JPH0429935A - Medicinal composition for curing cerebral diseases w194 abnormal blood vessel as pathogenesis or morbid state - Google Patents

Abstract

PURPOSE:To obtain the subject medicinal composition having lowering action on the blood flow in abnormal blood vessel, containing tumor necrosis factor (TNF) as an active ingredient. CONSTITUTION:The objective drug composition contains an effective amount of a human TNF produced by a recombinant DNA technique, a human TNF produced by culturing cell derived from human or homologous isomer of the human TNF, at least a species of carrier capable of administrating with the medicinal component and a diluent or an excipient. Said composition is extremely effective for curing of the cerebral diseases with an abnormal blood vessel as a pathogenesis (e.g. cerebral arteriovenous malformation or angioma) or the cerebral diseases with an abnormal blood vessel as a morbid state (e.g. meningioma, glioma or metastatic cerebral tumor), and also useful for reducing the fleeding in the operation to cure said cerebral diseases by abscission operation of the abnormal position.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention provides a pharmaceutical composition containing tumor necrosis factor (hereinafter abbreviated as TNF) as an active ingredient and used for treating a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels. relating to things. Here, "a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels" is:
For example, brain diseases caused by the presence of abnormal blood vessels such as cerebral arteriovenous malformations and hemangiomas, and pathological conditions caused by the presence of abnormal blood vessels such as meningiomas, gliomas, and metastatic brain tumors. This includes both brain diseases.

(Prior Art) Cerebral arteriovenous malformations are a typical example of a group of brain diseases caused by the presence of abnormal blood vessels. Macroscopically, cerebral arteriovenous malformations are a collection of dilated and tortuous abnormal blood vessels, with no capillaries intervening between the arteries and veins, and direct anastomosis via remnant blood vessels from the embryonic period. This anastomosis has extremely low vascular resistance compared to the surrounding normal tissue, and the amount of blood flowing through it increases. As a result, the arteries and veins at the anastomotic site are secondarily dilated significantly. A state of cerebral ischemia appears in the brain tissue around the anastomosis due to the shunt of blood flow, and rupture of blood vessels causes hemorrhage into the subarachnoid space and brain parenchyma. The majority of bleeding is subarachnoid hemorrhage, but about half of the patients are accompanied by neurological deficit symptoms such as movement disorders, aphasia, and visual field disturbances, and bleeding occurs within the brain at the same time as subarachnoid hemorrhage. There are many things.

(Rigakusha, Latest Neurosurgery, 1988) Currently, there is no radical treatment for venous malformation other than complete removal of the lesion through intracranial surgery, and the skill and experience of the surgeon are important factors in determining the prognosis. , it cannot be said that there is an established treatment method.

On the other hand, meningioma is a typical example of a group of diseases whose pathology is the presence of abnormal blood vessels. Meningiomas are generally benign tumors with clear borders, so if they can be completely removed without collateral damage, the prognosis is very good. However, due to the abundance of blood vessels, removal is not always easy and requires skillful surgical techniques. Significantly related to prognosis.

There are also many cases where surgery is not possible for the same reason. Radiation therapy is performed for cases with repeated recurrences or those showing significant vascular hyperplasia, but radiation necrosis of normal brain tissue becomes an important problem.

TNF is derived from viable Microbacterium bovic (formerly known as Crobacterium bovic).
e) Bacillus
It was first discovered in the serum of mice that had been pre-administered with S. Calmette Guerin strain (BGG) and then intravenously administered bacterial endotoxin. [Proc. Na1. Ac.
ad, Sci, U, S.

A,) Vol. 72, No. 9, pp. 3666-70 (1975)
]. Mouse serum containing TNF was prepared in vitro.
Although it has shown cytotoxic or cytostatic activity against a number of mouse and human transformed cell lines in tests, these effects are very weak against normal cells. Mouse serum containing TNF causes necrosis of tumors that can be implanted into mice. TNF is also produced in the serum of rats, rabbits and guinea pigs. Furthermore, TNF can also be produced under certain conditions by mononuclear phagocytes, fibroblasts, B cells, etc. of mammalian origin. This is discussed in Scientific American by Lloyd J. Old (01d).
tific American) Volume 258 No. 5 59-
There are many reports in the literature cited in the review on page 75 (May 1988).

(Problem to be solved by the invention) In order to solve these therapeutic problems, preoperative artificial embolization of arteries is performed for a group of diseases that include both of these, with the aim of reducing blood loss during surgery. It is often done. This method involves performing selective cerebral angiography and injecting finely chopped sponge-like gelatin through a catheter.
The site of embolization is not necessarily selective, and obstruction of the superior pharyngeal artery, lingual artery, superior artery, etc. can cause airway obstruction, tongue atrophy, postoperative skin flap necrosis, and impaired healing mechanism. There is a danger. (Medical Pew Inc. Illustrated Clinical [Cancer] Series No. 15 Brain Tumor, 1987) (Means for Solving the Problem) The present inventors had been conducting intensive research on the clinical effects of TNF, and unexpectedly found that The inventors discovered that TNF has the effect of reducing blood flow in abnormal blood vessels, and based on this finding, continued research and completed the present invention.

According to the present invention, an amount of TN effective for reducing blood flow in abnormal blood vessels
Provided is a novel pharmaceutical composition for treating a group of brain diseases whose etiology or pathological condition is the presence of abnormal blood vessels, which contains F and at least one pharmaceutically administrable carrier, diluent, or excipient. Furthermore, according to the present invention, there is provided a pharmaceutical composition for the purpose of reducing bleeding during surgery to remove an abnormal site in a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels. A group of brain diseases caused or characterized by the presence of abnormal blood vessels containing an amount of tumor necrosis factor effective to cause a reduction in blood flow and at least one pharmaceutically acceptable carrier, diluent or excipient. A therapeutic pharmaceutical composition is provided.

In the present invention, TNF obtained from mammalian-derived serum or mammalian-derived cells can be used as an active ingredient. Preferably, a composition is used.

Human I-T NF suitable for use in the present invention can be produced by recombinant DNA technology. Alternatively, human TNF can also be produced by culturing cells of human origin.

A suitable example of a method for producing Hi-TNF using recombinant DNA technology is, for example, Shilaiti = (Shi
rai T, ) et al., Neci + (Nature), 3
Volume 13, page 803,806 (1985) and JP-A-60-2
No. 52496 (European patent application publication number 0.158,286
(corresponding to the number).

For example, homogeneous TNF can be obtained by culturing E. coli. The human 1-TNF activity during purification was determined in L-M cells [American Type Culture Collection, CCL 1.2].
1ture collection, CCL 1.2)]
Williamson et al.
It can be determined by the cell killing activity against mouse L-cells by a modified method of the method of t, al,).

The number of amino acids that make up human-TNF varies depending on the manufacturing method used to obtain TNF. For example, human TNF produced by recombinant DNA technology as described in European Patent Application No. 0158286 consists of 155 amino acids. On the other hand, the above Penni
Human TNF produced by methods such as ca) is 157
It has a sequence consisting of 2 amino acids and 2 amino acids bonded to its N-terminus.

TNF produced by recombinant DNA technology consists of a polypeptide having a methionine residue attached to the N-terminus of the above amino acid sequence, and a polypeptide having a methionine residue attached to the N-terminus of the above amino acid sequence.
Also included are intermediates in which part or all of the NF signal peptide is bound. It is possible to change part of the structure of the DNA encoding a polypeptide by natural or artificial mutation without causing any significant change in the activity of the polypeptide.

Human TNF that can be used in the present invention is a homologous variant of the polypeptide having the above amino acid sequence.
It includes polypeptides having a structure corresponding to a logous variant). Examples of homologous variants include U.S. Patent Boxes 4,677.063 and 4,677.064.
Examples include the peptides described in No. All these bioactive peptides are also referred to hereinafter as "human TNFJ".

Natural human TNF is easily subject to biochemical or chemical modification, and is also likely to form aggregates such as dimers and trimers. These naturally produced TNF polypeptides, hereinafter referred to as "human TNFJ", can also be used as active ingredients in the pharmaceutical compositions of the present invention.

TNF is currently undergoing clinical research as an anticancer agent. However, the inventors unexpectedly found that T
We found that administration of NF reduces blood flow in various types of abnormal blood vessels. That is, the present invention is based on the discovery of a new effect of TNF that is different from any previously known effects. Specific clinical examples are shown below.

1 bed example 1) Using TNF produced by recombinant DNA technology according to the method described in European Patent Application Publication No. 158,286,
A clinical trial was conducted.

TNF was administered five times to a 45-year-old male patient with malignant astroglioma.

The first dose was administered at an actual dose of 50,000 units into the carotid artery over 15 minutes. The administration was repeated every week using the same administration method, and the second administration was administered at an actual dose of 100,000 units, and the 3.4.5th administration was administered at an actual dose of 300,000 units.

Approximately one month after the final administration, the tumor was removed, and it was found that the tumor had undergone coagulative necrosis, which was thought to be caused by the cessation of blood flow, and was removed very easily.

(Clinical Example 2) A clinical trial was conducted using TNF produced by recombinant DNA technology according to the method described in European Patent Application Publication No. 0,158,286.

This TNF was administered to a male patient with meningioma at a rate of 5 per square meter of body surface area.
A dose of 0,000 units was administered selectively into the carotid artery over 15 minutes. This method of administration was performed once, and then gelatin sponge was administered in the same manner. When surgery was performed four days later, the amount of bleeding was less than when sponge gelatin was used alone, and bleeding from the attachment of the tumor and meninges, which normally bleed, was also significantly reduced, making it extremely easy to remove. The center of the III tumor had developed necrosis, which was thought to be caused by cessation of blood flow.

As is clear from the above results, administration of human TNF has been shown to have the effect of reducing blood flow in abnormal blood vessels in the treatment of brain diseases whose etiology or pathology is the presence of abnormal blood vessels.

The pharmaceutical composition of the present invention for treating the above diseases can be administered as an intra-arterial, intravenous, intramuscular, subcutaneous or intradermal injection, or as an oral preparation.
It can be administered as an external preparation, suppository, or eye drops. Examples of formulations include solutions or lyophilized products. In formulating the formulation, excipients include starches such as pulp starch, corn starch, dextrin, wheat, and starch, starch derivatives such as hydroxypropyl starch, and saccharides such as lactose, glucose, sucrose, mannitol, and sorbitol. , celluloses such as methylcellulose, carboxymethylcellulose, and hydroxypropyl starch; inorganic substances such as thorium chloride, boric acid, calcium sulfate, calcium phosphates, and precipitated calcium carbonate; as a fluidizing agent, heavy magnesium oxide, synthetic Magnesium aluminate silicate, hydrated silicic acid, talc, magnesium stearate, anhydrous silicic acid, kaolin (
Examples of binders include synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol, and derivatives thereof, gum arahia, 1
~ Natural products such as lagant, sodium alginate, gelatin, and gluten; stabilizers include proteins such as albumin, gelatin, globulin, protamine, and protamine salt; and amino acids; pH regulators include hydrochloric acid, sodium hydroxide, Phosphates, citrates, carbonates, etc. can be used.

The pharmaceutical compositions of the present invention generally provide a daily dose of human 1-TNF for adults of about 5 per m 2 of body surface area.
from 0 to ioo, ooo, ooo units, preferably from about 50 to 500,000 units for intra-arterial administration and from about 50 to 50,000 units for topical administration.
0 unit dose, approximately 1,000 to 2,000,000 for common administrations such as intravenous or intramuscular administration.
In unit doses and for oral administration, approximately 10°O
A dose of 100,000,000 units from OO can be administered to patients with a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels. - The daily dosage varies depending on the patient's age and symptoms. As mentioned above, the pharmaceutical composition of the present invention includes:
Usually 50 to 100 - days, over a period of several days to several weeks.
It can be administered in doses of 1,000,000 units. This daily dose can be administered to the patient in one sitting or in several divided doses.

The pharmaceutical composition of the present invention can be administered daily or at intervals. Examples of typical administration methods are shown below.

a) Daily administration for 1 to 4 weeks b) Daily administration for 6 days, followed by intermittent administration with body medications in between for 7 days to several weeks c) Once a week administration d) Daily administration for 5 days, then 1 Intermittent administration with a period of several months of physical therapy.

As described above, according to the present invention, it is possible to provide a pharmaceutical composition for treating a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels for which there is currently no reliable treatment method.

An embodiment of the present invention will be specifically described below in Examples.

Example 1 Hi1-TNF was prepared by recombinant DNA technology according to the method described in European Patent Application No. 158,286,
A lyophilized injectable preparation having the following composition is prepared using the obtained TNF.

■ Composition Human TNF 50.000 Units D-mannitol 3 mg Normal serum albumin (human) 1 mg Sodium chloride 0.2 mg Sodium dihydrogen phosphate 0.4 mg (p with sodium hydroxide)
(Example 2) Human TNF was prepared by recombinant DNA therapy in the same manner as in Example 1, and the obtained human TNF was used to prepare an injectable product with the following composition. Prepare the lyophilized formulation.

Composition Human TNF 50,000 units Mannitol mg Normal serum albumin (human) 10 mg Sodium chloride 2.0 mg Sodium dihydrogen phosphate 3.9 mg (p with sodium hydroxide)
++ a. (prepared in 2008) (Effects of the Invention) The pharmaceutical composition of the present invention is extremely effective in treating a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels. Here, "a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels" includes, for example, a group of brain diseases whose etiology is the presence of abnormal blood vessels such as fan vein malformation and hemangioma, and, for example, It includes both a group of brain diseases whose pathology is the presence of abnormal blood vessels, such as meningiomas, gliomas, and metastatic brain tumors. By using the present invention to cause a decrease in blood flow in abnormal blood vessels, it is possible to directly treat a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels. Furthermore, when treating a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels by surgically resecting the abnormal site, the present invention can be used to reduce bleeding during surgery and facilitate treatment. .

Claims (2)

[Claims] (1) The presence of an abnormal blood vessel containing an amount of tumor necrosis factor and at least one pharmaceutically acceptable carrier, diluent, or excipient that is effective to cause a reduction in blood flow in the abnormal blood vessel; A pharmaceutical composition for treating a group of brain diseases as pathological conditions. (2) A pharmaceutical composition aimed at reducing bleeding during surgery to remove abnormal areas in a group of brain diseases whose etiology or pathology is the presence of abnormal blood vessels, which causes a decrease in blood flow in abnormal blood vessels. containing an amount of tumor necrosis factor effective to
A pharmaceutical composition for treating brain diseases whose etiology or pathology is the presence of abnormal blood vessels, which contains at least one pharmaceutically administrable carrier, diluent, or excipient.