Volume 1, Number 3 | Fall 2006

Clinical Report 3 (Japan)

Treatment of Obesity with Bofutsushosan:
Obesity is inflammation

Yoshiyuki Ishizuka
Ishizuka Clinic

Introduction
C-creative protein (CRP) identified by Tilet andFrancisin1930
intheplasmaof
pneumococcus-infected patients with pneumonia is amember of the class of acute phase proteins thatprecipitate with C-polysaccharide. As is well known,
CRP has been widely used as a marker for thepresence of inflammation and its activity factor,
especially in infectious diseases among inflammatory
diseases. With the recent development of ahigh-sensitive technique for CRP determination,
however, the levels of as low as 0.02mg/dl can be traced,leading to disclosure of sub-clinical inflammatory
conditions. Thus, disorders that previously were not in
the category of inflammation, like hypertension,
hyperlipidemia, diabetes, and obesity, and evenmetabolic syndrome that is a complex of these
disorders, are now regarded as chronic inflammationof vascular endothelium and adipose tissue. In fact, it
has been demonstrated that high-sensitive CRP(hsCRP) correlates with BMI, waist circumferencemeasurement, and amount of visceral fat. The hsCRP
is also considered as an independent risk factor in theevents of cardiovascular diseases and type 2 diabetes
mellitus, and is associated with the onset ofhypertension. The hsCRP level is an important
indicator in managing lifestyle-related diseases
inclusive of metabolic syndrome. Meanwhile,
bofutsushosan, a herbal medicine Liu wuan-su
originally prescribed to “rid of stagnation anddepression of all the wind-heat" is now often used forthe treatment of obesity rather than for that of
infectious diseases. In this paper, I would like to takeup the theme of “obesity is inflammation” through thetherapy of bofutsushosan for the treatment of a patient
who was obese with fatty liver.

Clinical Report
Patient: Male, 44-years old(school teacher forhandicapped children)
Chief complaint: Obesity and fatty liver
Present illness
The patient had been identified with liver function
abnormalities(ALT67IU/L)
inthe
medicalexamination of July, 2004 and made his first visit to us.
In his initial visit, obesity (weight 85 kg, BMI 29.4)
and moderate fatty liver were observed, and theextract of bofutsushosan was administered, resulting
in no reduction in weight. Three months later, thetreatment was discontinued on his own judgment. OnJuly 2005, the patient had a weight increase by 3 kgwith the elevated ALT to 85IU/L and returned to theclinic.
Physical findings
The patient’s height was 170cm, weight 88kg
(BMI30.4), and blood pressure 142/92mmHg. Therewerenoabnormalitiesincardiopulmonary
auscultation. Pulse palpitation was somewhat empty
but deep at the rate of 76/min. The tongue was bright
red colored, engorged, and somewhat excessively wet
without no scars of teeth, spots and dilation ofsublingual veins. The coating of the tongue wasyellowish white and moderately thick. There were noresistance and tenderness in the abdomen. The waist
circumference measured 94cm and obesity of visceralfat type was observed.
Laboratory findings
Laboratory tests revealed the following values:
peripheral erythrocyte count 470x106/mm3, Hb 14.1g/dl,
Ht 41%, total bilirubin 0.4mg/dl, AST 41 IU/L, ALT 85
IU/L, γ-GTP 48 IU/L, total cholesterol 204mg/dl, LDLcholesterol 105mg/dl, HDL cholesterol 62mg/dl,triglyceride 94mg/dl, uric acid 7.5mg/dl, FBS 90mg/dl,HbA1c 4.8%, hsCRP 0.158mg/dl, HBs antigen (-), andHCV antibody (-).

Clinical Course
The patient was not eager to play sports/doworkout. He liked sweet goods although he did not
drink alcohol. The therapy of bofutsushosan wasresumed under his usual diet and living habit. As
previously, no decreases were observed in weight andALT levels for three months after the resumption ofthe treatment. Meanwhile, the levels of hsCRP

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

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Volume 1, Number 3 | Fall 2006

droppedsharply.
Subsequently,
theoraladministration was continued, resulting in gradualdecreases in the weight and ALT levels. In July 2006,
improvement was achieved in the weight to 84kg, ALT
to 31 IU/L and hsCRP to 0.039mg/dl (Chart 1).
ALT(IU/L)

200
150
100

Divaricate Saposhnikovia Miraculous Powder (5g/day)

plasminogen activator inhibitor-1 (PAI-1) fromvascular endothelium; and induces secretion of IL-6and MCP-1 from endothelium. CRP is not merely aninflammation marker but also one of important factors
directly linked to the events of atherosclerosis andthrombosis.
symathetic nerve

0.20

A1 Radenosine

hsCRP

0.15
0.10

ALT

Licorice root, Fineleaf －schizomepeta herb,
Forsythia capsule－0BW(kg)
85
2004.70.05
88888885

8684

2005.7910

1112

2006.70Chart 1: Clinical course (Male, 44 years old)

TG

PKA

ATP

TNFα IL-6 NO＋＋TNFαMCP-1HSACRP＋Liver＋IL-6FFA＋

Obesity is a condition in which excessive fat isaccumulated in the body. As well as storing energy
surplus in cells in the form of triglycerides, enlarged
adipocytes in obese subjects secrete inflammatory
cytokines (TNFα,etc),
kemokines(monocyte
chemoattractant protein-1: MCP-1, etc.) and hormones(adiponectin, leptin, etc.). Adipose tissue is comprisedof mature adipocytes and stromata (stromal-vascular
fraction: SVF). SVF contains monocytes, macrophages,
preadipocytes, blood vessel components, andfibroblasts, presumably regulating reproduction /differentiation of adipocytes, and inflammation in theadipose tissue. In fact, Anty et al.1) have reported thatin obese patients there is a positive relation between
the amount of IL-6 and the amount of CRP mRNA andthat IL-6 and CRP exist in both mature adipose cells
and SVF, more of them existing in the latter five toeight folds. It is assumed that in obese subjects, TNFαand MCP-1 secreted from enlarged adipocytes allow
monocytes/macrophages to infiltrate into adipose
tissue, where IL-6 is released. And I consider that thereleased IL-6 enhances CRP secretion frompreadipocytes at local adipose tissue and from liver
cells at remote organs (Chart 2). There is a recent
report that CRP mediates LDL uptake bymacrophages; attenuates synthesis of NO while
increasing production of endothelin-1 (ET-1) and24cAMPFACRPDiscussion

5’AMP

adipocyte

PGE２ R－β3-AR

PDE50●■ ■monocyte/mφ■● ●AA＋ Ephedra PGE2－NAScutell●NFκB－ aria root
●iNOS－IL-6

endothelium

preadipocyte

Chart 2: Mechanism of CRP increase in obesity (assumption)

To prevent cardiovascular events in patients withobesity, losing 5% of the current weight is the initial
treatment goal to be achieved. It should, however, beremembered to reduce the levels of hsCRP. It is beyond
any doubt that weight control by diet/exercise therapy
alone can lower the hsCRP concentration. This isprobably

becauseburningof

tryglycerides

accumulated in adipocytes contributes to lower thesecretion of TNFα and MCP-1 from adipose tissue,
accompanying the reduced secretion of IL-6 frommonocytes/macrophages. For middle-aged working
people who are busy and have no exercise habit, likethe subject case in this report, however, weight
reduction through diet/exercise is often extremely
difficult. In this case with obesity, treatment wasperformed only with bofutsushosan without employing
diet/exercise, and the reduced hsCRP/ALT and weightloss were encountered. The ingredients making up thebofutsushosan are Ephedorae Herba, Saposhnikoviae
Radix, Schizonepetae Spica, and wild mint to expel
heat that does not diffuse from the body surface; Rhei
Radix and Natrii Sulfas that are excreted in stool;
Kasseki(talc) that is excreted in urine; Gypsum
Fibrosum, Scutellariae Radix, Gardeniae Fructus,
Forsythiae Fructus, and Platycodi Radix for internal

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

Volume 1, Number 3 | Fall 2006

heat to subside; Angelicae Radix, Peoniae Radix,of CRP induced by the bofutsushosan in obesity may be

Cnidii Rhizoma, Atractylodis Rhizoma, Zingiberis
Processum Rhizoma, and Glycirrhizae Radix toincrease Qi and blood. Ephedorine in Ephedorae Herbasignificantly attributed to an important role in direct

promotes the release of noradrenaline (NA) fromsympathetic nerve terminals2). When NA binds to
β3-adrenaline receptors present in the surface ofadipocytes, the concentration of cAMP in adipocytes iselevated and hormone sensitive lipase is activated bycatalytic PKA to decompose triglycerides. Whenadenosine A1 receptors and PGE2 receptors in thesympathetic nerve terminals are stimulated, therelease of NA from nerve terminals is suppressed.
Xanthine derivatives included in licorice, fineleaf
schizonepeta herb, and forsythia capsule work toinhibit adenosine A1 receptors, and scutellaria rootworks to inhibit synthesis of PGE2 through mediation
ofCOX2

inmonocytes/macrophages(aspirin-likeaction). These two functions indirectly serve tofacilitateNA

releasesterminals.

Moreover,

from

since

sympathetic

Xanthine

nerve

derivatives(licorice, fine leaf schizonepeta, and forsythia capsule)inhibit breakdown of cAMP in adipocytes through theinhibition of phosphodiesterase (caffeine-like action)2),

bofutsushosan can yield the effect of fat burning evenin Japanese people who often have β3-AR genemutation.

Thementholinwild

mintpossiblystimulates TRPM8, one of cold receptors, in peripheral
nerves and activates the sympathetic nerves throughthe hypothalamus to promote catabolic action.
In the subject case, however, lowering levels of
CRP were observed soon after the start of theadministration of bofutsushosan and subsequently
weight loss and improvement in ALT value wereencountered. This cannot be explained sufficiently by
the breakdown of triglycerides being accelerated inadipocytes and hepatocytes. Piao et al. 3) have reported
that in a rat reperfusion model of focal cerebral
ischemia, scutellaria root suppressed the release ofTNFα,IL-6andNOfromactivatedmicroglia(intracerebral macrophages) by inhibiting the NF-κB
signaling pathway. Daisaikoto, also frequently used
for the treatment of obesity or fatty liver, includes

Scutellariae Radix. I consider that the reduced levels

anti-inflammatory

activityof

Scutellariae Radix

against monocytes/macrophages.
Presently for Natrii Sulfas, mostly hydrous sodium
sulfate (Na2SO4・10H2O) is used, whereas it is shownby Masutomi 4) that mirabilite is hydrous magnesium
sulfate (MgSO4・7H2O). Both compounds have potent
purgation, but hydrous sodium sulfate is not desirable
to the obese patients who are frequently predisposed toan accompanying hypertension due to a sodium load.
Meanwhile, lowered levels of blood magnesium (Mg2+)
cause

aggravation

of

the

pathologic

statusofhypertension, hyperlipidemia, and atherosclerosis. In
fact, low levels of blood magnesium are observed inobese patients and there is a report that magnesium
supplementation

canachieve

weightreduction.

Magnesium is necessary for activating lipoproteinlipase

todecompose

tryglycerides.

Magnesium

deficiency can develop hypertriglyceridemia. Presently,
magnesium oxide, a laxative agent has been given as
an attempt to the obese patients with normal renal
function at low dosages. In this sense, it is preferable
that mirabilite in the bofutsushosan is hydrous
magnesium sulfate.
The bofutsushosan used this time was an extract
drug and administered twice a day, in the morning andat night. At the time of the first treatment, the dosing
schedule was conveniently set for the patient due todifficulty taking medication during working hours. Itwas amazing that the doses in two-thirds of theregular amount yielded sufficient decreases in thelevelsofhsCRP,

ALTandweightwithnocomplementary diet/exercise therapy. Meanwhile, for
the initial three months after the administration wasstarted, completely no weight loss was observed
regardless of the amount of dosage. Although I had
doubtstemporarily

about

theefficacyof

thebofutsushosan, the observation of a decrease in hsCRP
prompted me to continue the treatment.
The subject case of the report is on the borderlineof metabolic syndrome from the Japanese criteria for

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

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Volume 1, Number 3 | Fall 2006

metabolic syndrome. Among the patients on theborderline, however, some have increased levels of
hsCRP. The subject case had the history of no alcoholic
drinks with fatty liver, which cannot be discriminatedbetween simple fatty liver (steatosis) and nonalcoholicsteatohepatitis (NASH) since liver biopsy was not
performed. Even nonalcoholic fatty liver disease(NAFLD), a disease concept covering from
non-progressive simple steatosis to progressive NASH,
poses a variety of problems of hypercytokinemia,
oxidative stress, and insulin resistance withaccumulation of visceral fat. Chart 3 and 4 exhibit
results of the treatment with the bofutsushosan in 6
cases of obesity (5 males and 1 female) with NAFLD,inclusive of the subject case. With the consent of all
the patients, they received only bofutsushosan without
concomitant diet・exercise therapy. In the third monthsince the therapy started, the levels of hsCRP in blood
significantly dropped from 0.237±0.060mg/dl to0.140±0.065mg/dl (p ＜ 0.05), and other profiles
indicated decreases but were not statisticallysignificant; weight 86.1±3.0kg to 84.3±3.4kg, blood
AST values 37±4IU/L to 30±IU/L, and blood ALT
values 56±4IU/L to 50±10IU/L. It can be expected thatbofutsushosan calms inflammation in the adipose
tissue, vascular endothelia and liver not only by theeffect of weight reduction as previously mentioned but
also by lowering the levels of hsCRP, which prevent
progression of atherosclerosis and liver cirrhosis. In
the obese patients whose hsCRP values are 0.1mg/dl
or more with metabolic syndrome and/or NAFLD, theherbal therapy with bofutsushosan as well as diet andor exercise therapy should be attempted in a positive
manner.

hsCRP

Body weightkg

p<0.05np

1000 .5

950 .4900 .3850 .2

80

0 .1

75
700prepost

prepostChart 3■:Case 1 □:Case 2 ●:Case 3 ○:Case 4 ▲:Case 5 △:Case 6ASTALT

np

IU/L

np

IU/L6090805070406050304020302010100pre0post

prepostChart 4Chart 3, 4: Efficacy of bofutsushosan in obesity withnonalcoholic fatty liver disease (NAFLD)

Author's remarks
I have reported the case in which bofutsushosan waseffective for the obese patients with fatty liver. It wasinteresting that bofutsushosan afforded a decrease in
hsCRP levels during an early stage of administration,
which, I consider, suggests that obesity is persistentsystemic inflammation focused on adipose tissue even if it
is at low level. Excessive nutrition becomes “evil (jya)” in
the body. This evil turns out to be “flame (hi)” or“inflammation” that Liu wuan-su refers to. “Obesity isnothing less than inflammation.”

Reference1) Masutomi Y.: Shosoin yakubutsuwo chushintosuru
kodaisekki no kennkyu [Study of ancient stone

medicines, mainly focused on Shosoin medicines],
Nihon kobutsu shumi no kai [Japan Mineral
Hobbyists Group] 1957

26

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