JPS63145230A - Cerebral vasospasm prevention and treatment agent - Google Patents

Abstract

PURPOSE:To obtain a preventive and remedy for cerebrovascular contraction having suppressed side effects such as swelling, dull pain, fever, etc., and suitable for the treatment of intracerebral hemorrhage, by using a prostaglandin E1- containing fat emulsion as a main component. CONSTITUTION:Soybean oil, phospholipid, prostaglandin E1, water and, if necessary, an emulsification assistant, a stabilizer a polymeric substance, an isotonic agent, etc., are mixed with each other and heated. The obtained mixture is homogenized with a homogenizer, added with water and again homogenized with a homogenizer to convert the mixture to an O/W-type emulsion and obtain the objective agent. Sufficient effect can be attained by using a fat emulsion containing 100-0.2mug/ml of prostaglandin E1. Preferably, 0.1-10mug/kg body- weight of prostaglandin E1 is administered once or twice a day continuously for 5-10 days. The agent is administered preferably within several days after the fit of intracerebral hemorrhage.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a preventive/therapeutic agent for cerebral vasospasm containing a prostaglandin E1-containing fat emulsion (hereinafter referred to as LipO-PGEt) as a main component.

[Prior Art] Cerebral vascular atrophy is likely to occur after subarachnoid hemorrhage due to rupture of a cerebral aneurysm, occurs in about 273 patients with subarachnoid hemorrhage, and is an important factor that influences the prognosis of these patients.

Because vascular atrophy lasts for a long time, it differs from simple functional vasoconstriction in that it involves organic changes, including floating liver or necrosis of endothelial cells and smooth muscle cells, platelet adhesion to cell damage areas, and
Aggregation causes ischemic symptoms and is also involved in the occurrence of infarction.

Treatments for cerebral vasoconstriction include (1) attempts to inactivate the directrix substance, (2) attempts to re-expand the blood vessels causing the vascular directrix, and (3) treatment of the brain caused by vascular condensation. Those that attempt to correct the decrease in blood flow by various methods, (4)
Methods such as administration of drugs have been attempted to increase the brain's resistance to cerebral ischemia.

Recently, prostaglasin has attracted attention as one of the degenerate substances, and the influence of prostaglandin E1 on vascular atrophy has been studied.

[Problem that the invention attempts to solve] The inventors conducted various research and found that Lip.

The present invention was completed based on the discovery that -PG[+ exhibits remarkable preventive and therapeutic effects when administered to patients with subarachnoid hemorrhage.

Therefore, an object of the present invention is to provide a preventive/therapeutic agent for cerebrovascular disease.

[Means for solving the problems] The present invention provides cerebral blood vessels 9 containing LipO-PGEI as a main component.
Concerning anti-inflammatory and therapeutic agents.

LipO-PGE+ used in the present invention is a fat emulsion of PGE+, which is the main component of the formulation, and is already applied on the skin.

In the present invention, the fat emulsion refers to soybean oil 5~5°W/V
%, 1 to 50 parts, preferably 5 to 30 parts, of phospholipid per 100 parts of soybean oil, and an appropriate amount of water.

In addition, if necessary, an emulsification adjuvant [for example, 0.
up to 3% (w/v) m of fatty acids having 6 to 22, preferably 12 to 20 carbon atoms or physiologically acceptable salts thereof], stabilizers [e.g. 0.5% (w/v) , preferably 0.1% (w/v) or less of cholesterol or phosphatidic acid in an amount of 5% (w/v), preferably 1% (w/v) or less] polymeric substances [e.g. PGE + 0.1 to 5 parts by weight, preferably 0.5 to 1 part by weight of albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch, etc.], Isotonic agents (eg, glycerin, glucose, etc.) and the like can also be added.

The content of PGE 1 in a fat emulsion can be increased or decreased as appropriate depending on the form of the emulsion and its use, but it is generally sufficient to contain it in a very small amount, for example 100 to 0.2 μg/-, in the emulsion.

Details are disclosed in Japanese Patent Application Laid-Open No. 58-222014.

The fat emulsion of the present invention is produced, for example, by the following method.

That is, predetermined amounts of soybean oil, phospholipids, PGE+, and other additives mentioned above are mixed and heated to form a solution,
A water-in-oil dispersion is prepared by homogenization using a commonly used homogenizer (for example, a pressure jet type 1 homogenizer, an ultrasonic homogenizer, etc.), then the necessary amount of water is added to this, and the mixture is re-dispersed. The fat emulsion of the present invention can be produced by homogenizing it with the homogenizer and converting it into an oil-in-water emulsion. Depending on manufacturing convenience, additives such as stabilizers and isotonic agents may be added after the production of the fat emulsion.

The fat emulsion of the present invention is administered intravenously or dynamically. More preferred is continuous infusion into the carotid artery. Specifically, a catheter is retrogradely inserted from the superficial carotid artery to the common carotid artery bifurcation, which serves as an injection route for Lipo-PGEt.

The dosage is approximately 0.1 to 1 PGE per dose.
As a general rule, use 9 body weight per 0 μ'J/day once or twice a day, but the dose can be increased as appropriate depending on the symptoms. Preferably, administration is carried out continuously for 5 to 10 days.

The timing of administration is preferably within multiple days of the intracerebral hemorrhage attack.

Targets for administration are patients with intracerebral hemorrhage who may have cerebral vasoconstriction, such as patients with subarachnoid hemorrhage.

[Operations and Effects of the Invention] As a result of administering LipO-PGE+ to a patient suffering from intracerebral hemorrhage, it significantly prevented cerebral blood vessel directrix and also minimized brain damage caused by cerebral ischemia caused by cerebral vasoconstriction.

The fat emulsion of the present invention reduces the side effects of conventional PGE+ preparations, such as swelling, dull pain, redness, and fever at the injection site, which occur due to the vascular permeability enhancing effect and inflammatory effect that PGE+ inherently has. have an effect. Also, are there any other serious side effects? jA It is not noticed.

Thus, it is suggested that Lipo-PGE1 of the present invention is useful as a preventive/therapeutic agent for cerebral vasospasm in patients with intracerebral hemorrhage.

[Example] Experimental examples, manufacturing examples, and clinical examples of the fat emulsion of the present invention are not shown below, but the present invention is not limited thereto in any way.

The [05o value of the formulation of the present invention produced according to Production Example 1 described later in rats was 200 trdl/'S body weight or more as a 10% fat emulsion, and 1501 dl/K9 body weight or more as a 20% fat emulsion, which was higher than normal. No hemolysis was observed when the drug was infused at a high speed.

Production example 1 30g of refined soybean oil, 3.6g of egg yolk lecithin, PGE +
Add 900 μg of sodium balmitate and 0.15 g of phosphatidic acid, and heat at 40-75°C.
The mixture was heated and dissolved. Add 200 d of distilled water to this, then add 1.5 g of glycerin in the Japanese Pharmacopoeia, and add 20-40 d of distilled water.
All the mixtures were adjusted to 300 rd with distilled water for injection at ℃, and coarsely emulsified using a homomixer.

Using a Manton-Gallin type homogenizer,
The emulsification was carried out by passing the mixture 10 times under a pressure of 12 ONg/m and a total pressure of 500 Kg/cm. This resulted in a homogenized extremely fine fat emulsion containing PGE 1. The average grain size of this emulsion was 0.2 to 0.4 .mu. and contained no grains larger than 1 .mu..

Clinical Case ■ Subjects and Methods Eight patients who developed delayed cerebral vascular curvature after subarachnoid hemorrhage due to ruptured cerebral aneurysm were studied (Table 1).

Table 1 Case Gender 1 Age Aneurysm CT scan Subarachnoid
Date Grade of hematoma 1 M, 53 1HCA 1 Gr
oup32 F, 70 LPCoA 3
' GrOUl) 33 F, 69 Ba
5Bif 7 Group24 M, 6
3 RHCA 4 Group24
F, 51 L) 4CA 3 G
roup368.58 8CoA 2
Group 37 F, 71 ACoA
2 Group38
F, 61 RPCo^ 1 Gro
Up 3 Ages: 50 to 71 years old, gender: 3 males, 5 females
It was an example. The ruptured aneurysm was present in two cases:
Two cases involved the medial artery-posterior communicating artery branch, three cases involved the middle cerebral artery, and one case involved the basilar artery branch. Grade at admission (l
lunt & osnik) is grade II
1 case, grade III 5 cases, grade IV
There were 2 cases. In addition, Fisher's CT classification (F
isher C)4. 1stler JP and D
avis JH: Relation of cere
bral vasospasmto 5ubarach
noid hemorrhage visualize
d byComputed tomographic
scanning, NeUrO3urg, 6:
The degree of subarachnoid hematoma caused by gro
There were 21 cases in group 3 and 7 cases in group 3. Grad
e Clipping was performed on days 1 to 3 of the attack in all cases, except for the basilar artery bifurcation aneurysm case of IV. All patients received hyperosmolar diuretics and steroids in addition to regular fluids. In surgical cases, in addition to this, an album will be released after the surgery.
in (1g/Kg/day), hyper
volemia was performed. , Cerebral angiography was performed within 24 hours after the appearance of old blood symptoms, and the degree of blood vessel constriction was observed. A narrowing of the blood vessel diameter by 50% or more is called a directrix blood vessel, one that is localized to one main brain artery is called a focal type, and one that is present in two or more branches is called a diffuse blood vessel.

LipO-PGE+ administration was started 6 hours to 3 days after the onset of ischemic symptoms. LipO-PGEt was mixed with 15-20μ of PGE + in physiological saline for 100 d,
The infusion was continued for 60 minutes every 8 hours for 5 to 7 days.

Changes in blood pressure, peripheral blood images, and liver function tests were conducted before and after administration. In addition, as an indicator of effectiveness, the first Lip
Before and within 6 hours after administration of o-PGEI, local cerebral blood flow (
γCBF) and somatosensory evoked potentials (SEP) were measured.

7c is single photon ECT (Tom
omatic 32) by the Xe-133 inhalation method. ((Bonte FJ and 5to
kcly EM :Single-photon to
mographic 5tudy of region
alcerebral blood flow aft
er 5stroke, J, Nucl.

Hed, 22: 1049-10531981),
(Lassen NA.

Henriksen L and Paulson D
B: Regional cerebral bloo
d flow in 5 strokes by 133
enoninhalation and emissi
on tomography, 5 strokes 12
: 284-2881981), (Lassen NR
, Henrikscn Land Paulson O
B: Regional cerebral bro
oddflow by radioxenon-1331
nhalation and dynamic emis
sion tomoqraphy, Proa, Nu
cl.

Hed, 7: 110-1171981>)0M
Measurements were made by setting six regions of interest in the left and right anterior, middle, and posterior cerebral artery regions at 5 slices 4 to 6 cm above the 1 inch. In addition, 20 normal cases (26-6
The average CBF values of the anterior, middle, and posterior cerebral artery regions of 7o) were 64.2±9, 2.69, and 0±6.4.62 on the right side, respectively.
1±1.0, left 67.0±10.1.72.3±1.4
．． It was 61.1±6.2m/100g/min.

In addition, γCBF in each region due to LipO-PGEs administration
The rate of change ((γCBF after administration - γC8 before administration)/γCBF before administration x 100) was determined.

Regarding SEP, N14 originates from the medulla and N2 originates from the sensory cortex.
The inter-vertex latency of o is central conduction
n time (ccr). ((Hagra
dine JR, BranstonNM and Sy
mon L: Central conduction
n time implicit brainisc
hemia-A 5 studies in baboons.

5troke 11: 637-6421980),
(Symon L.

tlargadine J, Zawirski H
and Branston N:Central c.
induction time as an 1nd day
x ofischemia in 5ubarachn
oid hemorrhage, J.

Neurol, Sci, 44:95-1031
979)) His grades at the time of discharge were completely normal.
l 1ent), mild neurological deficit symptoms but able to live a social life (good), social life impossible but able to live at home on one's own (fair), unable to live at home on one's own (fair);
The disease was classified into five stages: poor, dead, and dead.

■Results Cerebral ischemic symptoms appeared 7 to 13 days after the hemorrhagic attack, and were diffuse (diHuse) in 8, 5 cases, and focal (focal).
l) tip Table 2).

Table 2 (6 months of total paralysis) Total aphasia (total aphasia) 2 Diffuse llemiparesi
s 2 days 5 days D
ied (total paralysis for six months) Motor aphasia (motor aphasia) 3 Diffuse Scmicoma
3days 5days Died〈half v3
11 ri Quadiparsis (Quadriparesis) 4 1ocal llemiparesis
1days 5days Excel
ent5 Focal Hcmiparcs
is 5hrs 5days Excel
llent6 lo1ffusc Somn
olcncc 1day 7
davs Good (tilt mouth) 11emiparesis 7 1ocal Hcmiparcsi
s 12hrs 7days
GoodTotal aphasia 8 Dil'fuse l1cm1pare
sis 1day 7days
Excellent (Results of γCBF (cerebral blood flow) measurements performed before and after the first LipO-PGEI administration) In the left cerebral hemisphere, γCBF in the anterior, middle, and posterior cerebral artery regions
are respectively average 52.1-): 9.2.49.1+
10.8.56.1+ 9.2d/100g/m111
From 60.8± 9.4.60.6± 9.7.60.
It increased to 6±7.2d/100g/min. The average γCBF of the anterior, middle, and posterior cerebral artery regions in the right hemisphere was 46.6±6.8.56.4±7.3.58.8, respectively.
± 8.9 to 53.0 ± 6.9.64.3 ± 5.3
．． It increased to 63.0±4.6m/100g/min.

The average increase rate of γC in areas where blood vessels do not constrict is 9.
The increase in γCBF was only 2±, io, o%, whereas the area with vascular degeneration showed an increase of 26.5 ± 19.0%. Ta.

[CCT (C
Internal conduction time (central conduction time) measurement results] The CCT on the side where the blood vessel* line was generated was prolonged in all cases (average 6.36 ± 0.18 m, 5e).
c) , 6.21±0. by LipO-PGE+ administration.
It improved to 20m SeC.

Lipo-PGE for blood pressure, peripheral blood image, and liver function test results
+No significant changes were observed after administration compared to before administration.

The results at the time of discharge were excellent in 3 cases and goo6.
2 cases were fair, 1 case was fair, and 2 cases were dead (Table 2). Note that in one case, the cause of death was cerebral infarction due to vascular traction, and in the other case, the cause of death was thought to be a concomitant heart disease.

Representative cases are presented below.

[Case 1] Male, 53 years old, left middle cerebral artery ruptured in 1985
On August 18, 2015, the patient developed a headache, vomiting, and lost consciousness. At the time of admission, he was unconscious and his limbs were not paralyzed. August 1
On the 9th, Hunt & Osnik grade II [
Therefore, direct surgery was performed. We started hypervolemic therapy on August 21st.
He became conscious on August 23rd, but was in a state of euphoric speech. On August 26th, the patient became somnolence, and on the 27th, he became comatose, had complete right hemiplegia, and had total aphasia. Angiography revealed vasoconstriction in the left anterior and middle cerebral arteries, and administration of Lit)O-PGE+ was started.

CBF (cerebra
l blood flow) was significantly improved. CCT
6.6 m sec from left 7.0 1 5. from right 6.2.
It was shortened to 8 msec. L ipo-PGE +
A clear improvement in the above symptoms was seen the day after the start, and the patient was admitted on September 1st.
On the following day, the patient became conscious, had mild right hemiplegia, and had motor aphasia. Lipo-PG[+ administration was discontinued on September 3rd, but there was no worsening of neurological symptoms, and the patient was discharged from the hospital on September 26th, walking with a cane.

In this case, Lipo-PGIE+ administration was effective and serious sequelae were avoided.

Claims (1)

[Claims] (1) A preventive/therapeutic agent for cerebral vasospasm whose main ingredient is a fat emulsion containing prostaglandin E_1.