2 of the 21 patients without ACoA aneurysms. The average A1-A2 angle was determined to be 116+/-24 degrees (mean+/-standard deviation) in 18 patients having ACoA complexes with normoplastic A1 segments with aneurysms; 17 patients without aneurysms had A1-A2 angles measuring 143+/-14 degrees (P < 0.0001). The A1-A2 angle associated with ACoA aneurysms was 103+/-20 degrees, which was much smaller than that of the non-aneurysm side in the former group (128+/-20 degrees) (P = 0.0036). CONCLUSION: ACoA aneurysms are associated with the smaller A1-A2 angle junction of the ACoA complex, where higher hemodynamic stress may occur in patients with normoplastic A1 segments.

Forme fruste of von Recklinghausen's disease: unilateral association of an orbital neurofibroma, a trigeminal neurinoma, and an acoustic neurinoma. Case Report.

A patient who presented with a tumor of the left ambient cistern, a left cerebellopontine angle tumor, and a left orbital tumor causing left hearing loss and left exophthalmos without café au lait spots or cutaneous neurofibromas is described. There was no family history of von Recklinghausen's disease. A cerebellopontine angle tumor removed by a suboccipital craniectomy was an acoustic neurinoma. An ambient cistern tumor was approached through a subtemporal route. A tumor arising from the trigeminal nerve was also a neurinoma. An orbital neurofibroma was excised by a frontal craniotomy with removal of the orbital roof. This rare unilateral association of neurinomas and a neurofibroma on the left side was thought to be a forme fruste of von Recklinghausen's disease, and it could be considered a presentation of a mosaic of von Recklinghausen's disease.

Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model.

Safety and efficacy of the thrombolytic agent urokinase (URO) in the elimination of subarachnoid clot and prevention of chronic vasospasm was compared with tissue-type plasminogen activator (rt-PA) in a blind, randomized placebo-controlled trial. Twenty monkeys were randomly assigned to one of five groups of four. Each group underwent baseline cerebral angiography followed by bilateral craniectomy and experimental subarachnoid hemorrhage. An Ommaya reservoir was inserted on the right side with its catheter placed into the ipsilateral subarachnoid space. Twenty-four hours later, depending upon group assignment, the animals received 100,000 IU URO, 200,000 IU URO, 1 mg rt-PA, 2 mg rt-PA, or the equivalent volume of normal saline (control group). On Day 7, angiography was repeated and the animals were killed. One animal died as a result of complications during the baseline angiography, presumably due to blood loss and prolonged anesthesia, and a replacement animal was obtained. No animals demonstrated any delayed neurological deficits. The study demonstrated that a single intracisternal bolus injection of rt-PA, 2.0 mg in 2 ml sterile water, or URO, 200,000 IU in 2 ml sterile water, 24 hours after induction of experimental subarachnoid hemorrhage in primates, was equally effective in thrombolysing ipsilateral clot, but neither dosage prevented angiographic vasospasm. Vasospasm occurred bilaterally in all groups. Whereas gross subarachnoid clot was found bilaterally in all animals in the placebo group and both smaller-dose URO and rt-PA groups, right-sided subarachnoid clot was virtually absent and left-sided clot reduced in both higher-dose URO and rt-PA groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage.

The cerebrospinal fluid (CSF) and plasma levels of the complement components C3a and C4a in 40 patients suffering from subarachnoid hemorrhage (SAH) were quantitated by radioimmunoassay. Serial measurements of the lumbar CSF levels revealed that the C3a and C4a levels were significantly elevated in the initial stage of SAH, but decreased rapidly. Within 48 hours after SAH, the mean C3a and C4a levels in the cisternal, lumbar, and ventricular CSF were significantly higher in patients with delayed ischemic neurological deficits (DIND) than in those without DIND. The serially measured plasma levels of C3a and C4a in patients with DIND were elevated more than in those without DIND, but they did not show a significant change over time. Simultaneous levels of fibrinopeptide A (FPA), an indicator of thrombin activity in CSF, were also measured by radioimmunoassay. There was a significant correlation between CSF-activated complement components and CSF FPA. These results suggest that complement activation occurred in the subarachnoid space soon after SAH, chiefly due to activation of the coagulation system. The higher CSF levels of C3a and C4a in patients with DIND may indicate a relationship between these components and the pathogenesis of cerebral vasospasms.