Novel application of tissue plasminogen activator

Abstract

Provided is a pharmaceutical composition with which it is possible to prevent the development of late-onset cerebral ischemia and obtain a prognosis-improving effect by performing active hematoma removal using a tissue plasminogen activator. This pharmaceutical composition contains a tissue plasminogen activator as an active ingredient and is for use in hematoma removal therapy in the cerebral cistern to remove a dislodged hematoma by suction by using the tissue plasminogen activator in an aqueous solution state as a cleansing agent, said therapy being performed at the same time as treatment of a cerebral aneurysm by means of craniotomy with clipping during the acute phase of a subarachnoid hemorrhage associated with a ruptured cerebral aneurysm.

Description

Novel uses of tissue plasminogen activator

[0001] The present invention relates to a novel use of tissue plasminogen activator.

[0002] 85% of subarachnoid hemorrhages are caused by ruptured cerebral aneurysms, and approximately 20% of subarachnoid hemorrhage cases result in sudden death soon after onset, with the overall mortality rate reaching 25-50% when subsequent deaths are included. Mortality from subarachnoid hemorrhage accounts for only 4.4% of all stroke deaths, but compared to other types of stroke, it occurs in younger generations, and in particular, more than 25% of stroke deaths in patients under 65 years of age are due to subarachnoid hemorrhage.

[0003] Factors that worsen function and life prognosis due to subarachnoid hemorrhage include cardiovascular events such as neurogenic pulmonary edema and heart failure due to a sudden increase in intracranial pressure in the hyperacute phase, rerupture, primary brain damage due to the hemorrhage itself, early brain damage due to increased intracranial pressure and subarachnoid hematoma, and delayed cerebral ischemic damage represented by subsequent cerebral vasospasm.In addition, functional impairment due to hydrocephalus after subarachnoid hemorrhage can occur from the subacute to chronic phases.

[0004] Acute treatment for ruptured cerebral aneurysms that have caused subarachnoid hemorrhage includes surgical clipping or endovascular coil embolization to prevent re-rupture, followed by intensive perioperative medical management to prevent delayed cerebral ischemic damage.

[0005] The incidence of delayed cerebral ischemic injury, even when limited to symptomatic cases presenting some kind of neurological symptom, has been reported to be 5.5-20%, and if asymptomatic cases detected only by diagnostic imaging are included, the incidence rate is over half (Non-Patent Documents 1-4). Multiple animal experiments have shown that cerebral vasospasm is caused by hematoma leaking into the subarachnoid space.

[0006] Based on this, reports of hematoma removal following craniotomy clipping were published in the 1980s and 1990s, but no significant improvement in prognosis was demonstrated (Non-Patent Document 5). Furthermore, the results of the large-scale ISAT study (Non-Patent Document 6) did not demonstrate the superiority of craniotomy clipping for hematoma removal compared with coil embolization, which does not remove the hematoma. Therefore, direct hematoma removal in the acute phase is no longer recognized as a valid treatment strategy, and drug therapy is now the primary method of preventing cerebral vasospasm. The following are thought to be reasons why conventional hematoma removal techniques have been ineffective: The cistern is not a single space but is divided into several compartments by the arachnoid membrane, and hematomas from subarachnoid hemorrhage are widespread throughout these compartments. Furthermore, subarachnoid hematomas are blood clots that do not circulate as effectively as normal cerebrospinal fluid. Therefore, direct hematoma removal poses a problem: removing the hematoma, which is firmly attached to the brain surface, simultaneously damages the pia mater.

[0007] In addition, a nationwide survey published in Japan in 2022 (Non-Patent Document 7) comparing craniotomy clipping and coil embolization showed that in univariate analysis, craniotomy clipping was associated with a significantly better prognosis than coil embolization, while multivariate analysis showed a slightly less significant difference, with an adjusted odds ratio of 0.82 (95% CI 0.63-1.07), suggesting the superiority of craniotomy clipping.

[0008] On the other hand, tissue plasminogen activator (hereinafter sometimes referred to as "t-PA") is a physiologically active substance in the body that converts plasminogen to plasmin on thrombi. In 1981, Collen succeeded in purifying human t-PA, and the following year, in 1982, Genentech, Inc. in the United States, succeeded in mass-producing highly purified human recombinant t-PA using genetic recombination techniques. In 1987, it was approved and marketed in the United States as a thrombolytic agent for acute myocardial infarction. In Japan, Kyowa Hakko Kogyo Co., Ltd. (now Kyowa Kirin Co., Ltd.) and Mitsubishi Kasei Corporation (now Tanabe Mitsubishi Pharma Corporation) began clinical trials in 1986, and were approved and marketed in March 1991.

[0009] There have been a number of past reports on the use of t-PA or urokinase, which has a similar thrombolytic effect, in the removal of cisternal hematomas for subarachnoid hemorrhage. However, the method of spraying t-PA into the cisterna after clipping (Non-Patent Documents 8-10) essentially involves spraying the cisterna and expecting subsequent hematoma dissolution; it is not a method in which the hematoma is freed from the surrounding tissue by the action of t-PA and then removed by lavage and aspiration. Furthermore, while there is a report that intraoperative lavage and aspiration removal of hematomas using urokinase dissolved in saline is useful for preventing delayed cerebral vasospasm (Non-Patent Document 11), there have been no reports to date of the lavage and aspiration removal of target hematomas using a lavage solution containing t-PA dissolved in saline or artificial cerebrospinal fluid (ArtCeleb®).

[0010] Brami J, Chousterman B, Boulouis G, Dorze ML, Majlath M, Saint-Maurice JP, Civelli V, Froelich S, Houdart E, Labeyrie MA. Delayed Cerebral Infarction is Systematically Associated with a Cerebral Vasospasm of Large Intracranial Arteries. Neurosurgery. 2020 Feb 1;86(2):E175-E183. doi: 10.1093 / neuros / nyz340. PMID: 31501886.Inagawa T, Yahara K, Ohbayashi N. Risk factors associated with cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo). 2014 Jun 17;54(6):465-73. doi: 10.2176 / nmc.oa.2013-0169. Epub 2014 Mar 27. PMID: 24670311; PMCID: PMC4533446.Rinaldo L, Rabinstein AA, Lanzino G. Increased Body Mass Index Associated With Reduced Risk of Delayed Cerebral Ischemia and Subsequent Infarction After Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 2019 May 1;84(5):1035-1042. doi: 10.1093 / neuros / nyy104. PMID: 29659999.Wachter D, Hans F, Kreitschmann-Andermahr I, Rohde V.老年患者动脉瘤性蛛网膜下腔出血和动脉瘤夹闭术后经颅多普勒检查及症状性血管痉挛的发生率较低?神经外科学。2011年8月;69(2):261 - 6;讨论266 - 7。doi: 10.1227 / NEU.0b013e31821d2b49。PMID: 21499142。佐佐木T,太田T,菊池H,高仓K,臼井M,近藤A,田边H,中村J,山田K。[鞘内注射rt - PA(TD - 2061)预防动脉瘤性蛛网膜下腔出血患者脑血管痉挛的初步临床试验]。《脑与神经》。1992年11月;44(11):1001 - 8。日语。PMID: 1296711。他莫利纽克斯AJ,克尔RS,余LM,克拉克M,斯奈德M,亚诺德JA,桑德科克P;国际蛛网膜下腔动脉瘤试验(ISAT)协作组。2143例颅内动脉瘤破裂患者神经外科夹闭与血管内栓塞的国际蛛网膜下腔动脉瘤试验(ISAT):对生存、依赖、癫痫发作、再出血、亚组及动脉瘤闭塞影响的随机比较。《柳叶刀》。2005 Sep 3-9;366(9488):809-17. doi: 10.1016 / S0140-6736(05)67214-5. PMID: 16139655.Irie K, Murayama Y, Urashima M, Ikawa F, Sano H, Sato A. Japanese Subarachnoid Aneurysm Trial of Neurosurgical Clipping versus Endovascular Coiling in 1863 Patients with Ruptured Intracranial Aneurysms. Neurol Med Chir (Tokyo). 2022 May 15;62(5):231-237. doi: 10.2176 / jns-nmc.2021-0249. Epub 2022 Apr 7. PMID: 35387943; PMCID: PMC9178111. Nakasu et al. Jpn J Neurosurg. 1996. [Japanese: Nakasu Yoko, Handa J., Effect of a single intraoperative administration of t-PA on delayed ischemic symptoms after subarachnoid hemorrhage, Journal of Neurosurgery, 1996, Vol. 5, No. 2, pp. 153-156, Published 2017 / 06 / 02, Online ISSN 2187-3100, Print ISSN 0917-950X, https: / / doi.org / 10.7887 / jcns.5.153, https: / / www.jstage.jst.go.jp / article / jcns / 5 / 2 / 5_KJ00002979013 / _article / -char / ja] Findlay JM. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery. 1995 Nov;37(5):1026-7. doi: 10.1227 / 00006123-199511000-00031. Erratum for: Neurosurgery. 1995 Jul;37(1):168-76; discussion 177-8.Erratum in: Neurosurgery 1995 Nov;37(5):1026-7. PMID: 8559330.Mizoi K, Yoshimoto T, Takahashi A, Fujiwara S, Koshu K, Sugawara T. Prospective study on the prevention of cerebral vasospasm by intrathecal fibrinolytic therapy with tissue-type plasminogen activator. J Neurosurg. 1993 Mar;78(3):430-7. doi: 10.3171 / jns.1993.78.3.0430. PMID: 8433145.Ota N, Noda K, Chida D, Kiko K, Miyoshi N, Kondo T, Haraguchi K, Kamiyama H, Tokuda S, Tanikawa R. Emergent Subarachnoid Clot Removal with Aneurysm Repair for Subarachnoid Hemorrhage Might Improves Clinical Outcome. World Neurosurg. 2022 Nov;167:e100-e109. doi: 10.1016 / j.wneu.2022.07.151. Epub 2022 Aug 8. PMID: 35953044.

[0011] Regarding the reason why a nationwide survey comparing craniotomy and coil embolization (Non-Patent Document 7) suggested the superiority of craniotomy and coil embolization, the inventors believe that hematoma removal, which is possible only during craniotomy, may be a factor in improving prognosis. Given this background, it is expected that simple hematoma removal will have little or no effect on improving the prognosis of subarachnoid hemorrhage cases by preventing delayed cerebral ischemic injury. However, if an aggressive intracisternal hematoma removal therapy could be established, in which tissue plasminogen activator, which can release hematoma adhering to the cistern, is used as a cleaning agent and the released hematoma is removed by suction, it is expected to have an effect on improving prognosis.

[0012] The present invention aims to provide a pharmaceutical composition that can prevent the occurrence of delayed cerebral ischemic injury and improve prognosis by actively removing hematomas using tissue plasminogen activator.

[0013] The gist of the present invention is as follows: (1) A pharmaceutical composition containing tissue plasminogen activator as an active ingredient, for use in intracisternal hematoma removal therapy in which the tissue plasminogen activator is used in the form of an aqueous solution as a detergent to aspirate and remove free hematoma simultaneously with craniotomy and clipping to treat the cerebral aneurysm during the acute phase of subarachnoid hemorrhage associated with ruptured cerebral aneurysm. (2) The pharmaceutical composition according to (1), in which the tissue plasminogen activator is dissolved in physiological saline or artificial cerebrospinal fluid and used as a lavage solution. (3) The pharmaceutical composition according to (1), which is used within 72 hours after the onset of subarachnoid hemorrhage. (4) The pharmaceutical composition according to (1), in which the hematoma removal therapy includes pressurized lavage of the cistern. (5) The pharmaceutical composition according to (1), in which the aqueous solution contains tissue plasminogen activator at a concentration ranging from 5,000 to 20,000 IU / ml. (6) The pharmaceutical composition according to (2) above, comprising a tissue plasminogen activator preparation diluted 10 to 200 times with physiological saline or artificial cerebrospinal fluid. This specification incorporates the disclosure of Japanese Patent Application No. 2024-053288, from which the present application claims priority.

[0014] According to the present invention, the occurrence of delayed cerebral ischemic damage can be prevented and the prognosis can be improved by actively removing hematomas using a tissue plasminogen activator preparation.

[0015] Figure 1 shows the state of the clots 24 hours after blood collection for specimens A, B, and C. Figure 2 shows the state of the clots 48 hours after blood collection for specimens A, B, and C. Figure 3 shows the color tone of the clots in the storage containers 48 hours after blood collection for specimens A, B, and C.

[0016] The present invention provides a pharmaceutical composition containing tissue plasminogen activator as an active ingredient, which is used in intracisternal hematoma removal therapy, in which the tissue plasminogen activator is used in the form of an aqueous solution as a detergent to aspirate and remove free hematoma, simultaneously with treatment of the cerebral aneurysm by craniotomy and clipping during the acute phase of subarachnoid hemorrhage associated with a ruptured cerebral aneurysm.

[0017] The pharmaceutical composition of the present invention is a lavage solution in the form of an aqueous solution in which tissue plasminogen activator is dissolved in saline or artificial cerebrospinal fluid (e.g., Artceleb (registered trademark)), and can be used for lavage and suction removal of hematomas to be treated.

[0018] Tissue plasminogen activator (TPA) has been identified as a naturally occurring protein in various animals. For example, in humans, a protein consisting of 562 amino acids is listed in databases such as the National Center for Biotechnology Information (NCBI) under Accession: NP_000921.1.

[0019] The tissue plasminogen activator used in the present invention may be any of the natural products described above. In this case, since it is contained in the rinsing solution that is ultimately removed by suction, it can be derived from humans or non-human animals, such as mammals (e.g., cows, pigs, mice, and rats), or birds (e.g., chickens), and is not particularly limited. Furthermore, the tissue plasminogen activator used in the present invention may be synthetic, and those obtained by genetic recombination are particularly suitable. Examples of genetically recombinant products include alteplase (e.g., ACTIVASE®), reteplase (e.g., RETEVASE®, RAPILYSIN®), and tenecteplase (e.g., TNKase®), and these can be used as appropriate.

[0020] Alteplase, reteplase, and tenecteplase are all known as thrombolytic agents in intravenous thrombolytic therapy. For example, alteplase is known to be administered intravenously to adult humans at a dose of 0.6 mg / kg to improve functional impairment associated with the acute phase of ischemic cerebrovascular disease, and at a dose of 0.5 to 0.75 mg / kg to dissolve coronary artery thrombus in acute myocardial infarction, each in the form of an aqueous solution of 600,000 international units / ml (IU / ml). Here, "IU" is a standardized unit defined by t-PA activity. Alteplase is contraindicated in patients suspected of subarachnoid hemorrhage.

[0021] Reteplase has a smaller molecular weight, a longer half-life, and a lower risk of bleeding compared to alteplase. Tenecteplase is a compound that replaces some amino acids in the alteplase molecule and is also believed to have a longer half-life than alteplase. Tenecteplase is being studied in clinical trials using intravenous administration at a dose of 0.25 mg / kg.

[0022] The tissue plasminogen activator in the pharmaceutical composition of the present invention is used as a detergent in the form of an aqueous solution. Examples of aqueous solutions include, but are not limited to, solutions in which tissue plasminogen activator is dissolved in physiological saline or artificial cerebrospinal fluid. The concentration of tissue plasminogen activator in the aqueous solution is not particularly limited, but is preferably in the range of, for example, 5,000 to 20,000 international units / ml (IU / ml), 6,000 to 15,000 IU / ml, or 6,000 to 12,000 IU / ml.

[0023] Clinically, as described below, it is preferable to dissolve and dilute an existing tissue plasminogen activator preparation (e.g., 24 million IU / V alteplase) before use when removing intracisternal hematomas by aspiration, and the pharmaceutical composition of the present invention is intended to encompass both the high-concentration composition before dilution (tissue plasminogen activator preparation) and the diluted composition (aqueous solution).

[0024] Therefore, in one embodiment, the pharmaceutical composition of the present invention is a composition obtained by diluting a tissue plasminogen activator preparation, which is conventionally used at a concentration of 600,000 IU / ml, with physiological saline or artificial cerebrospinal fluid 10 to 200 times, for example, 20 to 150 times, 30 to 120 times, 40 to 100 times, or 50 to 100 times.

[0025] The pharmaceutical composition of the present invention is used simultaneously with the treatment of cerebral aneurysm by craniotomy and clipping during the acute phase of subarachnoid hemorrhage. The acute phase of subarachnoid hemorrhage is generally considered to be about 14 days after the onset of the condition, but in the present invention, it is preferable to use the composition as soon as possible after the onset of the condition, for example, within 72 hours, 48 ​​hours, or 24 hours.

[0026] The pharmaceutical composition of the present invention is used for intracisternal hematoma removal therapy. Hematoma removal therapy preferably includes, but is not limited to, intracisternal pressure lavage. The pressure required for pressure lavage is not particularly limited, as long as it is within a range that can release the hematoma from the cerebral surface and surrounding tissues without damaging the pia mater on the cerebral surface. For example, pressure lavage of intracisternal hematomas can be performed using an lavage and aspiration device currently in clinical use, such as the Superbypass Suction Irrigation System (Takayama Medical Machinery Manufacturing Co., Ltd.) or the Strike Flow 2 Suction / Irrigation System (Stryker Japan Co., Ltd.). The device used for pressure lavage can be a combination of a device that performs pressure lavage and a device that aspirates and removes the lavage agent (including hematoma) after lavage. Alternatively, a lavage and aspiration device that can perform both pressure lavage and aspiration is preferred because it simplifies the operation. In this case, pressure lavage can use the lavage agent as a lavage perfusion solution in the cistern.

[0027] The hematoma is removed by suction until removal of the hematoma can be confirmed visually or until the irrigation fluid runs out. The amount of irrigation fluid used may vary depending on the amount of hematoma, but is, for example, in the range of about 2.5 L to about 4 L.

[0028] An example of the procedure for suction removal of intracisternal hematoma using the pharmaceutical composition of the present invention is shown below. 1. After craniotomy and clipping are completed, prepare saline or artificial cerebrospinal fluid (ArtCeleb) containing tissue plasminogen activator and place it in a high-pressure washer (recommended: 4 L). Also, prepare a suction device for suction removal of free hematoma. 2. In one cisternal compartment, spray the solution between the brain surface and the hematoma, and repeat this process to free the hematoma from the brain surface and surrounding tissue. The free hematoma is then suctioned and removed using the suction device. 3. Repeat step 2 for each accessible cisternal compartment.

[0029] The suction removal of intracisternal hematomas using this method is believed to be able to remove more hematomas in a shorter time and more efficiently without damaging the brain than conventional surface-only hematoma removal. Furthermore, the combined use of an irrigation and suction device offers additional value in that it allows for active release and removal of hematomas deep within the brain base, which is difficult to reach, depending on the craniotomy method (anterior or lateral approach), compared to the superficial areas of the brain that can be reached with simple cisternal drainage.

[0030] The present invention also provides a method for removing an intracranial hematoma in a patient, comprising irrigating and / or aspirating the hematoma with a detergent containing tissue plasminogen activator in an aqueous solution. In one aspect, the method of the present invention is a method for treating subarachnoid hemorrhage, and is performed on a patient in the acute stage of subarachnoid hemorrhage in combination with, preferably after, treatment for cerebral aneurysm by craniotomy or clipping. The detergent can be the pharmaceutical composition of the present invention described above in this specification.

[0031] The present invention also provides a tissue plasminogen activator for use in the treatment of subarachnoid hemorrhage. The tissue plasminogen activator is used in the form of an aqueous solution. In one embodiment, the tissue plasminogen activator for use in the present invention can be used during craniotomy for a patient in the acute stage of subarachnoid hemorrhage, in combination with treatment of cerebral aneurysm by craniotomy clipping, preferably after treatment of cerebral aneurysm, to wash and / or aspirate the hematoma at the affected site with a lavage solution in the form of an aqueous solution. The lavage agent can be the pharmaceutical composition of the present invention described above in this specification.

[0032] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0033] [Example 1] In the following example, alteplase, an intravenous recombinant tissue plasminogen activator preparation, was used as the tissue plasminogen activator. (1) Equipment and drugs used: (a) Surgical microscope; (b) Superbypass suction irrigation system (Takayama Medical Machinery Manufacturing Co., Ltd.); (c) Medical gauze; (d) 2 vials of alteplase, 6 million international units per vial; (e) 2 vials of alteplase, 12 million international units per vial; (f) 18 bottles of artificial cerebrospinal fluid (Art Celeb), 500 ml per bottle; (g) 3 servings of human blood, 20 ml per person (used for specimens A, B, and C, respectively).

[0034] (2) Method: Alteplase was diluted in artificial cerebrospinal fluid (ASF) at 6,000 international units / ml (IU / ml), 12,000 IU / ml, and a control group was treated with only ASF. Human blood (3 ml) was soaked in medical gauze (four-folded gauze) and left for approximately two hours to clot. The clot was entangled in the mesh of the gauze, mimicking a hematoma between the arachnoid pillars, arachnoid membrane, and normal blood vessels in the cistern. These samples were designated as samples A, B, and C. Human blood samples were collected from healthy adult volunteers after obtaining consent forms.

[0035] The effectiveness of the medical gauze was evaluated by washing and removing the clots 24 and 48 hours after soaking the gauze in human blood. The clots that recreated hematomas as described above were left for 2 hours, and once blood clot formation was confirmed, they were immersed in artificial cerebrospinal fluid to prevent drying and stored in an incubator at 37°C until use for evaluation. Figures 1 and 2 show the state of the clots before washing 24 and 48 hours after blood collection for specimens A, B, and C, respectively. Figure 3 shows the color of the clots immersed in artificial cerebrospinal fluid in the storage container 48 hours after blood collection for specimens A, B, and C.

[0036] Using a Superbypass suction irrigation system (set at 200 mmHg pressure) under a neurosurgical microscope, the clot was sprayed with artificial cerebrospinal fluid containing various concentrations of alteplase and immediately aspirated. The irrigation and aspiration were repeated until all clots were removed or a total volume of 250 mL of irrigation fluid was used for each specimen.

[0037] (3) Evaluation method The gauze was soaked with blood clots and washed sequentially from the upper left to the upper right. Once the clots were completely washed, additional washing was performed downwards, and continued until the bottom right. When all clots were removed, the total amount of solution and the total unit amount of alteplase were measured and recorded. If any clots remained, this was noted. The experimenters were blinded to the washing solution used and the results were verified afterward.

[0038] The dissolution and cleaning effects were judged to be successful if the clots were completely removed in all three samples. The clots consisted of those adhering to the gauze surface and those entangled in the mesh of the gauze. The amount of cleaning solution used when the clots on the gauze surface were removed was recorded, and an evaluation was also made to see if the clots in the mesh of the gauze had been dissolved and removed. The Japanese Standard Product Classification number and lot number of the alteplase used were recorded. The experimental results were recorded with the date in a digitally signed PDF file and in a laboratory notebook. A video of the experiment was also recorded and saved.

[0039] (4) Disposal All consumables used in this study, including the remaining and recovered cleaning solution or saline, gauze, and remaining blood, were disposed of as infectious waste.

[0040] (5) Results The results for specimens A, B, and C are shown in Tables 1 to 3, respectively.

[0041]

[0042]

[0043]

[0044] (6) Discussion As shown in Tables 1 to 3, when the pharmaceutical composition of the present invention (alteplase 6,000 IU / ml or 12,000 IU / ml group) was used, blood clots entangled in the mesh of the gauze were removed by pressurized lavage more effectively at 48 hours than in the control group (artificial cerebrospinal fluid only), particularly in a dose-dependent manner, and blood clots were removed in all cases at 48 hours. Furthermore, at 48 hours, the blood clots in specimens A and B had begun to dissolve and had softened compared to the blood clots at 24 hours, whereas the blood clots in specimen C had hardly dissolved at all (see Figure 3).

[0045] [Example 2] A separate test was conducted and evaluated using the same procedures as in Example 1, except as noted below. A hematoma was artificially recreated by soaking medical gauze in human blood and leaving it for three hours, causing the clot to become entangled in the mesh of the gauze. The clot was then washed and removed 24 and 72 hours after soaking in the human blood, and its effectiveness was evaluated. The clot that recreated the hematoma was left for three hours, then immersed in artificial cerebrospinal fluid and stored in a 37°C incubator until use for evaluation. The experimenter was blinded to the washing solution used, and the results were subsequently verified.

[0046] Table 4 summarizes the results for three specimens, specimens A to C. The evaluation was performed three times for each condition, and the amount of solution in the table indicates the amount (ml) required to wash off the surface clot.

[0047]

[0048] As shown in Table 4, after 24 hours, the clots could not be washed away from two-thirds of the specimens in the control group (artificial cerebrospinal fluid only), but they were washed away without any problems when the pharmaceutical composition of the present invention was used (alteplase 6,000 IU / ml or 12,000 IU / ml groups), confirming the usefulness of the pharmaceutical composition of the present invention.

[0049] On the other hand, after 72 hours, the clots adhering to the surface were washed away in all groups, but clots entangled in the mesh of the gauze remained in 2 / 3 of the control group specimens and 2 / 3 of the alteplase 6,000 IU / ml group specimens, even after the entire volume of washing solution was used. However, with alteplase 12,000 IU / ml, they could be washed away, and better results were obtained by increasing the dose. Furthermore, after 72 hours, the clots had softened during storage in the artificial cerebrospinal fluid, becoming softer before washing than those after 24 hours. Therefore, in all groups, the surface clots were removed with less solution after 72 hours than after 24 hours. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

1. A pharmaceutical composition containing tissue plasminogen activator as an active ingredient, for use in intracisternal hematoma removal therapy, in which the tissue plasminogen activator is used in aqueous solution form as a detergent to aspirate and remove free hematoma, while simultaneously treating the cerebral aneurysm with craniotomy and clipping during the acute phase of subarachnoid hemorrhage associated with a ruptured cerebral aneurysm.

2. The pharmaceutical composition according to claim 1, wherein the tissue plasminogen activator is dissolved in physiological saline or artificial cerebrospinal fluid and used as a washing solution.

3. The pharmaceutical composition according to claim 1, which is used within 72 hours after the onset of subarachnoid hemorrhage.

4. The pharmaceutical composition according to claim 1, wherein the hematoma removal therapy comprises pressure lavage of the cistern.

5. The pharmaceutical composition of claim 1, wherein the aqueous solution contains tissue plasminogen activator at a concentration ranging from 5,000 to 20,000 IU / ml.

6. The pharmaceutical composition according to claim 2, which contains the tissue plasminogen activator preparation diluted 10 to 200 times with physiological saline or artificial cerebrospinal fluid.

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