12 fasudil hydrochloride synthesis, pharmacological and clinical research advances


[Keywords:] fasudil hydrochloride; synthesis; pharmacology; clinical


Fasudil hydrochloride (Fasudil Hydrochloride, Fasudil, HA1077, AT877) its chemical name: hexahydro 1 (5 isoquinoline sulfonyl) 1 (H) 1,4 diaza hydrochloride, English name: Hexahydro 1 ( 5 isoquinolinesulfonyl) 1H 1,4 diazepine hydrochloride, molecular formula: C14H17N3O2S HCl, is Japan's Asahi Chemical Company in 1994, listing a new brand name Eril calcium antagonistic vasodilators, for the treatment of cerebral vasospasm caused by spider membrane hemorrhage. The product for the treatment of acute ischemic stroke, sequelae of cerebrovascular disease and angina pectoris in clinical trials the efficacy is [1-4].


1 Advances in research and development at home and abroad [5]


1.1 domestic and international market conditions since the late 90s of last century, cardiovascular disease has gradually become the first cause of death of urban and rural residents, which currently represents nearly 40% of deaths. The area was mainly due to atherosclerosis disease, diabetes, poor lipid hyperlipidemia, hypertension and obesity and other factors. as foreign patent expiry of several major products, with several new products coming soon, will make the big breakthrough occurred in the market change. more manufacturers preference to the more complex therapeutic agents, in particular, their development is considered to extend the life of mature products pharmaceuticals market growth and expansion of the whole way. Moreover, consumers prefer the therapeutic compound, as eliminating the inconvenience of taking many pills and improve the patient the possibility of recovery. According to Datamonitor's latest report, in 2007 the world's cardiovascular drug market will be worth over 52 billion U.S. Dollars, China's pharmaceutical market conditions the cardiovascular system in Table 1.


Table 1 shows, calcium channel blocker heart drugs that occupy the largest Market share, while fasudil hydrochloride as a first treatment that inhibits phosphorylation of myosin light chain of drug, with different calcium antagonists, France and Shu Seoul is not simply to block the calcium influx, but the effect on the cell. It can not only inhibit the activity of intracellular calcium, but also inhibit MLCK and PKC, and other proteases, thus inhibiting the final stages of vascular smooth muscle myosin light chain phosphorylation and the generation of free radicals that have spasm of vascular smooth muscle relaxation of blood vessels play a role in the expansion, the market prospect is very broad.


Table 1 of the sub-categories of cardiovascular system drugs market position


Sub-categories of cardiovascular system drugs


2003 market share (%)


2004


First half of 2005 around the heart treatment drug 49.4548.1547.00 13.1114.9014.90 vasodilator effects of calcium channel blockers on the renin-vascular 13.3412.9813.60


1.2 on the goods produced at home and abroad, the use of fasudil hydrochloride is a new 5-isoquinoline sulfonamide derivatives, is the first treatment that inhibits phosphorylation of myosin light chain of drug. This product is by blocking the blood vessels The final stage of the process, myosin light chain phosphorylation, to dilate blood vessels and inhibit vasospasm. by the Asahi Kasei Corporation and the joint development of new drugs, Nagoya University, in June 1995 was officially approved for marketing in Japan, for the control of spider under the membrane after hemorrhage associated cerebral vasospasm and cerebral ischemia symptoms .2001 August imports up in China to obtain approval to begin selling in our market, trade names, "according to Li Lu," .2001, Tianjin Institute of Pharmaceutical Research and Tianjin Red Sun Pharmaceutical Co., Ltd. to develop and fasudil hydrochloride injection, 17 March 2004 in Tianjin of China approved the production of red Pharmaceutical Co., Ltd. fasudil hydrochloride drug substance (Zhunzi H20040355) and specifications for the 2 ml: 30 mg fasudil hydrochloride injection (Zhunzi H20040356), trade name "Chuanwei." for the improvement and prevention of postoperative subarachnoid hemorrhage caused by cerebral vasospasm and cerebral ischemic symptoms.


Synthesis of 2


2.1 5 isoquinoline chloride hydrochloride review [5-13] isoquinoline chloride 5, we retrieved all documents and 5 using thionyl chloride acid reaction of isoquinoline prepared from different literature use catalyst and thionyl chloride and the amount of different materials, see Table 2. Table 2 Comparison synthesized parameters


Fasudil 2.2 Preparation of free base fasudil review the preparation of free base most of all the literature use 5 isoquinoline chloride and high-piperazine condensation reaction is the use of different solvents, the main solvent dichloromethane and chloroform, taking into account the toxicity, should be preferred methylene chloride.


Foreign patent documents are a direct use of tetrahydrofuran as solvent with 5 isoquinoline was condensed chloride hydrochloride, yield 41% by fasudil free base. According to the literature is too much trouble after the treatment, the yield is not high, we This process was exploratory research, after several studies, the resulting product quality and yield are not ideal, so there is no in-depth study.


2.3 Preparation of fasudil hydrochloride fasudil Summary prepared free base of fasudil hydrochloride reference literature, the use of chromatography, using silica gel as filler with chloroform and methanol as eluting solvent to obtain high purity of the law to Shu Seoul free base.


We consider the actual production from the industry plans to use good materials and workmanship, and then re-crystal method to get the products meet the quality requirements, and chromatographic separation methods to remove the cost of production greatly reduced.


Fasudil hydrochloride 2.4 Methods of purification by recrystallization in previous papers, there are two treatment methods, one for water, methanol, and the other methanol ether. We have carried out the above solvent, the results that the former is more suitable for a mixed solvent Our process.


2.5 Chemical reaction


(1)


(2)


(3)


(4)


3 summary of pharmacology and toxicology studies


3.1 The effectiveness of drugs [15] Fasudil by a variety of protein kinases play a role in inhibiting, such as Rho kinase, myosin light chain kinase (MLCK), protein kinase A, G, C, Ki values ​​were 0.33,36 , 1.6,1.6,3.3 mol / L. According to Ki values, can be inferred fasudil mainly through inhibition of Rho kinase play a pharmacological effect. Because Rho kinase involved in a variety of cell functions, such as smooth muscle contraction, stress fiber formation, cell skeleton reconstruction, cell differentiation and migration, apoptosis, etc., so fasudil by blocking Rho kinase can affect a variety of cell functions, to play its wide range of pharmacological effects.


3.1.1 Effect of inhibition of calcium sensitization, dilation of blood vessels has been confirmed that the process of smooth muscle contraction, myosin light chain (myosin lightchain, MLC) is to determine the phosphorylation level of smooth muscle contraction is an important factor, MLC phosphorylation be dependent on the level of Ca2 + / calmodulin (calmodulin, CaM) of myosin light chain kinase (myosin light chain kinase, MLCK) and Ca2 +-independent myosin light chain phosphatase (myosin light chain phosphase, MLCP) of dual regulation. MLCK phosphorylation of MLC in the Ser19 site, causing the actin - myosin system activation, resulting in smooth muscle contraction; MLCP inhibition can make MLC phosphorylation and smooth muscle contraction and further enhanced, an increase of contraction or adjustment device on the Ca2 + sensitivity, a phenomenon known as "calcium sensitization" (Ca2 + sensitization). In recent years, the mechanism of calcium sensitization progressing rapidly, a series of evidence that the calcium sensitization mechanism is mainly through three poly G-protein (Gq, and G12/13), RhoA and its substrate Rho kinase (Rho kinase, ROK)-mediated. fasudil, Rho kinase on MLCP by blocking the inhibitory effect of calcium sensitization, mediated guided vascular smooth muscle relaxation, dilation of blood vessels.


Hydroxy fasudil (fasudil in the hydroxylation of the active metabolite) in a dose-dependent inhibition of potassium chloride (KCl) (20 mmol / L), prostaglandin F2 @ (1 mol / L) and the excitement of thromboxane receptor agent U46619 (0.1 mol / L) induced the dog basilar artery and middle cerebral artery segments continue to contract.


Watanabe and other autologous arterial blood or artificial cerebrospinal fluid into the cisterna magna of rabbits, and the corresponding animals were divided into subarachnoid hemorrhage (SAH group) and control group, 2 d after the separation of the basilar artery and record the arterial ring tension. Found with 5-HT stimulated arteries can induce arterial contraction, in the SAH group especially, the muscle tension as a control group of 4 times (P <0.O1). fasudil (3 mmol / L) significantly inhibited 5-HT induced contraction.


Hydroxy fasudil at 1 nmol / L endothelin 1 (ET 1) and 20 mmol / L KCl pretreatment caused a complete rabbit basilar artery accompanied by concentration-dependent phosphorylation of MLC to the arteries, while the intracellular Ca2 + concentration had no significant effect; for the stripping of the basilar artery intima, Hydroxy fasudil inhibited by the ET 1, thio nucleoside triphosphate (GTP gamma S) or the Rho kinase catalytic subunit-induced vasoconstriction, but restricted in the MLCP conditions could not inhibit the Ca2 +-induced vasoconstriction, and ATP levels drop, the relaxation effect increases.


Xiang-Jun Meng, etc. .12 1 fasudil hydrochloride synthesis, pharmacological and clinical research advances


Visible through the lifting of fasudil on Rho kinase inhibition of MLCP, inhibiting effect of calcium sensitization, can antagonize the vasoconstriction induced by a variety of substances, the effective expansion of blood vessels.


3.1.2 inhibit the migration and infiltration of inflammatory cells, reduce the production of inflammatory mediators, reduce inflammation of actin - myosin system is not only involved in the contraction of smooth muscle in non-muscle cells during migration and morphological changes also played an important functions, such as leukocyte chemotaxis and morphological changes to the regulation by this system. As the actin - myosin by Rho kinase-mediated system of calcium sensitizing effect of the regulation, fasudil by antagonizing Rho kinase can effectively inhibit the migration and infiltration of inflammatory cells. In addition, fasudil by antagonizing Rho kinase and other protein kinases, can reduce the production of inflammatory mediators, thereby reducing inflammation, play a role in tissue protection.


Induced by angiotensin apolipoprotein apoE gene deficient mice in the abdominal aortic aneurysm, we see a lot of Mac 3-positive macrophages, accompanied by thickening of the wall tumors, the depigmentation of medial smooth muscle, elastic outer membrane protein damage and fibrosis, local organizations, matrix metalloproteinase and caspase 3 activity increased. Jiarufashu drinking water in the mice to Seoul [136 or 213 mg / (kg / d)] can reduce the local infiltration The Mac 3-positive macrophages, reduce the pathological changes mentioned above, reducing matrix metalloproteinase and tissue caspase 3 activity. can be seen, fasudil by antagonizing macrophage-mediated vascular inflammation, can inhibit apoptosis and proteolysis, reduce tissue damage.


Satoh and other experiments demonstrated that fasudil inhibited by the N-formyl a two sulfonyl leucyl phenylalanine (fMLP)-induced neutrophil migration, which is used in rat brain micro-infarction , can reduce brain tissue myeloperoxidase (myeloperoxidase, MPO) activity, reduced infarct size and improve neurological function in rats, said Ming Fashu to Seoul by inhibiting neutrophil infiltration and lack of brain to play Protective effect of blood.


Mouse model of myocardial infarction with Drinking tap water fasudil [100 mg / (kg d)] can inhibit the non-infarcted myocardium in the expression of inflammatory cytokines, such as transforming growth factor 2 and 3 (TGF 2 and TGF 3) and macrophage migration inhibitory factor, reducing non-infarcted myocardium in Rho kinase activity, inhibition of left ventricular remodeling after myocardial infarction.


Usage fasudil treatment of human neutrophils, can be concentration dependently inhibited the activation of NADPH oxidase and by phorbol ester tetradecane vinegar salt (PMA) and fMLP-induced O2 production. In addition, in the medium supplemented with fasudil could reduce 1,25-dihydroxyvitamin D3 treated HL 60 cells to produce the O2, and such cells will eventually differentiate into macrophage-like cells.


Breslin and other reports, fasudil inhibited the activation of the neutrophil C5a induced coronary vascular endothelial cells of bovine actin remodeling and endothelial barrier dysfunction and reduce endothelial permeability.


Can be seen by fasudil inhibited the infiltration of inflammatory cells, reduce the production of inflammatory mediators, can antagonize inflammation, reducing tissue damage.


3.1.3 increased endothelial nitric oxide synthase (eNOS) expression of nitric oxide (NO) generated by the expression of eNOS regulation of Rho kinase, but the specific mechanism is unknown. Fasudil, Rho kinase can increase by blocking eNOS expression, increased eNOS activity and NO production, to play its pharmacological effects.


Rikitake and other experiments demonstrated fasudil can increase eNOS mRNA and protein expression, increased eNOS activity and NO production; will be used fasudil infarction model in mice can increase blood flow to brain tissue and reduce infarct size and improve neurological function score; but in the eNOS gene-deficient mice, fasudil did not show a neuroprotective function of the above, to Seoul, said Ming Fashu mechanism of the neuroprotective effect is to increase the expression of eNOS, promote endothelial source of NO generation.


In the hypoxic environment (3% O2) cultured human saphenous vein and pulmonary artery endothelial cells, can induce the expression of Rho kinase increased by 50%, 74% activity increase, so that eNOS mRNA and protein expression decreased, eNOS activity decreased eNOS half-life shortened. the cells were treated with Hydroxy fasudil could reverse the effects of hypoxia on eNOS, but no effect on eNOS gene transcription.


Fasudil used to wild-type mice ischemia - reperfusion model, can inhibit leukocyte recruitment and adhesion of mesenteric vascular endothelial cells, and to apply it to eNOS gene-deficient mice can not play the same role. In addition, fasudil used the rat myocardial infarction model, you can reduce the area of ​​myocardial infarction 38%, while application of eNOS antagonist L NAME can be reversed fasudil on myocardial protection.


The experimental results show, Fasudil by inhibiting Rho kinase, can increase the expression of eNOS, promoting NO generation, playing the role of tissue injury.


3.1.4 inhibit cell proliferation, reducing recent research suggests that organ remodeling, Rho / Rho kinase pathway involved in cell proliferation and organ remodeling in regulation. Thus, fasudil is effective through inhibition of Rho kinase inhibition of cell proliferation, reduce organ reconstruction.


Shirotani observed by experiments such as fasudil in cultured bovine aortic smooth muscle cells, and confirmed that fasudil can be inhibited by fetal bovine serum, platelet-derived growth factor and insulin-induced cell proliferation and DNA synthesis. Wang et al reported will be used fasudil induced by the angiotensin apolipoprotein apoE gene deficient mice model of cardiac hypertrophy, can reduce cardiac hypertrophy, coronary perivascular fibrosis inhibition, inhibition of atrial natriuretic peptide gene expression and collagen and improve cardiac function, suggesting that fasudil can effectively reduce cardiovascular remodeling induced by angiotensin .


Matsnrnoto such reports, fasudil may inhibit the porcine coronary stent neointimal formation and restenosis, reducing coronary artery remodeling, including increasing the mechanism of neointimal TUNEL positive cells in the , which reduce the proliferation of bromodeoxyuridine-positive cell number, inhibited collagen deposition.


Geely base for agricultural fatal induced pulmonary hypertension model, fasudil long oral administration can increase the survival rate of rats. By inhibiting vascular smooth muscle cell proliferation and promote apoptosis of smooth muscle cells, the antagonistic mechanisms of endothelial dysfunction , fasudil reduced pulmonary artery pressure, reduce the right ventricular hypertrophy and pulmonary vascular disease. The findings suggest that fasudil can effectively reduce the reconstruction of the pulmonary circulation system, as used fasudil treatment of pulmonary hypertension provides experimental basis.


3.1.5 Other fasudil Shah et al reported pharmacological effects of fasudil and by reducing blood glucose concentrations of homocysteine, oxidative stress antagonist, can prevent diabetes and high homocysteine ​​large mouse vascular endothelial dysfunction.


Another scholar reported that fasudil will be applied to insulin resistance in Zucker obese rats, can lower blood pressure, glucose and lipid metabolism to correct, inhibition of insulin receptor substrate (IRS 1) serine phosphorylation and insulin signaling pathway disorder, Acetylcholine and Sodium Nitroprusside restore vascular expansion effect.

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Fasudil in addition to inhibit the pressure-induced contraction of rat cerebral artery and partial inhibition of arterial smooth muscle cell Ca2 + concentration increased, but also can inhibit the tyrosine phosphorylation, reduced the activity of protein tyrosine kinase pp60src.


Usage fasudil treatment unstimulated cultured rat cortical astrocytes, can make it flat polygonal cells by the rich protrusions into the satellite-shaped cells, said Ming Fashu to Seoul by antagonizing Rho kinase can affect the stars shaped glial cell morphology.


Fasudil used to cerebral ischemia - reperfusion model, you can dose dependently reversed the ischemia-induced high blood viscosity.


Fasudil by antagonizing Rho kinase completely abolished and pyridine neostigmine neostigmine-induced contraction of rat trachea, acetylcholine-induced contraction for some inhibition. In addition, fasudil may inhibit the induction of neostigmine of [3H] inositol monophosphate accumulation in the wall of the airway.


Hydroxy fasudil treatment with osteoblast cells, can increase bone morphogenetic protein 2 (BMP 2) and osteocalcin, mRNA expression, dexamethasone reversed the expression of these two inhibitory protein mRNA, suggesting that fasudil by Rho kinase inhibition may have therapeutic effect on osteoporosis.


Above results enhanced our understanding of fasudil and expand its clinical research.


3.2 The safety of the drug [15]


3.2.1 Acute toxicity in mice, oral administration of the LD50 in rats were: male mice was 273.9 mg / kg; female was 277.3 mg / kg; male rats was 335 mg / kg; female was 348 mg / kg. intravenous LD50 in mice was 69.5 mg / kg.


Sub-acute toxicity: the rats, monkeys administered intravenously 1 month, non-toxic dose: Rat 12.5 mg / kg, monkey 3.125 mg / kg.


3.2.2 Long-term toxicity in rats, monkeys were administered intravenously 6 months, the main toxicity manifested as self-activity, the ventral supine. This product is toxic to the kidney the target organ, showing that the kidney weight increase, tubular degeneration, interstitial edema. nontoxic dose in rats was 9 mg / kg, the monkey was 3.125 mg / kg (equivalent to mg/m2 respectively in the maximum recommended human clinical dose of 1 and 0.69 times).


3.2.3 Genotoxicity bacterial reverse mutation assay, the rodent micronucleus test were negative, staining aberration test in mammalian cells was found mutagenic effect.


3.2.4 Reproductive toxicity Reproductive toxicity in rats Section shows the product 1.56,6.25 and intravenous 25 mg / kg, 25 mg / kg body weight group increased parental inhibited luteal number and reduce the number of implantation. Mating rate pregnancy rate and no abnormal embryogenesis. on parental animals, non-toxic dose of 6.25 mg / kg; of reproductive toxicity in rats, intravenous administration of this product 1.6,8 and 40 mg / kg, 40 mg / kg group of the parent animals suppressed weight gain, fetal low birth weight, neonatal weight gain was inhibited Aberdeen, Aberdeen found the lethal effects of fetal and teratogenic effects on the offspring non-toxic dose of 8 mg / kg. of reproductive toxicity tests in rabbits showed that intravenous administration of this product 0.7,2 and 6 mg / kg (equivalent, respectively, the maximum recommended human clinical dose of 0.16,0.44 and 1.33-fold), on embryonic development have not been significantly affected. of reproductive toxicity in rats, intravenous administration of the Commodities 1.6,8 and 40 mg / kg group animals, the general state of poor maternal, newborn weight gain inhibition of Aberdeen. nontoxic dose of 8 mg / kg.


3.2.5 Carcinogenicity no relevant reports.


4 Summary of clinical trials and literature


4.1 Summary of clinical effectiveness [14] As for the pharmacological effects of fasudil deeper understanding, and its clinical applications have been continuously expanded. In addition to prevention and treatment of chronic post-SAH cerebral vasospasm, many scholars try to treat other diseases. believe that, after rigorous clinical trials, fasudil indications for clinical application will be continuously amended and supplemented.


4.1.1 Prevention of chronic ischemic brain after SAH vasospasm, SAH patients who reduce ischemic brain injury. First Hydroxy fasudil treatment in patients with aneurysmal SAH dose - Gradient trial enrolled 113 patients with aneurysmal rupture within 3 d after surgery patients, according to the daily administration of the amount of Hydroxy fasudil were divided into 20 mg / d, 40 mg / d, 60 mg / d, 90 mg / d, 120 180 mg / d 5 dose groups. Test results given the larger dose of Hydroxy fasudil in patients with severe cerebral vasospasm probability lower dose to 40 mg / d or more can get a good effect, a single 60 mg dose to the antihypertensive effect of only slightly .


Hydroxy fasudil treatment after aneurysmal SAH delayed cerebral vasospasm prospective randomized double-blind placebo-controlled trial conducted in Japan in 1992, the trial by the Centre 60 Neurosurgical completed, a total of 267 patients admitted after rupture within 3 d of patients undergoing surgery. patient medication after 14 d, each 30 mg, 3 times / d, intravenous infusion each time 30 min. The experimental results showed that patients who received Hydroxy fasudil treatment, which by angiography The lower the incidence of cerebral vasospasm by 38%, CT was associated with cerebral vasospasm low density lesions in the brain decreased by 58% of symptomatic vascular spasm by 30%. In addition, the use of Hydroxy fasudil to poor prognosis patients (1 month Glasgow Outcome Scale as moderately disabled and older) decreased by 54%, and did not cause serious adverse reactions.


Tong Huai Yu to nimodipine as the control, etc., using open randomized comparative trial and watch Cha Fashu to Seoul on aneurysm rupture within 7 d after surgery in patients receiving treatment. Test indicated that, for the disease outcome and recovery, similar to the two drug effects ; expansion of fasudil the role of cerebral artery spasm by DSA to confirm the role of nimodipine was not confirmed by DSA; for the CT examination revealed low density lesions in the brain, fasudil hydrochloride and nimodipine on average to narrow role; fasudil hydrochloride on the system of blood pressure, lighter than nimodipine.


Recently some scholars have used intra-arterial injection method of fasudil treatment of symptomatic vasospasm after SAH patients and found that this approach can effectively alleviate the vasospasm that 50% of patients 3 months after the Glasgow outcome score improved.


4.1.2 improve the prognosis of ischemic stroke patients reported a Shibuya etc. to assess the fasudil treatment of acute ischemic stroke, the efficacy and safety of multi-center, double-blind, placebo-controlled clinical trial. The trial enrolled 160 patients onset of ischemic stroke within 48 h after drug treatment of patients. patient medication after the onset of 14 d, each 60 mg, 2 times / d, intravenous infusion each time 60 min, and then assess the patient after treatment 2 weeks of onset of neurological conditions and 1 month after clinical recovery. The trial suggest that fasudil can improve the neurological status of patients and clinical recovery, and did not cause serious adverse reactions, said Ming Fashu in Seoul is available for the treatment of acute ischemic stroke is safe and effective drug. Recently, Asahi Kasei Co., Ltd. has formally apply to the Japanese Ministry of Health to expand the indications of fasudil, for use in acute cerebral thrombosis (within 48h after onset) treatment.


4.1.3 suppress coronary artery spasm, reducing myocardial ischemic injury and improve cardiac function in patients with Coronary heart disease Otsuka, etc. for the stable angina patients during coronary angiography has given nitroglycerin (200 mg) and fasudil (30 mg) and to measure coronary artery diameter concentric stenosis, found that fasudil can increase the diameter of stenosis, the effect is stronger than nitroglycerin.


Will be used fasudil coronary spastic angina patients, can significantly inhibit acetylcholine-induced coronary artery contraction, to prevent chest pain and ischemic electrocardiographic changes occur, and for baseline systemic hemodynamics and coronary blood flow no significant effect.


Japan conducted a multicenter phase clinical trial evaluated oral fasudil for patients with stable exertional angina effect. The test indicated that the long-term use of fasudil may improve exercise capacity, expressed as prolong treadmill test in the maximum exercise time, ST segment depression on ECG delay emergence. and the patient for long-term use of the drug was well tolerated and no serious adverse reactions.


4.1.4 Treatment of pulmonary hypertension such as observed Fukumoto fasudil single dose of 9 cases of severe pulmonary hypertension in patients with acute effects, that can be mild fasudil reduced pulmonary artery pressure, increased cardiac index, pulmonary vascular resistance decreased and did not cause side effects such as hypotension.


Ishikura, also observed the use of fasudil on the acute effects of pulmonary hypertension, also found that fasudil reduced pulmonary artery pressure, cardiac index increased. In addition, fasudil can also shorten the total time of pulmonary resistance (TPR ), lower systemic vascular resistance, systolic arterial pressure decreased slightly.


4.2 fasudil and other clinical research will be applied fasudil in patients with essential hypertension, can increase the forearm blood flow in patients with lower forearm vascular resistance. Fasudil used in heart failure patients also observed similar effect.


Fasudil hydrochloride is found in Japan in 1987, the Department of hydrochloric acid amide isoquinoline compounds, is a new calcium antagonist, protein kinase inhibitor, inhibit the activities of intracellular calcium, inhibition of myosin light chain phosphorylation, expansion of cerebral blood vessels, thus prevention and treatment of cerebral vasospasm, improved cerebral ischemic symptoms, effective treatment of spasticity caused by ischemic cerebrovascular disease. and can be inhibited due to the increase in intracellular calcium caused by abnormalities of various enzymes activities, protect brain cells and improve prognosis, reduce the mortality effect. fasudil hydrochloride injection in the treatment of CVS after SAH onset fast and effective, can prevent and relieve cerebral vasospasm, reduce mortality and CVS disability. In recent years application of fasudil hydrochloride injection in treatment of cerebral vasospasm after SAH, and achieved good effect, increase the cure rate improved to reduce the mortality.


Aneurysmal subarachnoid hemorrhage for the final functional prognosis of patients with GOS assessment, fasudil and nimodipine to improve the role of the same; vein Wilkie input method to the Shu system does not affect blood pressure, and nimodipine may cause systemic blood pressure slightly decreased, said Ming Fashu to Seoul than nimodipine on cerebral blood vessels have a better selectivity; aneurysmal subarachnoid hemorrhage for the delayed cerebral vasospasm after treatment, fasudil is a kinds of safe and effective treatments.


[References]


[1] MA Jingjian, YANG Shuyuan, HONG Guoliang, et al, Effect of fasudil hydrochloride on cerebral vasospasm following aneurysmal subarachnoid hemorrhage in Phase clinical Trial [J], Journal of Chinese Clinical Medicine ,2009,42:61-72.


[2] Yoshio Suzuki, Masato Shibuya, Shin ichi Satoh, et al.Safety and efficacy of fasudil monotherapy and fasudil Ozagrel combination therapy in patients with subarachnoid hemorrhage: Sub analysis of the post marketing surveillance study [J]. Neurologia Medico chirurgica, 2008 , 48 (6) :241-248.


[3] Yukito Shinohara, Makoto Kobayashi, Toshiya Umeda.Medico economic evaluation for the treatment of acute ischemic stroke using a placebo controlled clinical trial of fasudil [J]. Nosotchu, 2007,29 (1) :22-28.


[4] Toshiaki Otsuka, Chikao Ibuki, Takeshi Suzuki.Vasodilatory effect of subsequent ad ministration of fasudil, a Rho kinase inhibitor, surpasses that of nitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris [J]. Circulation Journal, 2006, 70 (4) :402-408.


[5] Koelsch CF, Albertson NF.Synthesis of N methylmorphinane [J]. J Am Chem Soc, 1953,75 (5) :2095-2098.


[6] EP.Appl, 187,371 (1986, Asahi).


[7] USP, 4,678,783 (1987, Asahi).

[8] Shin-ichi Satoh, Ichiro Ikegaki, Toshio Asano, et, al.Antiischemic properties of fasudil in experimental models of vasospastic angina [J]. Journal of Pharmacological Sciences, 2001,87 (1) :34-40.


[9] Cedric Loge.Synthesis and pharmacological study of Rho kinase inhibitors: pharmacomodulations on the lead compound fasudil [J]. J of Enzyme Inhibition and Medicinal Chemistry, 2003,18 (2) 127-138.


[10] USP, 4,456,757 (1984).

[11] USP, 5,942,505 (1999).

[12] Chinese patent application number 200610044980.0. Fasudil medicinal salt hydrate.



[13] Chinese patent, CN1080721C, 2002, the 1 (5-isoquinoline sulfonyl) piperazine hydrochloride hydrate high.

[14] Zhang, Sun Xiaochuan. Fasudil pharmacological effects and clinical application of research progress [J]. Shanxi Medical University, 2007,38 (4) :369-373.


[15] Pharmaceutical Co., Ltd. Tianjin red fasudil hydrochloride injection instructions.

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