Neurol Med Chir (Tokyo) 46, 421¿428, 2006 Effect of Fasudil Hydrochloride, a Protein Kinase Inhibitor, on Cerebral Vasospasm and Delayed Cerebral —Results of a Randomized Trial of Fasudil Hydrochloride Jizong ZHAO, Dingbiao ZHOU*, Jing GUO**, Zyuan REN***, Liangfu ZHOU†, Shuo WANG, Bainan XU*, and Renzhi WANG*** Department of Neurosurgery, Capital Medical University Affiliated Beijing Tiantan Hospital, Beijing, P.R.C.; *Department of Neurosurgery, General Hospital of the CPLA, Beijing, P.R.C.; **Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, P.R.C.; ***Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, P.R.C.; †Department of Neurosurgery, Shanghai Medical University Affiliated The efficacy and safety of fasudil hydrochloride, a novel protein kinase inhibitor, were evaluated forthe treatment of cerebral vasospasm and associated cerebral ischemic symptoms in patients withruptured cerebral aneurysm. This randomized open trial with nimodipine as the control included 72patients who underwent subarachnoid hemorrhage surgery for ruptured cerebral aneurysm of Hunt andHess grades I to IV. For 14 days following surgery, patients were administered either 30 mg of fasudilhydrochloride by intravenous injection over a period of 30 minutes three times a day or 1 mg/hr ofnimodipine by continuous intravenous infusion. Fasudil hydrochloride and nimodipine both showedinhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluatedby the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurolog-ical deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more thannimodipine. Adverse reactions occurred in 13 of 37 patients receiving fasudil hydrochloride and 15 of35 patients receiving nimodipine. There were no serious adverse events in the fasudil group. The resultsof this clinical trial indicate that fasudil hydrochloride is a safe and efficient agent for suppressingcerebral vasospasm after subarachnoid hemorrhage surgery for ruptured cerebral aneurysm.
postoperative management techniques. However,late cerebral vasospasm, which develops a few days Subarachnoid hemorrhage is a dangerous disease to 2 weeks after onset of the hemorrhage, is a major with a high mortality. Rebleeding and hydrocepha- cause of death or deficits and remains an unsolved lus, major complications of subarachnoid hemor- problem in the treatment of subarachnoid hemor- rhage, have been rendered less dangerous by the adoption of early surgery and improvements in Cerebral vasospasm is thought to be triggered by the interactions of multiple factors derived from extravasated blood, and progressive and protracted arterial narrowing may occur as a chain reaction continues. The massive increase of intracellular calcium in the arterial smooth muscle cells is con- The present study evaluated the efficacy and sidered to be the cause of early vasoconstriction of safety of fasudil hydrochloride for suppressing mechanism of vasospasm has now been elucidated.
ischemic symptoms following subarachnoid hemor- Phosphorylation of myosin light chain is one of the rhage surgery, compared to nimodipine in a ran- most important signal transduction pathways in the arterial smooth muscle contraction-relaxationprocesses.4) Muscle contraction results from the phosphorylation of myosin light chain induced bymyosin light chain kinase. Muscle relaxation results from dephosphorylation of phosphorylated myosin A total of 72 patients who underwent post- light chain by myosin light chain phosphatase. The subarachnoid hemorrhage surgery for ruptured activations of Rho kinase and myosin light chain cerebral aneurysms in five hospitals from October kinase promote the phosphorylation of myosin light 1998 to October 2000 were randomly divided into chain and cause the contraction of arterial smooth the fasudil group (37 patients) and the nimodipine muscle. The activated Rho kinase phosphorylates group (35 patients). Patients who met the following the myosin-binding subunit of myosin light chain inclusion criteria were selected for this study: phosphatase and inhibits phosphatase activity.10,19,28) surgery was performed within 7 days after the onset Protein kinase C activates the contraction of smooth of subarachnoid hemorrhage; computed tomo- muscle cells by phosphorylating the actin-binding graphy (CT) was performed before or within 48 hours after the operation and showed the presence of subarachnoid hematoma, high risk for the occur- fonamide derivative hexahydro-1-(5-isoquinolinesul- rence of vasospasm; age 20 years or older but fonyl)-1H-1, 4-diazepine hydrochloride, is a new younger than 70 years; first episode of ruptured potent vasodilator discovered and developed in cerebral aneurysm; and preoperative Hunt and Hess Japan. The mechanism of action is different from that of calcium channel blockers such as nimodi- The demographic characteristics, diagnosis, Hunt pine, which are widely used clinically for the and Hess grade, duration of operation, associated treatment of cerebral vasospasm.1,14–18) Fasudil disease, etc. of the patients are shown in Table 1.
hydrochloride inhibits protein kinases such as Rho Various indices observed at the time of enrollment kinase, myosin light chain kinase, and protein and before surgery showed no statistically sig- kinase C, resulting in the inhibition of myosin light nificant difference between the two groups. Patients chain phosphorylation.7,12,25) Animal experiments or their next of kin were given an explanation of the demonstrated that fasudil hydrochloride antago- nature of the drug and the purpose of the trial, and nizes the cerebral blood vessel contracting effect of consent was obtained for each patient prior to endothelin,5) and dilates spastic cerebral artery in a entrance into the trial. The present clinical trial was dog cerebral hemorrhage model,22,27) resulting in approved by the ethical committee and was carried decreased ischemic damage.3,20) The results of out as instructed by the Department of Public Health multi-center, prospective, randomized, double-blind of the People's Republic of China (1998) by the trials using placebo as the control revealed that departments of neurosurgery of five hospitals in fasudil hydrochloride suppresses cerebral vaso- spasm after subarachnoid hemorrhage surgery, The trial and observation period commenced from alleviates the subsequent cerebral ischemia, and the onset of the disease and continued for 1 month.
improves the prognosis of patients.26) The efficacy of Adverse reactions appearing during the period of fasudil hydrochloride may be related to the improve- the clinical trial were observed and analyzed.
ment of hemodynamic functions such as the All patients failing to complete the trial were treated cerebral blood flow, glucose metabolism,23,29) and as dropout cases. One patient (fasudil group) had the viscosity of red blood cells,9) and the reduction exceeded the postoperative time limit. Three of neutrophil-mediated damage by inhibition of patients (2 fasudil group and 1 nimodipine group) died of severe postoperative conditions despite migration.21,24) Furthermore, fasudil hydrochloride all rescue measures. Drug administration had to be has a protective effect on the anoxic neurodegenera- discontinued because of decreased blood pressure in tion of cultured hippocampal neuronal cells.11) The one patient (nimodipine group). One patient (fasudil drug was first marketed in 1995 and is currently in group) withdrew from the trial by choice, and one Neurol Med Chir (Tokyo) 46, September, 2006 Effect of Fasudil Hydrochloride on Cerebral Vasospasm subarachnoid hemorrhage in the two treat- The Glasgow Coma Scale was used to evaluate the level of consciousness. The degree of aphasia, andmotor disturbance of the upper and lower extremi- ties were evaluated and graded into classes 1–4(class 1: normal; 2: communication and verbaliza- tion are possible but sometimes poor, arm and leg joints can move and be extended; 3: communication and verbal understanding is sometimes possible bending of elbows, extending of legs, or bending of knees is possible; 4: communication and verbaliza- tion are completely impossible, prostrate stretching Neurological deterioration, either temporary or permanent, was considered to be due to vasospasm (symptomatic cerebral vasospasm) if all other poten- tial causes such as surgery, hydrocephalus, intra- cranial rebleeding, seizure, infection, cardiopulmo- nary dysfunction, electrolyte imbalance, and meta- bolic disturbances had been excluded.26) Vasospasm on cerebral angiography was graded as none (no spasm), mild (mild decrease in the vascular lumen), moderate (between mild and severe), and severe (the blood vessel became line-like or became almost The causes of newly appeared low density areas on CT after operation were analyzed. The appear- ance was considered to be due to cerebral blood vessel spasm if other factors such as brain damage, occlusion of artery or vein, hematoma, and hydrocephalus could be excluded. Low density areas Each value shows number of patients, except where on CT were evaluated as none, mild (distinctive otherwise indicated. Mean values are expressed ± moderate (moderate infarction with diameter great- ACoA: anterior communicating artery, ICA: internal er than 1 cm to infarction of the distribution of one carotid artery, MCA: middle cerebral artery, VB: ver- blood vessel), high (multiple small moderate infarc- tions), and severe (large scale infarction extendingover the distributions of two to three blood vessels orinfarction of the distribution of the middle cerebral patient (nimodipine group) asked to be discharged artery). The clinical outcome was evaluated accord- from the hospital during the period of drug adminis- Qualitative factors were compared with the x2 test Fasudil hydrochloride (Eril injection; Asahi Kasei or the precision probability method, whereas Pharma Corporation, Tokyo) was administered quantitative factors were compared with the Wilcox- three times a day, with a dose of 30 mg at each on rank test. Therapeutic efficacy was evaluated administration. The drug was dissolved in 100 ml between groups with the Wilcoxon rank test and of physiological saline and infused intravenously before and after comparison within a group with over a period of 30 minutes. Nimodipine was analysis of variance or the sign rank test. Severity of administered by continuous intravenous infusion symptomatic cerebral vasospasm was compared with a dose of 1 mg/hr. Drug administration was with the precision probability method. The clinical started within 24 hours of aneurysm surgery and outcome 1 month after the onset of disease was evaluated with the Wilcoxon rank test. The inci- Neurol Med Chir (Tokyo) 46, September, 2006 dences of adverse reaction were compared with the tion, 12.8 ± 2.30 to 14.0 ± 2.08 in the fasudil group (p º 0.01) and 13.0 ± 2.15 to 13.8 ± 1.97 in thenimodipine group (p º 0.05). The fasudil group showed more significant improvement than thenimodipine group. The fasudil group showed significant improvement in the degree of aphasia The levels of consciousness in the two groups (p º 0.01), and reduced motor disturbance in the were significantly improved after drug administra- upper and lower extremities (p º 0.05), whereasthe nimodipine group showed only significantlyimproved degree of aphasia (p º 0.05) (Table 2).
The rate of occurrence of symptomatic cerebral vasospasm in the fasudil group was lower than that in the nimodipine group, but there was no statistical-ly significant difference (Table 3). The degree of angiographical cerebral vasospasm was not statisti- cally significantly different between the two groups before operation (Table 4). The occurrences of more than moderate vasospasm in the patients with no vasospasm before operation were similar after the operation. The changes in degree of cerebral vasospasm observed before and after operation inboth groups were also not significant. The differ- Each value shows the mean ± standard deviation of ence in the degree of vasospasm observed before and after operation was also statistically not sig- different from assessment before treatment.
Each value shows the number of patients, except where otherwise indicated.
Incidence of angiographically detected vasospasm in the two groups Each value shows the number of patients.
aAfter operation (after treatment) denotes the first cerebral angiographic examination performed during the period within 7–17 days after the onset of disease. bSign rank test. Comparison ofbefore treatment and after treatment values. cWilcoxon rank test. Comparison of the two groups before treatment.
dWilcoxon rank test. Comparison of the difference in the before treatment and after treatment values between the twogroups.
Neurol Med Chir (Tokyo) 46, September, 2006 Effect of Fasudil Hydrochloride on Cerebral Vasospasm Incidence of low-density areas on computed tomography (CT) Each value shows the number of patients.
aAfter operation (after treatment) denotes CT performed 1 month after the onset of disease. bSign rank test. Comparison of before treatment and after treatment values. cWilcoxon rank test.
Comparison of the two groups before treatment. dWilcoxon rank test. Comparison of the two groups after treatment.
mmHg) in the fasudil group, and slight decreases in systolic (143.4 ± 23.56 to 129.32 ± 22.06 mmHg)and diastolic pressure (86.3 ± 11.57 to 74.1 ± 11.95 mmHg) in the nimodipine group. These decreases were statistically significant (p º 0.01). Comparison of the blood pressure before drug administration and at day 14 of drug administration revealed decreases in the systolic pressure (137.9 ± 18.66 to 127.8 ± 20.10 mmHg) in the fasudil group, and both the systolic (138.7 ± 21.20 to 119.4 ± 12.55 mmHg) and diastolic pressure (83.9 ± 10.41 to 76.0 ± 7.89mmHg) in the nimodipine group. These decreases Each value shows the number of patients and percen- were statistically significant (p º 0.05). Drug ad- tage (in parentheses) of the total within each group.
ministration was not stopped in any of the patients aWilcoxon rank test. Comparison of the two groups.
in the fasudil group due to decreased blood pressure,whereas drug administration was stopped in onepatient in the nimodipine group because blood No low density areas of more than moderate severity due to vasospasm were present in either Thirteen of the 37 patients (35.1%) in the fasudil group before operation (Table 5). The occurrence of group developed adverse reactions (16 episodes), such areas were similar at 1 month after operation whereas 15 of 35 patients (42.9%) in the nimodipine in the fasudil group and the nimodipine group. No group developed adverse reactions (22 episodes).
statistically significant difference was observed There was no marked difference in the occurrence between before and after operation within the of adverse reactions between the two groups. The liver function abnormality observed in both groups The functional outcome observed 1 month after was transient and mild in most cases. Mild bleeding the onset of disease is shown in Table 6. The rate of of the digestive tract appeared in one patient in the good recovery was higher in the fasudil group than fasudil group on day 4 after the operation, probably in the nimodipine group although the functional caused by a stress ulcer and not related to the drug outcome was statistically not significant between administration. Flushing of the face and chest related to administration of nimodipine appeared intwo patients. One patient showed marked decrease in blood pressure and had to stop taking nimodipine.
Changes in systolic and diastolic pressure were compared before the start of drug administration, and 15, 30, and 60 minutes after intravenousinfusion of the drug. There was a slight decrease in This study evaluated the efficacy and safety of the systolic pressure (136.1 ± 15.72 to 127.3 ± 16.68 fasudil hydrochloride for the treatment of cerebral Neurol Med Chir (Tokyo) 46, September, 2006 vasospasm and induced cerebral ischemic symp- Strom JA, Transou CR: Cerebral arterial spasm — a toms following subarachnoid hemorrhage surgery, controlled trial of nimodipine in patients with using nimodipine as the control. Both fasudil subarachnoid hemorrhage. N Engl J Med 308: hydrochloride and nimodipine significantly im- proved the consciousness levels and the degree of Arai M, Sasaki Y, Nozawa R: Inhibition by theprotein kinase inhibitor HA1077 of the activation of aphasia after subarachnoid hemorrhage. Fasudil NADPH oxidase in human neutrophils. Biochem hydrochloride also significantly improved motor disturbance whereas nimodipine did not. The inci- Asano T, Ikegaki I, Satoh S, Mochizuki D, Hidaka H, dence of symptomatic cerebral vasospasm in the Suzuki Y, Shibuya M, Sugita K: Blockade of intracel- fasudil group was lower than that in the nimodipine lular actions of calcium may protect against ischaem- group. Angiographical vasospasm of more than ic damage to the gerbil brain. Br J Pharmacol 103: moderate severity was rare in both the fasudil and nimodipine groups. Low density areas due to Asano T, Ikegaki I, Satoh S, Seto M, Sasaki Y: A vasospasm of more than moderate severity were protein kinase inhibitor, fasudil (AT-877): A novel also rare after 1 month in both the fasudil and approach to signal transduction therapy. Cardiovasc nimodipine groups. The number of patients achiev- Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, ing good recovery was about two thirds in both the fasudil and nimodipine groups. There were no sig- modulator of cerebral vasospasm. Eur J Pharmacol nificant differences between the two groups.
Evaluation of the safety of the agents found only a Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, slight decrease in systolic pressure in the fasudil Takayasu M, Hidaka H: Mechanism of action of a group, whereas both systolic and diastolic pressure novel antivasospasm drug, HA1077. J Pharmacol Exp decreased in the nimodipine group. One patient even had to discontinue nimodipine administration Asano T, Suzuki M, Tsuchiya S, Satoh S, Ikegaki I, because of dramatic decrease in blood pressure.
Shibuya M, Suzuki Y, Hidaka H: Vasodilator actions Fasudil hydrochloride has a selective vaso-relaxant of HA1077 in vitro and in vivo putatively mediated effect on cerebral arteries and can dilate spastic by the inhibition of protein kinase. Br J Pharmacol 98: basilar arteries with relatively smaller decline in the Hartshorne DJ, Mrwa U: Regulation of smooth systemic arterial blood pressure compared to muscle actomyosin. Blood Vessels 19: 1–18, 1982 calcium channel blockers.6) In this trial, fasudil Hitomi A, Satoh S, Ikegaki I, Suzuki Y, Shibuya M, hydrochloride caused smaller declines in systemic Asano T: Hemorheological abnormalities in ex- arterial blood pressure than nimodipine. Adverse perimental cerebral ischemia and effects of protein reactions were slightly but not significantly less kinase inhibitor on blood fluidity. Life Sci 67: This clinical trial demonstrated that fasudil Kimura K, Ito M, Amano M, Chihara K, Fukata Y, hydrochloride suppressed cerebral vasospasm and Nakafuku M, Yamamori B, Feng J, Nakano AT, associated cerebral ischemic symptoms. No severe Okawa K, Iwamatsu A, Kaibuchi K: Regulation of adverse effects or reactions were detected. The myosin phosphatase by Rho and Rho-associatedkinase (Rho-kinase). Science 273: 245–248, 1996 effect of fasudil hydrochloride was equal to that of Maiese K, Wagner J, Boccone L: Nitric oxide: a nimodipine, but further study of larger numbers of downstream mediator of calcium toxicity in the patients is required to clarify the superiority of this ischemic cascade. Neurosci Lett 166: 43–47, 1994 drug. Fasudil hydrochloride is a safe and effective Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, agent for treating patients after subarachnoid Takuwa Y: Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in aneurysm. This drug may provide a new therapeutic smooth muscle cells. Am J Physiol Cell Physiol 278: aneurysm surgery and for improving the functional Nagumo H, Seto M, Sakurada K, Walsh MP, Sasaki Y: HA1077, a protein kinase inhibitor, inhibitscalponin phosphorylation on Ser175 in porcine coro-nary artery. Eur J Pharmacol 360: 257–264, 1998 Neil-Dwyer G, Mee E, Dorrance D, Lowe D: Earlyintervention Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, hemorrhage. Eur Heart J 8 Suppl K: 41–47, 1987 Chou SN, Kelly DL, Weir BK, Crabbe RA, Lavik PJ, Ohman J, Heiskanen O: Effect of nimodipine on the Rosenbloom SB, Dorsey FC, Ingram CR, Mellitis DE, outcome of patients after aneurysmal subarachnoid Bertsch LA, Boisvert DPJ, Hundley MB, Johnson RK, hemorrhage and surgery. J Neurosurg 69: 683–686, Neurol Med Chir (Tokyo) 46, September, 2006 Effect of Fasudil Hydrochloride on Cerebral Vasospasm cerebral vasospasm in dogs. Acta Neurochir (Wien) Ohman J, Servo A, Heiskanen O: Long-term effects of nimodipine on cerebral infarcts and outcome after Shimokawa H, Seto M, Katsumata N, Amano M, aneurysmal subarachnoid hemorrhage. J Neurosurg Kozai T, Yamawaki T, Kuwata K, Kandabashi T, Egashira K, Ikegaki I, Asano T, Kaibuchi K, Petruk KC, West M, Mohr G, Weir BKA, Benoit BG, Takeshita A: Rho-kinase-mediated pathway induces Gentill F, Disney LB, Khan MI, Grace M, Holness enhanced myosin light chain phosphorylations in a RO, Karwon MS, Ford RM, Cameron GS, Tuker WS, swine model of coronary artery spasm. Cardiovasc Purves GB, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB, Godon A: Tsuchiya M, Sako K, Yonemasu Y, Asano T: The Nimodipine treatment in poor-grade aneurysm effects of HA1077, a novel protein kinase inhibitor, patients. Results of a multicenter double-blind on reductions of cerebral blood flow and glucose placebo-controlled trial. J Neurosurg 68: 505–517, metabolism following acute and/or chronic bilateral carotid artery ligation in Wistar rats. Exp Brain Res Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P: Prevention of vasospasm in subarachnoidhemorrhage. A controlled study with nimodipine.
Acta Neurochir (Wien) 82: 110–114, 1986 Sato M, Tani E, Fujikawa H, Kaibuchi K: Involve- Address reprint requests to: Jz. Zhao, M.D., Department of ment of Rho-kinase-mediated phosphorylation of Neurosurgery, Capital Medical University Affiliated myosin light chain in enhancement of cerebral Beijing Tiantan Hospital, 6 Tiantan Xili, Beijing Satoh S, Ikegaki I, Suzuki Y, Asano T, Shibuya M, Hidaka H: Neuroprotective properties of a proteinkinase inhibitor against ischaemia-induced neuronaldamage in rats and gerbils. Br J Pharmacol 118: Satoh S, Kobayashi T, Hitomi A, Ikegaki I, Suzuki Y, Fasudil hydrochloride inhibits protein kinases A, G, Shibuya M, Yoshida J, Asano T: Inhibition of and C and myosin light-chain kinase, the final neutrophil migration by a protein kinase inhibitor forthe treatment of ischemic brain infarction. Jpn J common pathway of smooth-muscle contraction.1) By this mechanism of action, fasudil hydrochloride Satoh S, Suzuki Y, Harada T, Ikegaki I, Asano T, prevents vasospasm. Shibuya et al.2) reported that Shibuya M, Sugita K, Hidaka H: Possible prophylac- intravenous administration of fasudil hydrochloride tic potential of HA1077, a Ca2+ antagonist and significantly reduced the incidence of both sympto- vasodilator, on chronic cerebral vasospasm. Eur J matic and asymptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The significance of Satoh S, Suzuki Y, Ikegaki I, Asano T, Shibuya M, this study is that it not only displayed the efficacy Sugita K, Hidaka H: The effects of HA1077 on the of fasudil hydrochloride for the prevention of cerebral circulation after subarachnoid haemorrhage vasospasm, but also compared its efficiency with in dogs. Acta Neurochir (Wien) 110: 185–188, 1991 nimodipine. The results tell us that the incidence of Satoh S, Yamamoto Y, Toshima Y, Ikegaki I, AsanoY, Suzuki Y, Shibuya M: Fasudil, a protein kinase symptomatic vasospasm, incidence of low-density inhibitor, prevents the development of endothelial areas on CT, and clinical outcome is similar for both injury and neutrophil infiltration in a two-haemor- drugs. It is noteworthy that while nimodipine lowers rhage canine subarachnoid model. J Clin Neurosci 6: both systolic and diastolic pressure, fasudil hydrochlo- ride lowers only the systolic pressure. This has an Seto M, Sasaki Y, Sasaki Y, Hidaka H: Effect of important message, because the main drawback of HA1077, a protein kinase inhibitor, on myosin nimodipine usage is a considerable drop in blood phosphorylation and tension in smooth muscle. Eur J pressure in patients who are vulnerable to a change in Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, In this well designed randomized study, the authors Takakura K, Nagata I, Kikuchi H, Takemae T, Hidaka demonstrate that intravenous fasudil hydrochloride is H, Nakashima M: Effect of AT877 on cerebralvasospasm after aneurysmal subarachnoid hemor- a safe and efficient agent for suppressing cerebral rhage. Results of a prospective placebo-controlled vasospasm after SAH. Fasudil hydrochloride is a very double-blind trial. J Neurosurg 76: 571–577, 1992 promising drug that should be studied in a larger Shibuya M, Suzuki Y, Takayasu M, Asano T, Harada number of patients to evaluate its precise role in the T, Ikegaki I, Satoh S, Hidaka H: The effects of an medical treatment of cerebral vasospasm.
intracellular calcium antagonist HA1077 on delayed Neurol Med Chir (Tokyo) 46, September, 2006 inhibitor (RKI) since other synthesized RKI com-pounds are supposed to be biologically toxic. In Seto M, Shindo K, Ito K, Sasaki Y: Selective inhibition of general, fasudil (RKI) is a multi-potential drug to myosin phosphorylation and tension of hyperplastic improve pathological conditions including vasospasm arteries by the kinase inhibitor HA1077. Eur J Phar- and brain ischemia.1,2) This result of this study, in this sense, may suggest the potential of fasudil as a ther- Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, apeutic drug for cerebral ischemia. Indeed, as clearly Takakura K, Okamoto S, Kikuchi H, Takemae T, shown in the conclusion of this paper, fasudil has not Hidaka H: Dose escalation trial of a novel calcium always shown significant difference as an anti-spasm antagonist, AT877, in patients with aneurysmalsubarachnoid haemorrhage. Acta Neurochir (Wien) agent compared to nimodipine. However, this agent has provided significant better neurological outcome.
This fact may be explained by the neuro-protective effect for brain ischemia of fasudil acting as a RKI.
More clinical study to reveal the effect of fasudil for The efficacy of fasudil to prevent vasospasm after subarachnoid hemorrhage is well established. Thisstudy is a well-designed randomized clinical trial to Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano add another confirmation of this anti-vasospasm T, Moskowitz MA, Liao JK: Inhibition of Rho kinase effect of fasudil by comparing with nimodipine that is (ROCK) leads to increased cerebral blood flow and also well-known clinical anti-vasospasm agent. In stroke protection. Stroke 36: 2251–2257, 2005 Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E; Fasudil conclusion, fasudil did not show any significant Ischemic Stroke Study Group: Effects of fasudil in acute difference to nimodipine in term of angiographical ischemic stroke: results of a prospective placebo-con- findings and CT findings. However, interestingly, trolled double-blind trial. J Neurol Sci 238(1–2): 31–39, it showed statistically significant improvement of neurological outcome including consciousness distur- As has been extensively investigated recently, fasudil is the only clinically available Rho kinase Neurol Med Chir (Tokyo) 46, September, 2006

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Keep in a cool place: exposure of medicines to high temperatures in general practice during a british heatwave

Keep in a cool place: exposure of medicines to hightemperatures in general practice during a British heatwaveExposure of medicines to high temperatures in storage or in transit could reduce their efficacy, and most licencesspecify storage at 258C or less. To assess whether this criterion was being met, maximum temperatures in a generalpractice drug cupboard and in drug bags placed in car boots

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