Volume 5, Number 4 | Winter 2010

Kampo Medicine – Current Research
Effectiveness of Goreisan for Eliminating Brain Edema due
to Intracranial Malignant Brain Tumors

Akimune Hayashi, M.D.

Department of Neurosurgery, Kanagawa Cancer Center
Yokohama, Japan[Introduction]
Treatment of cerebral edema is a critical issue
in the field of neurosurgery, but, for several
decades, almost no advancement has been made to
the therapy.
CurrentABSTRACT

medicaltherapyforreducing

intracranial pressure in cerebral edema is limited

Objectives:

Hypertonicandto two types of medicine: hyperosmotic diureticscorticosteroids are widely used to eliminate

and adrenocortical hormones. No new medical

brain edema complicated by malignant brain

treatment has been introduced for at least 30tumors.

years; that is the current situation surrounding

However,side

solutionseffects

sometimes

prevent long-term use of them.

To reduce

brain edema, the author studied a traditional
oriental medical prescription, goreisan, which
promotes diuresis and eliminates dampness,and is known for inhibiting the aquaporin 4activity.
Methods:

BetweenFebruary

2003

andOctober 2010, goreisan was prescribed to 60

cerebral edema. In clinical practice, excluding Dsorbitol and D-mannitol infusion used mainly inthe acute phase, concentrated glycerin/fructose
infusion, isosorbide liquid (oral), and adrenal
corticosteroids (oral/ drip infusion) are the mostcommonly-prescribed

hyperosmotic

diuretics.

However, they have some challenges that need topatients (73 cases) with malignant brain tumors

be resolved.

(Male 33, Female 27. Age: 24 to 82 years old,The

mostproblematicpointisthat

Mean 56.5). The efficacy was evaluated by theconcentrated glycerin/fructose infusion can only

level of improvement of subjective symptoms orbeneurological deficits: excellent (improvement

disadvantage is that the current national health-rate≧50%), good (improvement rate 30~50% or

insurance system in Japan defines the estimated

50% or more reduction in other medical

usage period as 2 weeks, or at most 3 weeks.

decompression

Dehydration and electrolyte abnormalities mustagents),

andnoeffect(improvement rate <30 %).
Results: An acceptable level of symptom
relief was observed in 52 cases (71.2 %). Therewerenocasesof

deterioration,andnosignificant complications were observed.
Conclusion ： goreisan

canbeusedforeliminating mild to moderate brain edema andcan be a substitute for hypertonic solutions andcorticosteroids.

beadministeredcarefullyintravenouly.

checkedforAnotherlong-termuse.

Corticosteroids can be taken either orally orintravenously and are significantly effective.
However, they can cause complications including
higher susceptibility to infection and hemorrhage
in the upper gastrointestinal tract. Hence,
corticosteroids are not suitable for long-term use.
Isosorbide, an oral agent, is difficult to takebecause of the taste (too sweet/ bitter). It is a liquid

Key words: goreisan,edema,

10aquaporin

brain tumor,

brainmedicine, which can be inconvenient.
From a kampo (Japanese traditional medicine)

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 5, Number 4 | Winter 2010

point of view, the pathological condition of cerebral

manufactured by Tsumura Co., Ltd. Patients withedema was diagnosed as local stasis of body fluid

raised intracranial pressure that required urgent(suidoku). Therefore, appropriate diuretics shouldadministration of hyperosmotic diuretics andimprove the condition. In this report, the author

adrenocortical hormones were excluded from thistakes up goreisan (Poria Powder with Five Herbs),study. In this study, goreisan was prescribed, nota representative Kampo diuretic prescription, tobased on Kampo medical findings ( sho ) , but on

examine its efficacy in improving the symptoms of

the Western medicine diagnosis of cerebral edema.

cerebral edema. The author also reviewed thePrior to the commencement of the therapy,

efficacy from a modern medical point of view topatients were informed that “edema” is one of thedetermine whether goreisan can become anindications for goreisan covered by the national

alternative drug to the modern drugs for reducing

health insurance system. Patients received 3

brain edema.

packs per day, in accordance with the instructionof usage. When the improvement of the symptoms[Cases and methods]
From February 2003 to October 2010, 60 patients(73 cases in total) with malignant brain tumors
were treated with goreisan: 33 male and 27 female.

Age 24-82 years old (mean 56.5). The following isthe details of the brain tumors by type: 18 patientswith primary brain tumor (8 glioblastoma, 5malignant glioma, 3 primary cerebral malignant
lymphoma,

1meningioma,neuroectodermaltumor);

and

39

1

primary

patientswithmetastatic brain tumor (13 lung cancer, 9 breastcancer, 3 stomach cancer, 3 kidney cancer, 2esophageal cancer, 2 colon cancer, and 1 each ofpancreatic cancer, bladder cancer, ovarian cancer,
thyroidcancer,

melanoma,andhepaticcancer,

nasopharyngeal

malignantcancer);wasgoreisan was immediately

insufficient,replacedbysteroidsoranother

cerebraldecompression therapy.
The efficacy was assessed based on theimprovements of subjective symptoms of raised
intracranial pressure or neurological symptoms
using the overall ratings: markedly improved (≧50%),

effective

improvement),(30%ortolessthanconcomitant50%

cerebraldecompression drugs reduced to at least 50% ordiscontinued.);ineffective(lessthan30%improvement).
[Results]
Improvements were observed in 52 cases

3(71.2%): markedly improved in 19 cases (26.0%),

patients with delayed radiation necrosis of theeffective in 33 (45.2%), and ineffective in 21

brain.

(28.8%). Some of the patients who showed no31 patients showed symptoms related to raised

improvement with goreisan did not respond to

intracranial pressure such as headache, nausea

steroids

andvomiting,neurologicaland54

symptoms

patients

hadmarkedly improved in 11 (35.5%), effective 15(48.4%),

Granules(31patients),

improvement was observed in 26 cases (83.9%):

Goreisan used in this study was TSUMURA
Extractheadachefocal

multiple symptoms).

goreisanForwithpatients(someeither.

(2.5g/pack),

ineffectivein5(16.1%),

andnoaggravated case. When a favorable response wasobserved, the efficacy appeared in a short time, at

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

11

Volume 5, Number 4 | Winter 2010

the latest within several days. Furthermore, nocausing neurological deficits, no improvement inside-effects were reported for goreisan.

neurological symptoms was observed. They did
not respond to steroids either.

[Representative case]
Effective case (Fig. 1). 52 year-old female with[Discussion]

metastatic cerebellar tumor caused by lung cancer.

In Shang Han Lun (Treatise on Febrile andShe complained of headache, nausea and vomiting,

Miscellaneous Disease), goreisan is mainly used

and ataxic gait. She is very close to developing

for symptoms of wind-stroke (syndrome of Taiyang

obstructive hydrocephalus.

stricken by wind) associated with fever, which doAccording to her diagnostic images, mostphysicians

wouldchoose

thenot resolve in 6 to 7 days, and a severe condition

cerebellar

with exterior and interior symptoms, become

decompression therapy by infusion. In this study,

thirsty and crave for water, but drinking of water

however, both goreisan (TJ17) 7.5g and saireito

makes patients vomit like a non-stop fountain.

(Minor Bupleurum Decoction) (TJ114) 7.5g were

These

administered. Then the above symptoms were

gastrointestinal symptoms. However, when windrelieved. The co-administration of the two drugs

stroke, heat sensation, and vomiting are examined

was intended to double the dosage of goreisan.
Ineffective case (Fig. 2/ Left). 66-year old
female with metastatic brain tumor from lungcancer. Left-sided hemiparesis. No improvement

descriptions

areoften

explainedasfrom the perspective of neurosurgery, they could
resembled a headache, disturbed consciousness,and vomiting attributable to a raised intracranialpressure. The pathological concept of “symptomsin neurological symptoms with goreisan becausecoming from the increased intracranial pressure”

the motor area in the brain was directly damaged.

likely did not exist when the Shang Han Lun waswritten. However, there is a strong possibiliy that

Right side: 82-year-old male with metastaticgoreisan was prescribed based on the diagnosis ofbrain tumor from colon cancer which triggered

signs and symptoms. In addition, there is aagnosia. goreisan was not effective. Oral steroids

published article confirming that our Japanese

were not effective either. The potential factors that

pioneers were using goreisan at the dawn of therender goreisan ineffective are as follows:

history of brain tumor treatment1).

1) Large tumor,
2) Growth speed of tumors is fast,3) Rapid development of edema associated braintumors,
4) Associated cerebral edema is small in volume.
The above factors were more prevalent in tumors
developed in smaller areas with scarce space forbuffering intracranial pressure such as in theposterior cranial fossa. When a tumor was directly

12

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 5, Number 4 | Winter 2010

Treating the symptoms of raised intracranialpressure complicated with cerebral edema isessential for treating not only the brain tumors,
but also head injury and cerebrovascular disorder.
Urea, 50% hypertonic glucose, and other diuretics
used to lower the pressure at the early stage of thetreatment have become outdated. That was due tothe rebound phenomenon where the intracranialpressure is elevated again after administration oftheagents

mentioned

above.

Hyperosmotic

diuretics and adrenocortical hormones are the two

best

drugs,amongthecurrently

available

therapies, for lowering the intracranial pressure.
However, as mentioned before, they cannot beregarded as the ideal treatment due to various
constraints on the usage and side effects.
On the other hand, oriental medicine defines
Figure 1

cerebral edema as a localized stasis of cerebralEffective case. 52-year-old female with metastatic

fluid (suidoku). Therefore, the “promoting diuresis

cerebellar tumor caused by lung cancer.

and eliminating dampness” therapy could be used
as one of the treatment methods. Goreisan, one of
the representative diuretics2)3) has a very different
diuretic

property

fromWestern

medicines.

Although it acts to adjust the systemic waterbalance,itrarelycauseslocal

electrolytes

abnormality. The risk of creating dehydration4) islow. This makes goreisan a highly safe drug forusage.
Left左Left左 Right
右右Right
Figure 2

The efficacy of goreisan for cerebral edema
complicated with intracranial malignant brain

withtumor was examined in this study. The overall

metastatic brain tumor caused by lung cancer. Her

improvement rate was 71.2%. The improvement inleft hemiparesis did not resoled by gireisan.

headache alone was 83.9%. Since the relieving ofRight: 82-year-old male with metastatic brain tumor

theby colon cancer complained of agnosia. Did notneurological damages caused directly by tumors,

Ineffectivecase.

Left:

66-year-old

respond to oral steroids either.

femalecerebral

edema

will

notimprovethethe overall improvement rate of 71.2% issatisfactory.

In spite of a selection bias, thisstudy still supports the value of goreisan as an
The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

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Volume 5, Number 4 | Winter 2010

option against mild to moderate symptoms.

tumor, trauma, cerebrovascular damages, and“suidoku” -which result in forming vasogenic

The pharmacological mechanism of the water

cerebral edema- it is known that the expression ofgoreisan hasn’t been

AQP4 increases in the perivascular glial endfeet,

uncovered yet; however, the effects on aquaporins

which is an important component of the blood-(AQP), known as a water channel has gathered

brain barrier. Hence, it is assumed that AQP4 re-attention5)6) in recent years.

absorbs extracellular fluids, functioning in thedraining

property

indirection

ofrelieving

cerebraledema.

InAQP, a membrane protein, was reported inmalignant glioma, the expression of AQP4

1990 as a water channel that selectively transport

significantly increases in the tumor itself ratherelectrolytes7).

than in the area of tumor infiltration, i.e. edema

Thirteen types of AQPs have been identified so far.

in tumor periphery. The degree of expression andExpressions of AQP13,4,5,8,9,11,12) have been verified

the extent of brain edema formation seem to havein the brain but the major AQP subtypes are twoco-relation11). AQP4 seems to have bilateraltypes; AQP1 and AQP48). AQP1 mainly appears

natures, edema formation and edema relief, butin the choroid plexus epithelia. AQP4, whichfurther functions of AQP4 remain unknown.

appears mainly in the central nervous system, isHowever, it is currently expected that theprevalent in the subarachnoid cavity, ventricles ofinhibition of the AQP4 could lead in reduction of

the brain, and neuroglia cells close to cerebral

cerebral edema12).

water molecules without moving

blood vessels. They are all believed to be deeply
engaged in the water metabolism of the brain.

The expression of AQP1 increases in theTherefore, the study on AQP4 has now become one

cytoplasm of malignant glioma. The level of theof the most advanced research areas9).

expression co-relates with the degree of themalignancy and the expansion of the edema in theFactors attributable to cerebral edema aretumor periphery. There is a report13) that evenclassified into five types; vasogenic, cytotoxic,

when the expression of AQP1 is not observed inosmotic, hydrostatic, and interstitial. Major ones

metastatic cerebral tumor, the increase in theare vasogenic and cytotoxic. The most common

AQP1 expression was confirmed in the edema intype of cerebral edema caused by brain tumor isvasogenic edema triggered by a damage or loss ofthe blood-brain barrier.

the tumor periphery. Based on this report, AQP1
inhibitors may also bring about a new treatment
modality for cerebral edema complicated withAccording to an animal experiment using AQP4

malignant cerebral tumor.

null mice10), AQP4 works to protect cells against acytotoxic cerebral edema, whereas it aggravates
cerebral edema if it is vasogenic. This signifies
that AQP4 promotes water flowing into cells if
cerebral edema is cytotoxic, while promoting theexcretion of water in vasogenic cerebral edema. Infact, with pathological conditions of malignant

14

Out of crude drugs composing goreisan (Arisma
Rhizoma, Polyporous Schlerotium, Atratylodes
Lancea Rhizoma, Tuckahoe, and Cassia Bark), it
isreported

that

PolyporousSchlerotium,Atratylodes Lancea Rhizoma, and Tuckahoe
inhibit AQP4 and control it in a concentrationdependent manner the water permeability of cell

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 5, Number 4 | Winter 2010

membraines14)15). Since no aggravation of the[References]

symptoms by goreisan was observed in any case in1)

YAMADA K: Kampo no Kuden – Chikuan nothis study, at least, the AQP4 inhibiting effect ofHitorigoto – Taniguchi Shoten (Tokyo), p31,

goreisan does not seem to promote brain edema.

2009.

This suggests that goreisan could be a safe drug

2)52-57, 2007

for an AQP4 inhibitor, and it is expected to reduce
cytotoxic edema in tumors as well as vasogenic
edema in the peripherial area of tumor.

3)

Nie Yimin: goreisan [2], Chui Rinshou 28(3):80-83, 2007

4)

TASHIRO S: goreisan no Risui-sayo. Kidney andDialysis, Supplementary volume 34-37, 1989

For the future, measures must be taken toenhance goreisan’s clinical efficacy. Japanese

Nie Yimin: goreisan [1], Chui Rinshou 28(2):5)

DonaldE.

G.

Griesdale,HoneyCR:

extracts contain lower volumes of crude drugs

Aquaporins and brain edema. Surg Neurol

compared to decoctions of Traditional Chinese

61:418-421, 2004

Medicine. Thus, it is assumed that medicinal

6)

edema and aquaporin 4. Shinkei Shinpo,

efficacy of Japanese extracts is inferior. To
enhance the efficacy in a regular clinical practice,which uses the extracts as the main drug, the7)dosage-increase or combination with choreito(Umbellate Fungus Decoction) or bukuryoin(Tuckahoe Decoction) for the purpose of increasing
the total volume of Polyporous Schlerotium,

SATO S, ADACHI K, KANOU T, et al.: Brain

8)50(2): 183-189, 2006
Gregory M. Preston, Agre P: Isolation of thecDNA for erythrocyte integral membraneprotein of 28 kilodaltons: member of anancient channel family. Proc Natl Acad Sci
USA88: 11110-11114, 1991
SOBUE K, HIRATA H, IIDA Y, TAKAYANAGI

Atratylodes Lancea Rhizoma, and Tuckahoe may

T: No-Fushu no Hasshou Kijyo to Mizu-

be considered. From the perspective of thechanneru [Aquaporin] no Kinou. Anesthesia

combination usage of goreisan and steroids, the21 century 10:51-55, 2008
9) Marios C. Papadopoulos, Verkman AS:
Aquaporin-4 and brain edema. Pediatr
Nephrol: Pediatr Nephrol 22(6):778-784, 2007
10) Geoffrey T. Manley, Binder DK, Papadopoulos
MC et al: New insights into water transportand edema in the central nervous system fromphenotype analysis of aquaporin-4 null mice.
Neuroscience 129(4): 983-991, 2004
11) Arne Warth, Simon P, Capper D, et al:
Expression pattern of the water channel
aquaporin-4 in human gliomas is associatedwith blood-brain barrier disturbance but notwith patient survival. J Neurosci Res 85:
1336-1346, 200712) Orin Bloch, Manley GT: The role of aquaporin4 in cerebral water transport and edema.
Neurosurg Focus 22:1-7, 2007use of saireito (Minor Bupleurum Decoction) that
could induce endogenous hormones is also worth
considering.
[Conclusion]

Goreisan can be applied for treating cerebral
edema complicated with malignant brain tumor.
Since goreisan is safe and suitable medicine forlong-term usage, it can be used as an alternativeand complimentary medicine to Western oraldrugs such as steroids and isosorbide.

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

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Volume 5, Number 4 | Winter 201013) Samira Saadoun. Papadopoulos MC, Davies
DC, et al: Increased aquaporin 1 water
channel expression in human brain tumors.
Br J Cancer 87: 621-623, 2002
14) ISOHAMA Y: Risuizai “goreisan” no Sayo
Mekanizum. Kampo Igaku 29(5): 213-215,
2005
15) ISOHAMA Y: Kampoyaku no Risui Sayo to
Aquaporin. Shoni-Kanjya no Mijikana Kampo
Chiryou.

10thNippon

ShouniKampo

Kondankai Kiroku-shu. Medical Review Sha(Tokyo), p8-31, 200916

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)