Safety

AHCC is confirmed to be nontoxic and safe food product by numerous in vitro, in vivo, and clinical studies. Genotoxicity was tested by reverse mutation test and micronucleus test, single dose oral toxicity and 90-day repeated dose oral toxicity were examined in rodents, and a phase I clinical test was conducted in healthy subjects. In addition, AHCC is a compound made from mushroom with a long history of human consumption. Moreover, several hundred thousands people have used AHCC with no reports related to its toxicity or side effects since its introduction to the market in 1989. Roberts, A. et al. (Cantox Health Sciences International, Canada) Regul. Toxicol Pharmacol. doi:10.1016/j.yrtph.2010.10.006 (2010) Walshe, T. et al. (Harvard Medical School, USA) J Nutr Sci Vitaminol. 53, 536-539 (2007)

References
Abe, S. et al. (Teikyo University, Japan) Yakugaku Zasshi 120 (8), 715-719 (2000) Chutaputthi, A. et al. (Phramongkutklao Hospital, Thailand) The 18th International Congress on Nutrition and Integrative Medicine, Sapporo, Japan (2010) Fujii, H. et al. (Amino Up Chemical Co., Ltd., Japan) Journal of Experimental Therapeutics and Oncology 8, 43-51 (2009) Gardner, E. et al. (Michigan State University, USA) Experimental Biology, Anaheim CA, USA (2010) Hisajima, T. et al. (Teikyo Heisei University, Japan) The 18th International Congress on Nutrition and Integrative Medicine, Sapporo, Japan (2010) Kamiyama, Y. et al. (Kansai Medical University, Japan) Journal of Hepatology 37, 78-86 (2002) Kamiyama, Y. et al. (Kansai Medical University, Japan) Nutrition and Cancer 60 (5), 643-651 (2008) Martinez-Augustin, O. et al. (University of Granada, Spain) The Journal of Nutrition, Nutritional Immunology 137 (5), 1222-1228 (2007) Nishioka, H. et al. (Amino Up Chemical Co., Ltd., Japan) Toxicology and Applied Pharmacology 222, 152-158 (2007) Sumiyoshi, Y. et al. (Shikoku Cancer Center, Japan) Japanese Journal of Clinical Oncology 40 (10), 967-972 (2010) Wakame, K. et al. (Amino Up Chemical Co., Ltd., Japan) Cancer Epidemiology 33, 293-299 (2009) Walshe, T. et al. (Harvard Medical School, USA) Human Immunology 71, 1187-1190 (2010) Wang, T. et al. (University of Texas Medical Branch, USA) The Journal of Nutrition, Nutritional Immunology 139, 598-602 (2009)

Active Hexose Correlated Compound

Scientifically-proven patented dietary supplement for optimal immune system

100% Natural Source

Processed polysaccharide of cultured mushroom mycelium Partially-acylated a-1,4 glucan as main component

Worldwide Recognized Dietary Supplement

#1 immune supplement in Japan Developed and fully-manufactured in Japan Used in more than 20 countries for over 20 years Scientifically safety proven without reported side effects

Industrial Forms Available

Fine granule Freeze dry Hard capsule Soft capsule Liquid

Award
AHCC received the NutrAward for the Best New Product of the Year 2002 at the Natural Products Expo West.

Future Developments
Various studies to date revealed that AHCC has numerous applications in many fields. We are now conducting research to prove the effects conclusively through phase II and III clinical trials, and to elucidate the fundamental action of AHCC in immune response modulation as well. In addition since 1994 an increasing body of researchers worldwide are affiliating to the AHCC Research Association to share the foremost research from the fields of molecular biology, pharmacy, medicine, veterinary medicine and integrative medicine. The AHCC Research Association gathers every year in Japan at the International Congress on Nutrition and Integrative Medicine. For more information on AHCC: http://www.ahccresearch.com/

Extensive Scientific Research

Studied at more than 70 leading institutions worldwide Over 30 publications listed in PubMed

Immune Response Improvement

Enhances immune cell number and activity Helps prevent infections Supports intestinal immunity

Amino Up Chemical Co., Ltd.

363-32 SHIN-EI, KIYOTA SAPPORO, 004-0839 JAPAN TEL: +81-11-889-2277 FAX: +81-11-889-2288 Hajime Fujii, Ph.D. hfujii@aminoup.co.jp Kohei Homma, Ph.D. kohei.homma@aminoup.co.jp http://www.aminoup.co.jp/e/

AHCC is a product of Amino Up Chemical (AUC), a biotech company of Sapporo, Japan. AUC is specialized in developing and manufacturing novel bioactive substances from natural sources. Our products are all based on scientific evidences as we devote to research and conduct collaborations with leading universities and institutes worldwide. Our products are manufactured in a dietary supplement GMP-certified eco-friendly plant in Sapporo that complies with ISO 9001:2008 and ISO 22000:2005.

About Us

Use in oncology field Improves liver function

Integrative Medicine & Clinical Nutrition

Research use only

Benefits for Healthy People

HUMAN Study Overview
Method: double-blind placebo-controlled Subjects: 21 healthy adults (10 AHCC treated, 11 control) Dose: 3 g/day Period: 4 weeks Measurement: number of dendritic cell (DC)
p<0.05 p<0.05

Immune Cell Production

Immunity Reinforcement
Walshe, T. et al. Human Immunology (2010)

Oncology Field

30
Number of DC (103)

6 5 4 3 2 1 0

* p<0.01 vs day 0 ** p<0.05 vs day 0

* * ** *

A IFN-g B TNF-a C IFN-g and TNF-a

*

Method: prospective cohort, open-label Subjects: 269 hepatocellular carcinoma patients that underwent resection of liver tumor (113 AHCC treated, 156 control) Dose: 3 g/day Period: from hospital discharge until death or the end of observation period Measurement: survival rate
Kamiyama, Y. et al. Journal of Hepatology (2002)

Total survival rate

Method: open-label Subjects: 30 healthy adults at age over 50 Dose: 3 g/day Period: 60 days of AHCC intake, 30 days after discontinuing AHCC Measuement: population of CD4+ T cell producing IFN-g and TNF-a

HUMAN Study Overview

Longer Postoperative Survival

HUMAN Study Overview

Postoperative survival
1.0
*p<0.01 vs Control

0.5

0.0 0

Control AHCC

20

3 4 5 6 7 Years after surgery

% of cells

10 0

AHCC

Control

(day)

Kamiyama, Y. et al. Nutrition and Cancer (2008)

AHCC

Prevention of Wide Range of Infections

Animals: 4 week-old Crl:CD1(ICR) mice, female Treatment: mice were infected with methycillin-resistant Staphylococcus aureus (MRSA) at day 0 and AHCC was given 50 or 500 mg/kg/day from day 4. Period: 28 days Measurement: survival rate
100

ANIMAL Study Overview

MRSA

HUMAN Study Overview

*
*p<0.05 vs Control

2
Fold change

Control AHCC
*p<0.05 vs Control

* 2
Fold change

Control AHCC
*p<0.05 vs Control

Cell viability (% of Control)

Method: open-label Subjects: 29 healthy adults after immunization with influenza vaccine [A(H1N1), A(H3N2), B] (14 AHCC treated, 15 control) Dose: 3 g/day started on the day of vaccination Period: 2 weeks Measurement: blood immune cell phenotypic analysis using flow cytometry, CD8+ T cell and CD56+/CD3+ NKT cell

Influenza

Animals: ddY mice, male (n=8~11 each group) Treatment: AHCC; 360~1000 mg/kg/day, anticancer drugs used per day; TAX (paclitaxel; 15~20 mg/kg), CDDP (cisplatin; 8 mg/kg), 5FU (5-fluorouracil; 100 mg/kg), CPT (irinotecan; 50 mg/kg), DXR (doxorubicin; 8 mg/kg), CY (cyclophosphamide; 120 mg/kg) Period: 25 days Measurement: bone marrow cell viability
150
* p<0.01 vs Control, ** p<0.01 vs Control, AHCC group Control Drugs only Drugs + AHCC

ANIMAL Study Overview

Animals: 6 week-old BALB/cA mice, female (n=17 each group) Treatment: Colon-26 tumor cells were inoculated (5 x 105 cells/mouse) 3 days before cisplatin initial injection. AHCC; 100 mg/kg/day, Cisplatin; 8 mg/kg at day 0, 6, 13, 20 Period: 28 days Measurement: tumor size

Tumor size (mm3)

pre

post

pre

post

B 0

B 30

B 60

B 90

Side Effects Reduction of Most Common Chemotherapy Agents

Chemotherapy Support
ANIMAL Study Overview

8,000

6,000

Control Cisplatin Cisplatin + AHCC

*p<0.01 vs Control **p<0.01 vs Control, p<0.05 vs Cisplatin *

4,000

2,000

**

Nishioka, H. et al. Toxicology and Applied Pharmacology (2007)

Days after tumor inoculation

10

20

30

100
* ** ** * ** * ** ** *

Survival rate (%)

80 60 40 20 0

50

Anxiety score

AHCC 500 mg (n=8) AHCC 50 mg (n=8) Control (n=9)

Improvement of Quality of Life

70 60 50 40 30 20 10 0

p<0.01

p<0.01

HUMAN Study Overview

0
0 7 14

Abe, S. et al. Yakugaku Zasshi (2000)

Days after infection

21

28

Young (<60)

CD8+ T cell

Elderly (>60)

0
Young (<60)

Control

TAX

NKT cell

Elderly (>60)

TAX + CDDP

5FU + CPT

CDDP + 5FU

DXR + CY

Method: open-label Subjects: 74 patients with early prostate cancer Dose: 4.5 g/day Period: 6 months Measurement: state anxiety, trait anxiety
Sumiyoshi, Y. et al. Japanese Journal of Clinical Oncology (2010)

Gardner, E. et al. presented at Experimental Biology (2010)

*p<0.05 vs Control * *p<0.05 vs Control 100

Fujii, H. et al. Journal of Experimental Therapeutics and Oncology (2009)

Before After

State

Before After

Trait

WNVE/b-actin x10-5

ANIMAL Study Overview

Animals: 21-22 month-old C57BL/6 mice Treatment: 600 mg/kg every other day for 1 week before infection and at day 1 and 3 postinfection. 80 PFU (close to 100% lethal dose) of WNV isolate NY99 was innoculated intraperitoneally. Period: 28 days until mice showed signs of morbidity Measurement: WNV-specific IgG and viremia at day 4, and survival rate post infection
Wang, T. et al. The Journal of Nutrition (2009)
IgG OD

0.5 0.4 0.3 0.2 0.1 0.0

100 80 60 40 20 0

West Nile virus

Percent survival
80 60 40 20 0

AHCC (n=11) Control (n=10)

Intestinal Immunity

Intestinal Condition Improvement

ANIMAL Study Overview
Animals: Wister rats, female (200-250 g, n=6 each group) Treatment: AHCC (500 mg/kg/day) or sulfasalazine (200 mg/kg/day) to TNBS(10 mg/rat)-induced colitis rats A Pathogenic Clostridium Period: 2 days pre-colitis-induction + 6 days post-colitis-induction B Bifidobacteria Measurement: colonic damage, intestinal flora
C Lactic Acid Bacteria
*
* p < 0.05 vs Control

Immune Stimulation
ANIMAL Study Overview
Animals: 6 week-old ICR mice, male (n=5 each group) Treatment: 1000 mg/kg/day Period: 5 days Measurement: secreted IgA
Control AHCC *p<0.05 vs Control, Day 1
400

Control AHCC
(n=8) (n=8)

Control AHCC
(n=10)

WNV-specific IgG

Viremia

(n=9)

Days post infection

12

16

20

Survival rate

Liver Function
Reduction of Liver Damege
Animals: 8 week-old ddY mice, male (n=6 each group) Treatment: AHCC; 1000 mg/kg, liver damage was induced by 6MP (6-mercaptopurine; 2.5 mg/kg) and MTX (methotrexate; 30 mg/kg). Period: 28 days Measurement: serum hepatic enzyme activity
180

ANIMAL Study Overview

HUMAN Study Overview

10
120 115 110 Control AHCC

* * * *

Enzyme activity (IU)

160 140 120 100 80 60 40 20 0

Control AHCC 6MP+MTX AHCC+6MP+MTX

p<0.05

105 100 95 90 85 80 *p<0.01 vs Control

Change of ALT (%)

p<0.05

Method: double-blind placebocontrolled Subjects: 39 hepatitis C virus (HCV) carrier (19 AHCC treated, 20 control) Dose: 6 g/day Period: 24 weeks Measuement: HCV-RNA amount, ALT level in blood

120 115 110 Change of HCV-RNA (%)

Control AHCC

Secreted IgA levels ( g/ml /0.1g)

Improvement of Hepatitis C Symptoms

12

* p < 0.05 vs TNBS

500

8
DAMAGE SCORE

6
Log CFU

*
300

6 4 2 0

105 100 95 90 85 80 *p=0.01 vs Control

200

100

TNBS Sulfasalazine

AHCC

A B C
Control

A B C
TNBS

A B C
Sulfasalazine

A B C
AHCC

Day 1

Day 3

Day 5

AST

ALT
Chutaputthi, A. et al. presented at 18th ICNIM (2010)

Baseline

After 24 weeks

Baseline

After 24 weeks

Wakame, K. et al. Cancer Epidemiology (2009)

HCV genotype 3 RNA

ALT (all genotype)

Colonic Damage
Martinez-Augustin, O. et al. The Journal of Nutrition (2007)

Intestinal Flora
Hisajima, T. et al. presented at 18th ICNIM (2010)