Anti fibrosis agent in chronic liver

disease( Sho-saiko-To)

Fibrosis : reaksi inflamatorik

Respons parenkim hati, berupa

wound healing terhadap injury akut / kronik

Akumulasi matriks ekstraselular baru

menggantikan matriks lama Membentuk scar, menyelimuti daerah injury

Etiologi fibrosis hati

Infeksi kronik VHB

Infeksi kronik VHC

Alkoholisme Obat NASH

Fibrogenesis hati,

• Dimulai dari aktivasi HSC• Aktivasi : transdifferentiasi 3 tahap

Inisiasi Perpetuasi Resolusi

Inisiasi• Ditandai dengan perubahan ekspresi gen dan fenotip (transdeferensiasi) HSC• Fenotip baru menjadi lebih sensitif thd :• - Sitokin - stimuli

TGF 1 GF1 PDGF EDF TNF Free radical

Perpetuasi

Proliferasi HSC

Fibrogenesis

Chemotaksis

Kontraktility

Kemoatraktan

Produksi sitokin

Retinoid menghilang

Degradasi matriks

Growth factor :- PDGF - Epidermal GF - Fibroblast GF - IGFa- SMAUp regulasi reseptor PDGF

Proliferation

Contractility

Pemicu :

Thrombin Angiotensi II Vasopresin Prostaglandin ET ( paracrin dan autocrin)

.

HSC chemotaxis / migrasi

Stimuli : PDGF, ET-1, Chemokine ( MCP-1)

Deposisi kolagen

• HSC aktif menghasilkan : - MMPs (metalloproteinase) degradasi - TIMPs (Spesific tissue inhibitor) TIMPs >< MMPs alat pengatur fibrotisasi TIMP > MMPs fibrosis >> TIMP < MMPs fibrosis <<

APOPTOSIS

Dari aktif berubah menjadi quiscens jarang

Bila injury reda, pemacu aktifitas reda, apoptosis

Apoptosis dipacu : - soluble factor - komponen matriks

Strategies for Antifibrotic Therapies

A. Removal of the Fibrotic stimulus

Alcohol

TherapyAntiviralPhlebotomy (iron >>)Copper ChelationTherapy antihelminthicStop drugs/toxin (c/ methotrexate)

Textbook of Gastroenterology 2003

B Inhibit activation of HSC

Antioxidan : vitamin E, reservatrol, sylimarin Quercetin,

Sho-saiko-toInterferon-gamma,HGF IL-10PPAR gamma LigandsEndotelin reseptor antagonis : LU135252

Textbook of Gastroenterology 2003

C. Treatment of the Consequences of HSC ActivationHOE 077Beta-AminopropionitrilePolyenylphosphatidylcholine ( PPC )Soluble TGF beta receptorIndolinonesSho-Saiko-ToCorticosteroidHalofuginoneAlpha PenicillamineMMP-1

Textbook of Gastroenterology 2003

D. Stimulation apoptosis of HSC Gliotoxin

E. Other Herapeutic Agents Interferon alpha dan ribafirin

Colchicine Prostaglandin E UDCA Fumagillin TNP 470 Farnesyl transferase inhibitor Sho-Saiko-To Glycyrrhizin

Textbook of Gastroenterology 2003

Mekanisme Kerja Sho-Saiko-To

•Anti Fibrosis Natural Medicine

Review : Gastroenterol Hepatology 2000

HSC Initiation

• SST- inhibit Lipid peroxidase• Increased hepatic retinoid• Reduced deposition of type1

collagen• Reduced MDA• Number of a-SMA

Hepatology 1999

•Proteksi membran plasma liver •Proteksi HSC from injury•Meningkatkan SOD, Gluth Peroxidase

( Bio& Pharm Bull 1998 )

HSC-Proliferation

• Hambat aktivasi HSC

• Hambat proliferasi HSC yang diinduksi PDGF

Hepatology 1998

HSC-Proliferation

SST = antiproliferative and anti fibrogenic effects, in experiment hepatic fibrosis• decreased [3H]thymidine incorp cells• decreased cell number in cell stimulated with fetal calf serum• Suppressed [3H]leucine and [3H]proline incorp.

•Turunkan alpha-SMA•Hambat

migrasi

(Eur J Pharmacol 1999)

Hepatology 1999

SST suppressed procollagen mRNA expression of Type I and Type III

Deposisi kolagen

Decreased kolagen tipe 1

J. of Hepatology 1998

Hepatology 1999

SST increased MMP-2 activity and prevented TIMP-1 activities on HSCsLife Sciences 2004

APOPTOSIS

Cancer Res 1994

SST inhibits proliferation of cancer lines by inducing apoptosis and arrest at the G0/G1 phase

Implikasi Klinik Treatment of Hepatitis B

a randomized trial conducted in Japan in the 1990s, 222 patients chronic active HBV:

106 patients received SST for 12 weeks, followed for a further 12 weeks

106 patients received placebo for 12 weeks, followed by a cross over to SST for another 12 weeks

Control group

ALT : Decreased significantly with SST in 12 weeks

AST : Decreased significantly with SST in 12 weeks

Control group

SST groupControl group

SST group

HBe Ag: Tendency decreased of HBeAg antibodies with SST

Anti HBe : Tendency increased of anti HBe antibodies with SST

Control groupSST group SST group

Control group

In peripheral blood mononuclear cells from 8 patients with

HBV Chronic active ,

SST enhance both IFN-gamma and antibody production,

SST modulate cellular and humoral immune responses specific for HBV-associated antigens.

Immunomodulation of SSTa key role in the therapeutic effect on HBV:

(Int’l J of Immunopharmacology. 1991)

Treatment of Hepatitis C• In a controlled study, 80 patients HBV chronic

• followed for 7 years.

• Result :

(Prog Med 1994)

SST, N=40 Control, N=40

GOT/GPT normalized 5 1

Anti HCV ( - ) ve 1 0

Dev. With HCC 1 5

Treatment of Hepatitis C

• In vitro study, 11 patients of HCV-(+) liver cirrhosis & 12 patients of healthy subjects.

• SST increased IL-12 in HCV (+) approximately three fold

• SST increased monocyte/macrophage fraction in HCV ( + ) until almost same as healthy subjects

(Developmental Immunology. 1999)

Treatment of Hepatitis C

SST adjust the decreased of IL-10 and excessive IL-4 and IL-5 production of mononuclear cells from HCV patients.

(Hepatology. 1997)

the Memorial Sloan-Kettering Cancer CenterClinical Trial

A Phase II Study, single arm, single center trial,

31 patients will receive 52 weeks therapy with SST 7.5 gram per day.

Outcome : liver biopsies. There is improvement of 2 points or greater on Knodell score

SST for Chronic HCV Patients who are Intolerant to or Have Contraindication to Interferon

Initial results : New York Nov 18, 2004

10 patients completed the study :

8 patients : ALT/AST reduced

4 out of 7 reduction of viral load

2 out of 10 decrease in Knodell score of 2 points or more

• A large prospective study was conducted in Japan in the late 1980s and published in Cancer in 1995.

• 260 patients with cirrhosis were randomized to treatment with SST or control.

• HCC was the primary endpoint and was confirmed by angiography, CT and biopsy.

• Patients were followed for 5 years with bimonthly alpha-fetoprotein measurements and quarterly USG.

Cancer 1995

Sho-saiko-to: Prevention of Hepatocellular Carcinoma

Result

CATEGORY SST Control

Total pasien 130 130

HCC terjadi dalam 6 bulan 3 4

Total pasien yang dianalisa 127 126

Pasien dg HCC 23 33

Hidup dengan HCC 17 24

Meninggal karena HCC 6 9

Meninggal bukan dari HCC 19 28

Pasien yang survived 5 th 102 89

Control group

SST group

Control group

SST group

SST menurunkan insiden HCC sebesar 33 % ( 23 % SST vs 34 % kontrol )

SST menurunkan angka kematian sebesar 40 % ( 24 % SST vs 40 % kontrol )

Control group Control group

SST group SST group

Grafik 3 :

Kumulatif incidence HCC pada pasien dengan tingkat AFP awal dibawah 20 ng/ ml dari SST( n=93 ) dibandingkan dengan control ( n=91)

Grafik 4 :

Kumulatif incidence HCC pada pasien dengan tingkat AFP awal antara 20 – 200 ng/ml dari SST ( n=34) dibandingkan dengan control ( n=35)

Precautions and Side EffectsSST related pneumonitis was reported in 74 patients,

approx. 1 in 20,000, leading to 8 deaths. an underlying lung disease, had been elderly, taking SST longer after the onset of pneumonitis, severe hypoxemia. (Nihon Kyobu Shikkan Gakkai Zasshi 1997).

• In 5 cases, combination SST and interferon causing pneumonitis more likely than each given alone.

(Nihon Kyobu Shikkan Gakkai Zasshi. 1995).

Conclusion• Berdasar penelitian-penelitian yang telah dilakukan,SST

terbukti memiliki efek anti fibrosis untuk mengatasi gangguan liver dan chemopreventive

• Hasil dari Clinical Trial, membuktikan bahwa SST memberikan manfaat pada penderita Hepatitis B dan C.

• Pemakaian SST (7.5 gram of granule per day) perlu dalam pengawasan dokter dengan adanya kemungkinan efek samping pada fungsi paru

Thank you!