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PICIBANIL® 必醫你舒®
5 KE 針劑
(OK-432) MULTI-CYTOKINE INDUCER
Excellent Anticancerous BRM Agent
台灣中外製藥(股)
癌性胸水/腹水首選用藥
Introduction
Mechanism of OK-432 antitumor activity
Clinical efficacy of OK-432
Effect on malignant pleural
effusion/ascites
The product of OK-432
Outline
History of the Development
1868 Busch
Report of contraction of giant tumor due to complication of erysipelas
1882 Fehleisen
Affirmation of tumor contraction by erysipelas
Explication of Streptococcus being a etiologic agent of erysipelas
1939 Okamoto, Koshimura
Start of research for the relation between Streptococcus and cancer
1954 Discovery of the phenomenon : the destruction of cancer cells caused by
the mixing of Streptococcus and cancer
1966 Development of OK- 431 : heat-treated Su strain in Bernheimer’s basal medium
1968 Development of OK- 432 : Lyophilized OK-431
1975 Launch of Picibanil ® (OK-432)
Gram positive bacterium
Serologic grouping : A to V
Pyogenic exotoxin (erythrogenic toxin) :
exotoxin A, B, C stimulate T cells
Streptodornase A-D : deoxyribonuclease,
ribonuclease activities
Streptococcus pyogenes
Process of OK-432 Production
Streptococcus Pyogenes Su strain (Group A3)
Elevation of antitumor activity
Elevation of antitumor activity
Loss of streptolysin S production
OK-432 (Picibanil® )
Exposure to H2O2 at 0℃
Bernheimer’s basal medium
Containing 27000 Units / ml penicillin G potassium
Incubation at 37℃ for 20 min
Incubation at 45℃ for 30 min
Lyophilization
OK-432 (Picibanil ® ) Composition
Picibanil 1 KE 5 KE
Ingredient Content in each vial
Active ingredient
Lyophilized powder 2.8mg 14mg Amount of the dried cells 0.1mg 0.5mg
Inactive ingredients
Magnesium sulfate 0.10 mg 0.48 mg DL-methionine 0.20 mg 1.00 mg Maltose 8.37 mg 1.34 mg Benzylpenicillin potassium (JP) 2,690 U 13,470 U
Streptococcus pyogenes Su strain (group A)
Elevation of antitumor activity Loss of streptolysin S production (SLS)
OK-432 (Picibanil® )
Exposure to H2O2 at 0℃ / Bernheimer’s basal medium Containing 27,000 units/ml of penicillin G potassium Followed by incubation at 37 ℃ for 30min. Incubation at 45 ℃ for 30 min.
Lyophilization
The Meaning of “KE”
KE (Klinische Einheit) : Clinical Unit
The strength of the preparation / amount of the cells.
1 KE ≒ 0.1 mg of the lyophilized cells ( 1×108 cells )
Cancer Treatment Report 70 (1) ;171-176, 1986 National Cancer Institute (NCI)
Biological Response Modifier
生物反應調節劑
BRMs are those agents of approaches that
modify the relationship between the tumor
and host by modifying the host’s
biological response to the tumor cells,
which resultant therapeutic effects.
凡任何製劑或方法,可經由宿主調節對腫瘤細
胞之生物反應,而改變宿主與腫瘤關係進而達
到治療效果者,稱為生物反應調節劑。
Direct Cytocidal effect on tumor cells
Growth inhibition Inhibits DNA and RNA synthesis
Effector cell Activity Neutrophil Macrophage Lymphocyte Natural Killer Other cells
Multi-cytokine inducer IL-1β IFN- α, γ IL-2 TNF-α,β IL-6 TGIF IL-8 Others IL-12
Indirect Host –Mediated Actions (BRM)
Prolongation of survival
Mechanisms of OK-432
Antitumor Activity
OK-432
The Possible Mechanisms of Tumor Cell Disappearance in Ascitic Fluid
M. Torisu et. al., Management of malignant effusion
Attachment Infiltration Disconnection
Cluster of tumor cells
Activation
Peritoneal metastasis
Destruction
M. Torisu et al., Management of malignant effusion
The Possible Mechanisms of Fluid Disappearance in Peritoneal Cavity
M. Torisu et al., Management of malignant effusion
Release from Symptoms (Anorexia) Elevation of serum Protein level
Peritoneal cavity
Activation of Complement system OK-432
Disappearance of ascites fluid
Fibrosis Block of fluid production
M. Katano et al., Anti-Cancer Research (18);3917-26 (1998)
IFN-γ- induced ICAM -1 expression on tumor cells
IFN-γ↑ TNF-α↑
TNF-α - induced CD11b/CD18 expression on neutrophil
Enhanced Adherence Activity of Peritoneal Neutrophils to Tumor Cells by OK-432
Clinical Efficacy
Reduction of Malignant Pleural Effusion /Ascites
Inhibition of recurrence and metastasis
Activation of bone marrow function
Reduction of Tumor size
Prolongation of Survival of Cancer Patients
Fig. 1. Effect of intraperitoneal or intrapleural injection of OK-432 on disappearance of ascitis fluid and pleural effusion.
Effect of OK-432 Therapy on Disappearance of Effusion
M. Torisu et al., Management of malignant effusion
0 10 20 30 40 50 60 70 80
61.5%
38.5%
76%
24%
112 Responders
38 Responders
Non-Responders
Non-Responders
Patient groups with cancer: gastric, colorectal, breast, biliary tract, pancreas etc.
Relationship between Disappearance of Ascites and Cytologic Findings of Ascitic Fluid before the Treatment with OK-432
These results strongly suggest that this therapy is more effective for patients with tumor cell bearing ascites than for those who only have ascitic fluid.
M. Torisu et al., Management of malignant effusion
Positive for tumor cells n = 85
80%
68/responders
Negative for tumor cells n = 65
24.6%
16/responders
Duration of OK-432 Injection to Disappearance of Ascites and
Pleural Effusion
M. Torisu et al., (1983)
With ascites 100 6-56
(22.5 ±7.8)
With pleural 38 1.5-42
Effusion (15.4 ±15.1)
No. of Duration: days patients (mean ± SD)
Typical Change in Numbers of Intraperitoneal Neutrophils and Lymphocytes after an OK-432 Injection
These results strongly indicate that OK-432 induced neutrophils might have a major cytostatic effect against the tumor cells
Time in Days
Neu
tro
ph
ils (
/mm
3)
Lym
ph
oc
yte
s (
/mm
3) OK-432(I.P) OK-432(I.P) OK-432 (I.P)
Neutrophils
Lymphocytes
M. Torisu et. al., Management of malignant effusion
This observations indicate that neutrophils induced by OK-432 play an important role in tumor cell destruction.
M. Torisu et. al., Management of malignant effusion
Neu
tro
ph
ils (
/mm
3)
Tu
mo
r c
ell
s
(/m
m3)
Neutrophils Tumor cells
OK-432 I.P
Time in Days
Typical Change Numbers of Intraperitoneal Neutrophils and Tumor Cells after OK-432 Injection
Changes of OK-432 Induced
PEC Population
Nu
mb
er
of
cell
s (/
mm
3)
Hours after OK-432 injection
K. Ogawa, et al., Biotherapy 4(2) ; 155-65, (1990) PEC : Peritoneal exudate cells
H. Kitsuki, et al. Clin Immunol Immunopathol 78; 283-90, (1996)
IFN- γ
IL-1β TNF- α
OK-432 (5-10KE) Time after OK-432 injection (hr)
Representative Kinetics of
Induction of Cytokines in the Ascitic
Fluid after OK-432 Injection
Host Inflammatory Cells Induced by OK-432 Before administration
Cancer cells form clusters and few inflammatory cells exit
After 12 hrs
The cluster is getting out of shape by infiltrating neutrophils
After 3 days
Infiltrating macrophages are attacking cancer cells
After 4 days
Infiltrating lymphocytes are attacking cancer cells
Responders (112 cases)
Non-responders (70 cases)
Palliative therapy (50 cases))
These results indicate that OK-432 therapy induces significant prolongation of survival time for patients with malignant effusion.
M. Torisu et. al., Management of malignant effusion
Su
rviv
al ra
te (
%)
Time in months
*15.6 *2.9
*P<0.001
Comparison of Survival Rate between Responders and Non- responders or Palliative Therapy Group
Responders (112 cases)
Non-responders (70 cases)
Palliative therapy (50 cases))
Treatments for Malignant
Pleuritis and Peritonitis
Agent Method Mechanism Side effects
BRMs (OK-432, IL-2) Anticancer drugs (BLM, MMC, ADM) Tetracycline Minocycline Talc Insufflation
Non-specific inflamation Tumoricidal effect Non-Specific inflamation Fibrogenic effects Pleural adhesion Non-specific inflamation
Pleural adhesion
Intraperitoneal
Intraperitoneal Paracentesis Tube drinage
Non-specific inflamation Tumoricidal effect
Non-Specific inflamation No tumoricidal effect Removal of ascites
Fever
(>39℃ : ~48%)
Systemic reaction
BM suppression
Pain
Induced pneumothroax/ pneumonia
BRMs (OK-432)
Anticancer drugs (CDDP, MMC, 5-FU)
Diuretic, Systemic Chemotherapy
Fever (>39℃ : ~48%)
Frequent Peritonitis Fibrosis lead ileus
Lead to worsen of nutritional condition
Poor effect
Treatment for Malignant Peritonitis
Treatment for Malignant Pleuritis
Pleurodesis Intrapleural Pleurodesis Intrapleural
Pleurodesis Pleurodesis/ Thoracoscopy
Complication after Pleurodesis with OK-432 and Mitomycin C in Patients with Malignant Pleural Effusions
Luh et al., Cancer 89;874-9 (1992)
Complication OK-432 Mitomycin C n=26 n=27
Fever (>38℃ ) 20 3
Chills 4 0
Pain 2 2
Dyspnea 3 2
Leukopenia 0 1
(< 3000/ul)
No toxicity 5 18
Summary
Efficacy Both OK-432 and MMC are effective for control MPE patients
Complete Response
Pleurodesis with OK-432 has higher complete response rate than with MMC
Survival Time Medium survival time were similar
Luh et al., Cancer 89;874-9 (1992)
Effusion- Free period
OK-432 group was significantly longer and recurrences of pleural effusion were less frequent
Adverse Reactions
Reported in 8,312 out of 26027 patients (31.9%)
at the end of the adverse reaction incidence report : March 1982
Adverse Reactions Incidence (%)
Fever 6019 23.1
Injection site pain 2893 11.1
Injection site redness 1198 4.6
General malaise 848 3.3
Anorexia 789 3.0
Administration Method of Picibanil® for Malignant Ascites
Treatment & control of patients
Diagnosis & adjuvant therapy
Penicillin intradermal reaction
Cytological diagnosis of ascites
Abdomen touch
Poor nutrition condition, give albumin etc.
Confirm the aspiration site CT/ echo
Picibanil® 10KE Injected with 100-200ml N/S
Sufficient change of positions ~2hrs
Fever Analgesic antipyretic
Picibanil®
5-20 KE 3– 4 times
Positive patients for cancer cells
by cytological diagnosis of ascites (if negative, included with consideration of the performance status)
Patients
Treatment schedule
Days
( ) ( )
Picibanil® Intraperitoneal Injection
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Complete drainage of Pleural Effusion as possible (<100- 200ml), then close 3-way
Infusion of OK-432 10KE dissolved in 20-100ml of N/S
Postural change (~2 hrs)
Drainage of OK-432 and the remaining effusion Chang Gung HP
Intrapleural Administration Pleurodesis --- Pig-tail Drainage
Pig-tail 裝置一覽表 固定 3 – way 完成
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Days
Picibanil®
10-20 KE
Picibanil Thoracentesis Method
Patients Treatment resistant malignant
pleuritis (8 patients: lung cancer
/adenocarcinoma)
Injection time
Median frequency of injection = 2.5 times
Treatment schedule
Indications & Dosage
In patient with gastric cancer or primary lung cancer under concomitant use with chemotherapy. Initiate : 0.2-0.5 KE, Maintain : 2-5 KE, 1-2 times a week.
In patients with digestive tract cancer or lung cancer. 10-20 KE, inject into serous cavity 1-2 times a week
(maxillary cancer, laryngeal cancer, pharyngeal, cancer, tongue cancer) and thyroid cancer where the other medicine have been ineffective. 5-10 KE, inject into tumor daily/every of few days.
initiate : 0.05-0.1 KE, Max dosage : 2 KE, the dosage may be adjusted depending on the patient’s age and symptoms.
1.Extensive of survival period
2.Reduction of cancerous pleural effusion/ascites
3. Head and neck cancer
4. Lymphangioma
OK-432 (Picibanil® ) Package
OK-432 (Picibanil® ) Storage and Handling
Use only freshly prepared suspension Powerful and designated drugs. Use only pursuant to the prescription or directions of a physician, etc. Store at a temperature below 10℃, avoid freezing. 2 years (specified on the outer package)
Notice
Regulatory classification
Storage
Expiration date
A potent biological response modifier (BRM)
Clinical efficacy Prolongation of survival Reduction of cancerous pleural effusion/ascites
Dual function activities Direct tumoricidal Immunopotentiating
A penicillin-treated Streptococcus pyrogenes lyophilized preparation
Summary
Picibanil (OK-432) 健保使用規範
限惡性腫瘤患者患有惡性腹水、
肋膜積水或心包膜積水時使用,須
檢附病歷摘要。
Thanks for your attention
~ The End ~