biosuccess biotech v. rich pharmaceuticals et. al

8/13/2019 Biosuccess Biotech v. Rich Pharmaceuticals et. al.

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EXHIBIT A


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Biosuccess Biotech Co. Ltd. | Biosuccess Biotech Co. Ltd.

Home About Us Technology Studies Patients Medical Professionals News & Releases Investor Information Contact Us

meout Usompany Historyadership Team

hnologydies

ML Stu diesDS Studiesents

MLDefinitionPrognosisPreventionsCausesSymptomsDiagnosisTestsTreatmentsComplicationsDeathDS/HIVDefinitionPrognosisPreventionsCausesSymptomsDiagnosisTestsTreatmentsComplicationsDeathood Cancerne Cancer

dical ProfessionalsML DocumentsDS Documentsntact UsQs

About Us

Founded in 2005, Biosuccess Biotech Co. Ltd. is a privately held company. It focuses on the

development of PD-616 (12-O-tetradecanoylphorbol-13-acetate, also known as TPA) for the

treatment ofAMLandAIDS/HIV .The work of two scientists, Prof. Richard Chang & Prof.

Zhang Tao Han sustained by their knowledge of this agents characteristics and their wide

experience of years is the basis for the companys interest in using PD-616 in treatment.

AML Studies wi th TPA (PD-616)

Clinical studies were conducted in China in patients who had few (sometimes none)

remaining options for therapy in acute myelogenous leukemia (AML). These patients were

refractory to standard therapy and had debilitating symptoms. Findings showed that some

patients were put into partial remission and established the short term safety for the

intravenous admini stration of PD-616.

Encouraged by the clinical results from China, Roger Strair MD, PhD, a leading oncologist at

The Cancer Institute of New Jersey (CINJ), at the University of Medicine and Dentistry of

N.J. (UMDNJ), obtained an investigator IND, and conducted a Phase 1 study in patients the

majority of whom also had relapsed/refractory AML. Based on Phase 1 findings, BiosuccessBiotech was encouraged by Dr. Strair to conduct a Phase 2 study in relapsed/refractory AML.

Currently, a Phase 2 study is underway and the recruitment of refractory AML patients is

actively done by Dr. Strair.

AIDS/HIV Studies wi th TPA (PD-616)

Three preliminary experiments, part of the clinical research process, were conducted in China

on AIDS/HIV. These patients had few treatment options, as they presented many of the

injurious effects of this disease and were refractory to standard anti-AIDS drugs. Following

treatment wit h PD-616, there was a disappearance of symptoms and a return to normal

in almost all patients. In t he third cl inical stu dy, the number of CD4 T-cells was

somewhat reduced while the concentration of the virus in blood increased in all

patients in 30 days after st arting PD-616 treatment, but was almost undetectable at 60

days. These results are clinical evidence that support the unique mechanism of action

proposed for PD-616 in AIDS/HIV. Future clinical studies are needed, but it appears that PD-

616 can be a totally new and highly effective drug for the treatment of AIDS. In order to

confirm these clinical findings, Biosuccess Biotech Co. Ltd. has plans to conduct rigorously

controlled clinical trials in the U.S. during a large Phase 2 study.

Legal Grounds

Biosuccess Biotech is protected by an issued use patent that provides sole rights to use the

intravenous administration of PD-616 for therapeutic purposes (2001).

A patent application was filed on the use of PD-616 to treat AML in January, 2007. In

January, 2008, a patent application was filed for the use of PD-616 in HIV/AIDS and includes

coverage of many other phorbol ester structures in the PD-616 chemical class.

Biosuccess Biotech Co. Ltd. has 20 years exclusive right s to t he use of PD-616 in AML

and HIV/AIDS, beginning with January 30th, 2008.

In June 2011, AML Phase 2 protocol was approved by FDA.

Company History

Leadership Team

Latest News

April 27th, 2012

Biosuccess has received an IND approval fro

FDA. An Acute Myelocytic Leukemia (AML) studythis IND will be underway shortly.

March 23rd, 2012

A corporate IND has been submitted to the FDA f

of TPA in Acute Myelocytic Leukemia (AML).

June 16th, 2011

Jace Chew joins our team as President of A

India sub-continent and Australia operations.

June 16th, 2011

AML Phase 2 trial begins recruiting patients.

Read More News

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essbiotech.com/aml/diagnosis/http://www.biosuccessbiotech.com/aml/symptoms/http://www.biosuccessbiotech.com/aml/causes/http://www.biosuccessbiotech.com/aml/preventions/http://www.biosuccessbiotech.com/aml/prognosis/http://www.biosuccessbiotech.com/aml/definition/http://www.biosuccessbiotech.com/aml/http://www.biosuccessbiotech.com/patients/http://www.biosuccessbiotech.com/studies/aids/http://www.biosuccessbiotech.com/studies/aml/http://www.biosuccessbiotech.com/studies/http://www.biosuccessbiotech.com/technology/http://www.biosuccessbiotech.com/about-us/leadership-team/http://www.biosuccessbiotech.com/about-us/company-history/http://users/kaseekinzler/Desktop/About%20Biosuccess%20Biotech%20Co.%20Ltd.%20%20%20Biosuccess%20Biotech%20Co.%20Ltd._files/About%20Biosuccess%20Biotech%20Co.%20Ltd.%20%20%20Biosuccess%20Biotech%20Co.%20Ltd..htmlhttp://www.biosuccessbiotech.com/http://www.biosuccessbiotech.com/contact-us/http://www.biosuccessbiotech.com/investor-information/http://www.biosuccessbiotech.com/news-releases/http://www.biosuccessbiotech.com/medical-professionals/http://www.biosuccessbiotech.com/patients/http://www.biosuccessbiotech.com/studies/http://www.biosuccessbiotech.com/technology/http://users/kaseekinzler/Desktop/About%20Biosuccess%20Biotech%20Co.%20Ltd.%20%20%20Biosuccess%20Biotech%20Co.%20Ltd._files/About%20Biosuccess%20Biotech%20Co.%20Ltd.%20%20%20Biosuccess%20Biotech%20Co.%20Ltd..htmlhttp://www.biosuccessbiotech.com/


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About Us | Rich Pharmaceuticals.com

www.richpharmaceuticals.com/about-us/ 1

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This text is also editable in the same page

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Rich Pharmaceuticals.com About Us

About UsRich Pharmaceuticals is a biopharmaceutical company that became a public entity August 26, 2012 as a

result of a reverse merger with Nepia Inc. The Company is focused on the development of its lead product,

TPA (12-O-tetradecanoylphorbol-13-acetate), for the treatment of acute myelogenous leukemia (AML) in

refractory patients, and the reversal of physical disabilities resulting from stroke. The basis for the interest

of the Company to pursue clinical development of TPA in these and possibly other indications is the result

of the work of two scientists, Prof. Richard Chang and Prof. Zhang Tao Han. Both have conducted research

on TPA for many years and have become experts in the characteristics of this molecule. Their findings form

the scientific basis for the clinical use of TPA.

AML Studies with TPA

Initially, clinical studies were conducted in leading hospitals in China in patients who had few, if any, options

remaining for the treatment of AML. These patients were refractory to standard therapy and had debilitating

symptoms that were life threatening. The clinical status of some of the patients treated with TPA changed

favorably to partial remission. In addition, the short term safety of TPA was established in these individuals

using an intravenous formulation of TPA.

Encouraged by the clinical results with TPA in China, Roger Strair MD, PhD, a leading oncologist at the

University of Medicine and Dentistry at Rutgers University, obtained an investigator IND and successfully

completed a Phase 1 study in patients, the majority of whom had relapsed/refractory AML. Rich

Pharmaceuticals was encouraged by Dr. Strair to conduct a Phase 2 study in relapsed/refractory AML. A

Phase 2 study is currently underway under the direction of Dr. Strair who is actively enrolling appropriate

patients in this study.

Legal GroundsRich Pharmaceuticals is protected by an issued use patent that gives sole rights to the Company to use the

intravenous administration of TPA for therapeutic purposes. Since TPA can only be administered for

therapeutic purposes by this route, this patent provides complete protection for the use of TPA for any

other use.

About UsCompany H istory

Leadership Team

NewsOctober 2nd, 2013

Rich Pharmaceuticals Inc. has

been licensed to pursue the

clinical development of their

lead drug, TPA, in acute

myelogenous leukemia (AML)

and stroke.

October 1st, 2013

Rich Pharmaceuticals appoints

Robert Thomas as COO

September 6th, 2013

Rich Pharmaceuticals appoints

David Chou, Phd. to the Board

of Director

View All News

Morbi accumsan convallis est,

sit amet varius sapien

commodo.

Read More

Stock Ticker
http://www.richpharmaceuticals.com/about-us/http://www.richpharmaceuticals.com/technology/http://www.richpharmaceuticals.com/studies/http://www.richpharmaceuticals.com/patients/http://www.richpharmaceuticals.com/medical-professionals/http://www.richpharmaceuticals.com/category/news/http://www.richpharmaceuticals.com/investor-information/http://www.richpharmaceuticals.com/contact-us/http://www.richpharmaceuticals.com/http://www.richpharmaceuticals.com/about-us/company-history/http://www.richpharmaceuticals.com/about-us/leadership-team/http://www.richpharmaceuticals.com/category/news/http://www.richpharmaceuticals.com/category/news/http://www.richpharmaceuticals.com/about-us/leadership-team/http://www.richpharmaceuticals.com/about-us/company-history/http://www.richpharmaceuticals.com/http://www.richpharmaceuticals.com/contact-us/http://www.richpharmaceuticals.com/investor-information/http://www.richpharmaceuticals.com/category/news/http://www.richpharmaceuticals.com/medical-professionals/http://www.richpharmaceuticals.com/patients/http://www.richpharmaceuticals.com/studies/http://www.richpharmaceuticals.com/technology/http://www.richpharmaceuticals.com/about-us/http://www.richpharmaceuticals.com/


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About Us | Rich Pharmaceuticals.com

www.richpharmaceuticals.com/about-us/ 2

Contact Us

Contact Rich Pharmaceuticals by going to our contact us page.

Sitemap

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Studies

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Questions

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EXHIBIT B


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Alamilla : About Us

Home About Us Technology Studies Patients Medical Professionals News & Releases Investor Information Contact Usmeout Usompany Historyadership Teamhnology

diesML StudiesDS Studiesents

MLDefinitionPrognosisPreventionsCausesSymptomsDiagnosisTestsTreatmentsComplicationsDeathDS/HIVDefinitionPrognosisPreventionsCausesSymptomsDiagnosisTestsTreatmentsComplicationsDeathood Cancerone Cancerdical ProfessionalsML DocumentsDS Documentsntact UsQs

About Us

Founded in 2005, Biosuccess Biotech Co. Ltd. is a privately held company. It focuses on the

development of PD-616 (12-O-tetradecanoylphorbol-13-acetate, also known as TPA) for the

treatment of AMLand AIDS/HIV.The work of two scientists, Prof. Richard Chang & Prof.

Zhang Tao Han sustained by their knowledge of this agents characteristics and their wide

experience of years is the basis for the companys interest in using PD-616 in treatment.

AML Studies with TPA (PD-616)

Clinical studies were conducted in China in patients who had few (sometimes none)

remaining options for therapy in acute myelogenous leukemia (AML). These patients were

refractory to standard therapy and had debilitating symptoms. Findings showed that some

patients were put into partial remission and established the short term safety for the

intravenous administration of PD-616.

Encouraged by the clinical results from China, Roger Strair MD, PhD, a leading oncologist at

The Cancer Institute of New Jersey (CINJ), at the University of Medicine and Dentistry of

N.J. (UMDNJ), obtained an investigator IND, and conducted a Phase 1 studyin patients the

majority of whom also had relapsed/refractory AML. Based on Phase 1 findings, BiosuccessBiotech was encouraged by Dr. Strair to conduct a Phase 2 study in relapsed/refractory AML.

Currently, a Phase 2 study is underway and the recruitment of refractory AML patients is

actively done by Dr. Strair.

AIDS/HIV Studies with TPA (PD-616)

Three preliminary experiments, part of the clinical research process, were conducted in China

on AIDS/HIV. These patients had few treatment options, as they presented many of the

injurious effects of this disease and were refractory to standard anti-AIDS drugs. Following

treatment with PD-616, there was a disappearance of symptoms and a return to normal

in almost all patients. In the third clinical study, the number of CD4 T-cells was

somewhat reduced while the concentration of the virus in blood increased in all

patients in 30 days after starting PD-616 treatment, but was almost undetectable at 60

days. These results are clinical evidence that support the unique mechanism of action

proposed for PD-616 in AIDS/HIV. Future clinical studies are needed, but it appears that PD-

616 can be a totally new and highly effective drug for the treatment of AIDS. In order to

confirm these clinical findings, Biosuccess Biotech Co. Ltd. has plans to conduct rigorously

controlled clinical trials in the U.S. during a large Phase 2 study.

Legal Grounds

Biosuccess Biotech is protected by an issued use patent that provides sole rights to use the

intravenous administration of PD-616 for therapeutic purposes (2001).

A patent application was filed on the use of PD-616 to treat AML in January, 2007. In

January, 2008, a patent application was filed for the use of PD-616 in HIV/AIDS and includes

coverage of many other phorbol ester structures in the PD-616 chemical class.

Biosuccess Biotech Co. Ltd. has 20 years exclusive rights to the use of PD-616 in AML

and HIV/AIDS, beginning with January 30th, 2008.

In June 2011, AML Phase 2 protocol was approved by FDA.

Company History

Leadership Team

Latest News

Read More News

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aceuticals.com/patients/http://www.richpharmaceuticals.com/studies/aids/http://www.richpharmaceuticals.com/studies/aml/http://www.richpharmaceuticals.com/studies/http://www.richpharmaceuticals.com/technology/http://www.richpharmaceuticals.com/about-us/leadership-team/http://www.richpharmaceuticals.com/about-us/company-history/http://www.richpharmaceuticals.com/about-us/http://www.richpharmaceuticals.com/http://benalamilla.me/contact-us/http://benalamilla.me/investor-information/http://benalamilla.me/news-releases/http://benalamilla.me/medical-professionals/http://benalamilla.me/patients/http://benalamilla.me/studies/http://benalamilla.me/technology/http://users/kaseekinzler/Desktop/Ben%20Alamilla%20%20%20About%20Us_files/Ben%20Alamilla%20%20%20About%20Us.htmlhttp://benalamilla.me/


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EXHIBIT C


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US006063814AUnited States Patent [ 1 9 ] [ 1 1 ] P a t e n t N u m b e r : 6 , 0 6 3 , 8 1 4Chang e t a l . [ 4 5 ] D a t e o f P a t e n t : May 6 , 2 0 0 0[ 5 4 ] PHORBOL ESTERS A S ANTI-NEOPLASTIC [ 5 6 ] R e f e r e n c e s C i t e d2 ? g i S I I T E B L O O D C E L L E L E V A T I N G P U B L I C A T I O N S

_ S h i h e t a l . , C a r c i n o g e n e s i s ( 1 9 9 3 ) , 1 4 ( 4 ) , 7 0 9 1 2 , 1 9 9 3 .[ 7 6 ] I n v e n t o r s : R i c h a r d L . Chang, 1 0 7 K o n n e r A v e . ,P i n e B r o o k , N J . 0 7 0 5 8 ; Zheng T 3 0 P r i m a r y E x a m i n e r J e r o m e D . G o l d b e r gH a n , 4 Dongming R o a d , Z h e n g Z h o u , A t t o r n e y , A g e n t , o r F i r m B e r n a r d S . L e o nH e n a n , C h i n a [ 5 7 ] ABSTRACT

[ 2 1 ] A p p l - N93 0 8 / 8 3 7 , 0 8 5 P h o r b o l e s t e r s a n d p a r t i c u l a r l y p h o r b o l - 1 2 - m y r i s t a t e - 1 3[ 2 2 ] F i l e d A p r - 1 4 1 9 9 7 a c e t a t e ( T P A ) a r e d e s c r i b e d a s e f f e c t i v e i n t r e a t i n g p a t i e n t s

With neopla stic diseases such a s leukemia as Well a s i n[ 5 1 ] I n t . C l . 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A61K 1/21 i n c r e a s i n g t h e White blood c e l l c o u n t .[52] . . . . . . 514/510[ 5 8 ] F i e l d of Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514/510 2 0 Claims, N0 Drawings


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6 , 0 6 3 , 8 1 41

PHORBOL ESTERS AS ANTI-NEOPLASTICAND WHITE BLOOD CELL ELEVATING

AGENTSBRIEF DESCRIPTION OF THE INVENTION

The i n v e n t i o n r e l a t e s t o t r e a t i n g n e o p l a s t i c d i s e a s e s u c h a sl e u k e m i a a n d i n c r e a s i n g t h e W h i t e b l o o d c e l l c o u n t s i np a t i e n t s s u f f e r i n g f r o m n e o p l a s t i c d i s e a s e s o r u n d e r g o i n gc h e m o t h e r a p y b y a m e t h o d W h i c h c o m p r i s e s a d m i n i s t e r i n gp a r e n t e r a l l y t o p a t i e n t s a n e f f e c t i v e amount o f a p h o r b o le s t e r o f t h e F o r m u l a :

10

1 5

25

or isomers thereof 3 0

W h e r e i n R 1 a n d R2 a r e s e l e c t e d f r o m t h e g r o u p c o n s i s t i n go f h y d r o g e n ,

0 35

OCalkyl

W h e r e i n t h e a l k y l g r o u p c o n t a i n s 1 t o 1 5 c a r b o n a t o m s , 4 0

OCloWer l k e n y l , OCphenyl,45

OCbenzyl

and s u b s t i t u t e d d e r i v a t i v e s t h e r e o f . At l e a s t one o f R1 5 0a n d R2 s o t h e r t h a n h y d r o g e n a n d R 3 i s s e l e c t e d f r o mt h e g r o u p c o n s i s t i n g o f h y d r o g e n a n d

55C-l oWer l k y l .

P r e f e r r e d a r e Comp ounds o f t h e Formula Wherein one o fR 1 a n d R 2 i s s e l e c t e d f r o m t h e g r o u p c o n s i s t i n g o f

60

a n d R 3 i s h y d r o g e n .E s p e c i a l l y p r e f e r re d i s a compound f t h e f o r m u l a I W h e r e

R 1 : OC(CH2)12CH3 i . e . m y r i s t a t e )

i . e . a c e t a t e )

i . e . p h o r b o l - 1 2 - m y r i s t a t e - 1 3 - a c e t a t e o r a s i t i s a l s o knoWn1 2 - O - t e t r a d e c a n o y l p h o r b o l - 1 3 - a c e t a t e h e r e i n T P A )The t e r m l o W e r a l k y l o r l o W e r a l k e n y l a s used h e r e i ns h a l l mean m o i e t i e s c o n t a i n i n g 17 c a r b o n a t o m s . I n t h eCompounds o f t h e F o r m u l a I , t h e a l k y l o r a l k e n y l g r o u p smay b e s t r a i g h t o r b r a n c h e d c h a i n a n d p r e f e r a b l y c o n t a i n a tl e a s t o n e o f R 1 o r R 2 , a l o n g c h a i n c a r b o n m o i e t y ( d e c a n o a t e

o r m y r i s t a t e ) .T h e a l k y l , a l k e n y l , p h e n y l a n d b e n Z y l g r o u p s may b e

u n s u b s t i t u t e d o r s u b s t i t u t e d W i t h h a l o g e n , p r e f e r a b l y ,c h l o r i n e , ? u o r i n e o r b r o m i n e , n i t r o , a m i n o a n d s i m i l a r t y p er a d i c a l s .

BACKGROUND OF THE INVENTIONThe compounds o f t h e Formula a r e g e n e r a l l y knoWn t o

b e t u m o r p r o m o t e r s a n d a s b e i n g h i g h l y i r r i t a n t t o s k i n a n dt h e m u c o u s membrane.The p r e f e r r e d e x e m p l a r TPA i s a b i o l o g i c a l l y a c t i v en a t u r a l compound Which c a n be e x t r a c t e d from c r o t o n o i l .TPA a s been knoWn f o r many y e a r s t o be a c o - c a r c i n o g e no r t u m o r p r o m o t e r . S e e Merck I n d e x , 1 1 t h E d i t i o n , P a g e1164 No. 7 3 0 6 . I t i s a l s o knoWn o b e a h i g h l y p o t e n t i r r i t a n tt o s k i n a n d t o b e h a r m f u l i f i n g e s t e d o r a l l y . I n a p r o d u c tb r o c h u r e d i s t r i b u t e d b y Chemsyn S c i e n c e L a b o r a t o r i e s o fL e n e x a , K a n s a s , TPA s d e s c r i b e d a s a n e x t r e m e l y p o t e n tmouse s k i n c a n c e r prom oter and a s a poWerful m itogen i nc e l l c u l t u r e s . The product brochure Warns t h e u s e r t o t r e a tTPA With extreme c a r e . The l i t e r a t u r e d i s c l o s e s t h a t TPAi n d u c e s d i f f e r e n t i a t i o n i n t h e s t a b l e human p r o m y e l o c y t i cl e u k e m i c c e l l l i n e HL-60. W e i n b e r g , J P ( S c i e n c e2 1 3 : 6 5 5 6 5 7 , 1 9 8 1 ) f u r t h e r d i s c l o s e s t h a t TPA c a u s e s d i ff e r e n t i a t i o n o f c e l l s o f t h e human l e u k e m i a c e l l l i n e HL-60t o n o n d i v i d i n g m a c r o p h a g e - l i k e c e l l s . T h e s e d i f f e r e n t i a t e dc e l l s a r e c y t o t o x i c f o r tumor c e l l s i n c l u d i n g c u r r e n t ,u n t r e a t e d HL-60 c e l l s i n v i t r o . HoWever, noWhere i n t h ep r i o r a r t h a s i t b e e n s u g g e s t e d t h a t compounds o f t h eFormula When d e l i v e r e d p a r e n t e r a l l y t o humans Would b ee f f e c t i v e i n t r e a t i n g n e o p l a s t i c d i se a s e s o r i n r a i s i n g t h eW h i t e b l o o d c e l l c o u n t , much l e s s W i t h o u t s i g n i ? c a n tunWanted s i d e e f f e c t s .

Leukemia s a n e o p l a s t i c d i s e a s e i n Which W h i t e c o r p u s c l em a t u r a t i o n i s a r r e s t e d a t a p r i m it i v e s t a g e o f c e l l d e v e l o pm e n t . The d i s e a s e i s c h a r a c t e r i Z e d by a n i n c r e a s e d numbero f l e u k e m i c b l a s t c e l l s i n t h e b o n e marroW a n d by v a r y i n gd e g r e e s o f f a i l u r e t o p r o d u c e n o r m a l h e m a t o p o i e t i c c e l l s .The c o n d i t i o n may e e i t h e r a c u t e o r c h r o n i c . Leukemias a r ef u r t h e r t y p i c a l l y c h a r a c t e r i Z e d a s b e i n g l y m p h o c y t i c o r


39/51

6 , 0 6 3 , 8 1 43

from bone m a r r ow h e m a t o p o i e t i c stem c e l l s o r t h e i r proge n y . The t e r m a c u t e m y e l o c y t i c leukemia subsumes s e ve r a l s u b t y p e s o f l e u k e m i a e . g . m y e l o b l a s t i c l e u k e m i a , p r om y e l o c y t i c l e u k e m i a a n d m y e l o m o n o c y t i c l e u k e m i a .

C h r o n i c m y e l o g e n o u s l e u k e m i a i s c h a r a c t e r i z e d b y a b n o rm a l p r o l i f e r a t i o n o f i m m a t u r e g r a n u l o c y t e s , f o r e x a m p l e ,n e u t r o p h i l s , e o s i n o p h i l s a n d b a s o p h i l s , i n t h e b l o o d , b o n em a r r o W , t h e s p l e e n , l i v e r a n d sometimes i n o t h e r t i s s u e s . Al a r g e p o r t i o n o f c h r o n i c m y e l o g e n o u s l e u k e m i a p a t i e n t sd e v e l o p a t r a n s f o r m a t i o n i n t o a p a t t e r n i n d i s t i n g u i s h a b l efrom t h e a c u t e form o f t h e d i s e a s e . T h i s change s knoWn a st h e b l a s t c r i s e s : The p r e s e n t i n v e n t i o n i s g e n e r a l l y s u i t a b l ef o r t r e a t i n g l e u k e m i a s , a s W e l l a s o t h e r n e o p l a s t i c d i s e a s e s .

DETAILED DESCRIPTION OF THEINVENTION

Comp ounds o f t h e Formula I a r e u s e f u l a s a n t i - t u m o ra g e n t s i n p a t i e n t s s u f f e r i n g f r o m n e o p l a s t i c d i s e a s e s a n d f o rr a i s i n g t h e W h i t e b l o o d c e l l c o u n t i n p a t i e n t s s u f f e r i n g f r o mn e o p l a s t i c d i s e a s e s s u c h a s l e u k e m i a and o t h e r f o r m s o ft u m o r s s u c h a s s o l i d t u m o r s a n d u n d e r g o i n g c h e m o t h e r a p y .

T h e p r e f e r r e d compound TPA h a s d e m o n s t r a t e d i nhumans t h e a b i l i t y t o r e d u c e t h e abnormal bone marroWp r o ? l e i n p a t i e n t s W i t h AML n d o t h e r t y p e s o f l e u k e m i a t ot h e p o i n t Where t h e p a t i e n t c a n b e c o n s i d e r e d t o b e i nr e m i s s i o n . Of t h e p a t i e n t s t r e a t e d W i t h TPA, a l l h a d b e e nd i a g n o s e d a s h a v i n g p r o g r e s s e d t o a n a c u t e form o f l e u k emia and t h e p r o g n o s i s f o r a f a v o r a b l e outcome Was n o t veryb r i g h t . P r i o r t o t h e a d m i n i s t r a t i o n o f TPA, l l o f t h e p a t i e n t sh a d r e c e i v e d v a r i o u s f o r m s o f c o n v e n t i o n a l c h e m o t h e r a p yi n c l u d i n g h y d r o x y u r e a , b u s u l f a n a n d Ara-C e t c W i t h o u ts u c c e s s o r i g i n a l l y o r b e c a u s e o f t h e development o f r e s i st a n c e t o t h e s e d r u g s . Upon a d m i n i s t r a t i o n o f TPA o t h e s er e f r a c t o r y p a t i e n t s , c l i n i c a l r e m i s s i o n Was a c h i e v e d i n ar e l a t i v e l y s h o r t t i m e . I n a d d i t i o n , d u r i n g a n d a f t e r t h et r e a t m e n t With TPA, t h e r e Was no bone m a r r oW s u p p r e s s i o n ,i n f e c t i o n o r b l e e d i n g . Many o f t h e p a t i e n t s h a v e b e e n i nc l i n i c a l r e m i s s i o n f o r o v e r s i x months from t h e t i m e t h et r e a t m e n t W i t h TPA r s t s t a r t e d .

A d d i t i o n a l l y , t h e Compounds o f t h e Formula I c a n b eu s e d t o t r e a t p a t i e n t s Who a r e u n d e r g o i n g c h e m o t h e r a p y f o rt h e t r e a t m e n t o f s o l i d tumors a s a method o f e l e v a t i n g t h e i rW h i t e b l o o d c e l l c o u n t s ( l e u k o c y t e s ) . C h e m o t h e r a p e u t i ca g e n t s a r e knoWn t o e x e r t t o x i c e f f e c t s on c e r t a i n normalc e l l s i n t h e b o d y . The W h i t e b l o o d c e l l s i n t h e body t h a t a r er e s p o n s i b l e f o r h e l p i n g t h e b o d y ? g h t o f f i n f e c t i o n s a r ee s p e c i a l l y s e n s i t i v e t o c h e m o t h e r a p e u t i c a g e n t s . I f t h e s ei n f e c t i o n ? g h t i n g c e l l s , t h e W h i t e b l o o d c e l l s ) f a l l t o v e r yl o W l e v e l s i n t h e p a t i e n t r e c e i v i n g c h e m o t h e r a p y , t h e p a t i e n tW i l l become more s u s c e p t i b l e t o s e r i o u s i n f e c t i o n . TPA a sshoWn h e p r o p e n s i t y t o h e l p s p e e d t h e r a p i d r e c o v e r y o f t h ei n f e c t i o n ? g h t i n g c e l l s , b o t h a f t e r a n d d u r i n g c h e m o t h e r a p yt r e a t m e n t a n d t h e r e f o r e TPA s e s p e c i a l l y u s e f u l i n r e d u c i n gt h e c h a n c e s o f a p a t i e n t d e v e l o p i n g s e r i o u s i n f e c t i o n s . O f t e nt h e e l e v a t i o n of h e White bloo d c e l l count occurs W i t h i n oned a y o f t r e a t m e n t . The p r e s e n t i n v e n t i o n i s u s e f u l i n r a i s i n gt h e W h i t e b l o o d c e l l c o u n t i n p a t i e n t s u n d e r g o i n g chemot h e r a p y f o r a l l t y p e s o f s o l i d t u m o r s s u c h a s b r e a s t , l u n g ,p r o s t a t e a n d c o l o n c a n c e r s . TPA e l p s t o m a i n t a i n a d e q u a t el e v e l s o f W h i t e b l o o d c e l l s o r i n f e c t i o n ? g h t i n g c e l l s . Thesec e l l s Work b y s u r r o u n d i n g a n d d e s t r o y i n g b a c t e r i a t h a t mayh a v e e n t e r e d t h e b o d y . T P A , b y p r e v e n t i n g t h e n u m b e r o fW h i t e b l o o d c e l l s f r o m f a l l i n g t o loW l e v e l s f o r l o n g p e r i o d so f t i m e , l e s s e n s t h e p o t e n t i a l f o r i n f e c t i o n , t h e u s e o f

10

1 5

20

25

30

35

40

45

50

55

60

4B e c a u s e o f t h e a b i l i t y t o e l e v a t e t h e W h i t e b l o o d c e l l

c o u n t , t h e p r e s e n t i n v e n t i o n may a l s o b e u s e f u l i n a n yp a t i e n t W i t h c o m p r o m i s e d W h i t e b l o o d c o u n t s i n c l u d i n gp a t i e n t s s u f f e r i n g f r o m A I D S .A l s o , compounds o f t h e F o r m u l a t a b o v e i n a n i m a l s t u d i e s

h a v e e v i d e n c e d t h e a b i l i t y t o i n h i b i t s o l i d t u m o r g r o W t h i nl a b o r a t o r y a n i m a l s .D o s a g e d e l i v e r y s y s t e m s , p r e f e r a b l y a q u e o u s d o s a g e

d e l i v e r y s y s t e m s , s u i t a b l e f o r p a r e n t e r a l a d m i n i s t r a t i o n o fcompounds o f t h e F o r m u l a I i n a p h a r m a c e u t i c a l a c c e p t a b l ec a r r i e r , c a n b e p r e p a r e d b y d i s s o l v i n g a Compound o f t h eFormula I i n a n a p p r o p r i a t e so l v e n t Which i s m i s c i b l e ,d i s p e r s a b l e o r s o l u b l e With W a t e r , such a s an a l c o h o l e g .e t h a n o l , p r o p a n o l , i s o p r o p a n o l a n d t h e l i k e . O t h e r W a t e rs o l u b l e s o l v e n t s s u i t a b l e f o r t h e p u r p o s e o f t h e p r e s e n ti n v e n t i o n i n c l u d e g l y c o l s s u c h a s p r o p y l e n e g l y c o l o r p o l ye t h y l e n e g l y c o l , g l y c e r i n e g l y c e r o l ) , g l y c e r o l f o r m a l a n d t h el i k e . There c a n b e added t o t h e dosage forms a n t i m i c r o b i a lp r e s e r v a t i v e s s u c h a s b e n Z y l a l c o h o l , p h e n o l , c r e s o l o r t h o ,meta o r p a r a o r m i x t u r e s o f t h e f o r e g o i n g ) and p h e n y l e t h yl a l c o h o l . There can a l s o be added loW c o n c e n t r a t i o n s o fs u r f a c t a n t s knoWn t o be s u i t a b l e f o r i n t r a v e n o u s use a t loWc o n c e n t r a t i o n s i n c l u d i n g E m u l p h o r E L - 6 2 0 , C r e m o p h o r E L ,P o l y s o r b a t e 8 0 ( T W e e n 8 0 ) o r P o l y s o r b a t e 2 0 ( T W e e n 2 0 ) .Any s o l v e n t o r m i x t u r e s o f s ol v e n t s a n d / o r p r e s e r v a t i v ea n d / o r s u r f a c t a n t c a n b e s e l e c t e d by t h e p e r s o n s k i l l e d i n t h ea r t a s t h e p h a r m a c e u t i c a l l y a c c e p t a b l e c a r r i e r i n a c c o r d a n c eW i t h c o n v e n t i o n a l p r a c t i c e s f o r p r e p a r i n g p a r e n t e r a l d o s a g ef o r m u l a t i o n s . A l l t h a t i s r e q u i r e d o f a component o f t h ep h a r m a c e u t i c a l l y a c c e p t a b l e c a r r i e r t o b e s u i t a b l e f o r t h ep u r p o s e s o f t h e p r e s e n t i n v e n t i o n i s t h a t i t b e s a f e Wheni n j e c t e d i n t o a human; i s m i s c i b l e , d i s p e r s i b l e o r s o l u b l e i nW a t e r ; h a s n o c y t o t o x i c i t y ; a n d d o e s n o t d i m i n i s h t h e s h e l fl i f e o f t h e p h a r m a c e u t i c a l f o r m u l a t i o n s o t h a t i t may b es t o r e d .

The compounds o f t h e Formula I i n t h e t r e a t m e n t o fn e o p l a s t i c d i s e a s e s s u c h a s l e u k e m i a o r f o r r a i s i n g W h i t eb l o o d c e l l c o u n t s c a n b e a d m i n i s t e r e d p a r e n t e r a l l y (IV) i nd o s a g e amounts from a b o u t 0 . 0 0 1 mg e r d o s e t o a b o u t 1 . 5mg e r d o s e , f o r a b o u t 17 t i m e s p e r Week f o r a b o u t 110W e e k s ; more p r e f e r a b l e from a b o u t 0 . 0 5 t o a b o u t 1 mg , 17t i m e s p e r W e e k , f o r 1 7 W e e k s ; a n d s t i l l more p r e f e r a b l yfrom a b o u t 0 . 1 mg o a b o u t 0 . 6 mg , 17 t i m e s p e r Week f o ra b o u t 1 7 W e e k s . The m o s t p r e f e r r e d d o s a g e f o r m i s d e l i ve r e d t h r o u g h I . V . i n f u s i o n and c o n t a i n s 0 . 1 mg , 0 . 2 5 mg r0 . 5 mg e r d o s e . The c o u r s e o f t h e r a p y p r e f e r r e d i s 1 7Weeks W i t h 1 mg e i n g a d m i n i s t e r e d o v e r a Week i n d i v i d e dd o s e s .

I n p a t i e n t s r e c e i v i n g c h e m o t h e r a p y f o r s o l i d t u m o r s , t h emost p r e f e r r e d t i m e f o r a d m i n i s t r a t i n g a s i n g l e d o s e o f acompound o f t h e F o r m u l a I i s a b o u t t h e t i m e t h e p a t i e n t i st o r e c e i v e o r h a s j u s t undergone a c o u r s e o f chemotherapyd e s i g n e d t o combat t h e s o l i d t u m o r s .

The p r e c i s e d o s a g e a m o u n t a n d t h e d u r a t i o n o f a d m i n i st r a t i o n o f a compound o f t h e Formula W i l l depend on t h ee x i g e n c i e s o f t h e m e d i c a l s i t u a t i o n a n d t h e j u d g e m e n t o f t h ep h y s i c i a n t r e a t i n g t h e p a t i e n t i n a c c o r d a n c e W i t h c o n v e nt i o n a l p r a c t i c e among m e d i c a l p r o f e s s i o n a l s . The e x a c t d o s eW i l l depend upon s u c h f a c t o r s a s t h e a g e , W e i g h t a n dc o n d i t i o n o f t h e p a t i e n t , t h e f r e q u e n c y o f a d m i n i s t r a t i o n a n dt h e manner i n Which t h e p a t i e n t r e s p o n d s t o t h e t r e a t m e n t .

EXAMPLEThe f o l l o W i n g compounds a r e i l l u s t r a t i v e o f t h e c o m


40/51

6 , 0 6 3 , 8 1 41 ) P h o r b o l 1 3 - B u t y r a t e2 ) P h o r b o l 1 2 - D e c a n o a t e3 ) P h o r b o l 1 3 - D e c a n o a t e4 ) P h o r b o l 1 2 , 1 3 - D i a c e t a t e5 ) P h o r b o l 1 3 , 2 0 - D i a c e t a t e6 ) P h o r b o l 1 2 , 1 3 - D i b e n Z o a t e7 ) P h o r b o l 1 2 , 1 3 - D i b u t y r a t e8 ) P h o r b o l 1 2 , 1 3 - D i d e c a n o a t e9 ) P h o r b o l 1 2 , 1 3 - D i h e x a n o a t e1 0 ) P h o r b o l 1 2 , 1 3 - D i p r o p i o n a t e1 1 ) P h o r b o l 1 2 - M y r i s t a t e1 2 ) P h o r b o l 1 3 - M y r i s t a t e1 3 ) P h o r b o l 1 2 - M y r i s t a t e - 1 3 - A c e t a t e a l s o known s TPA

o r PMA1 4 ) P h o r b o l 1 2 , 1 3 , 2 0 - T r i a c e t a t e1 5 ) 1 2 - D e o x y p h o r b o l 1 3 - A n g e l a t e1 6 ) 1 2 - D e o x y p h o r b o l 1 3 - A n g e l a t e 2 0 - A c e t a t e1 7 ) 1 2 - D e o x y p h o r b o l 1 3 - I s o b u t y r a t e1 8 ) 1 2 - D e o x y p h o r b o l 1 3 - I s o b u t y r a t e - 2 0 - A c e t a t e1 9 ) 1 2 - D e o x y p h o r b o l 1 3 - P h e n y l a c e t a t e2 0 ) 1 2 - D e o x y p h o r b o l 1 3 - P h e n y l a c e t a t e 2 0 - A c e t a t e2 1 ) 1 2 - D e o x y p h o r b o l 1 3 - T e t r a d e c a n o a t e2 2 ) P h o r b o l 1 2 - T i g l i a t e 1 3 - D e c a n o a t e2 3 ) 1 2 - D e o x y p h o r b o l 1 3 - A c e t a t e2 4 ) P h o r b o l 1 2 - A c e t a t e2 5 ) P h o r b o l 1 3 - A c e t a t e

EXAMPLEF o r m u l a t i o n T y p e A

0 . 1 0 , 0 . 1 2 5 , 0 . 2 5 o r 0 . 5 mg f TPA a s d i s s o l v e d i n 1 . 3m l 95100 U . S . P . e t h a n o l a n d 0 . 7 m l a l i n e . Under t e r i l ec o n d i t i o n s , TPA as ? r s t d i s s o l v e d i n e t h a n o l , t h e n s a l i n eWas a d d e d , m i x e d v i g o r o u s l y , b a c t e r i o l o g i c a l l y ? l t e r e d , a n ds t o r e d i n s e a l e d s t e r i l e amber v i a l s c o n t a i n i n g e i t h e r 0 . 1 0m g / 2 m l , 0 . 1 2 5 m l / 2 ml o r 0 . 2 5 m g / 2 m l , 0 . 5 m g / 2 m l .F o r m u l a t i o n T y p e B

0 . 1 0 , 0 . 1 2 5 , 0 . 2 5 o r 0 . 5 mg f TPA a s d i s s o l v e d i n 0 . 2ml o f e t h a n o l , 1 . 2 ml o f i s o p r o p a n o l a n d 0 . 6 m l a l i n e . Unders t e r i l e c o n d i t i o n s , TPA as ? r s t d i s s o l v e d i n t h e e t h a n o l andi s o p r o p a n o l , t h e n s a l i n e Was a d d e d , and t h e m i x t u r e Wasv i g o r o u s l y m i x e d , b a c t e r i o l o g i c a l l y ? l t e r e d a n d s t o r e d i ns e a l e d s t e r i l e a m b e r v i a l s c o n t a i n i n g e i t h e r 0 . 1 0 m g / 2 m l ,0 . 1 2 5 m l / 2 ml o r 0 . 2 5 mg/2 ml o r 0 . 5 mg/2 m l .

A n a l y t i c a l r e s u l t s shoWed t h a t t h e r e i s no c h e m i c a lc h a n g e i n t h e TPA s o l u t i o n s s t o r e d i n t h e d a r k a t c o l dt e m p e r a t u r e f o r up t o one y e a r ; a l s o , t h e r e i s no chemicalchange i n t h e TPA o l u t i o n s s t o r e d i n t h e d a r k a t r o o mt e m p e r a t u r e up t o tWo m o n t h s .

EXAMPLE1 . E f f e c t o f TPA n a Human P r o m y e l o c y t i c Leukemia C e l lL i n e ( H L - 6 0 ) :

HL-60 c e l l s a t 2 > < 1 0 6 c e l l s / m l Were t r e a t e d W i t h TPA. The? n a l c o n c e n t r a t i o n s o f TPA ere 1 0 , 2 0 , o r 100 n g / m l . Thee t h a n o l c o n t e n t Was l e s s t h a n 0.01 . A f t e r 3 h o u r s o f TPAt r e a t m e n t , t h e c e l l s s t o p p e d p r o l i f e r a t i n g a n d c e l l a g g r e g at i o n and a t t a c h m e n t t o t h e d i s h Were o b s e r v e d . A f t e r 48 h o ft r e a t m e n t , t h e r e W e r e m o r p h o l o g i c a l c h a n g e s . A f t e r 4 6

10

20

25

30

35

40

45

55

60

6EXAMPLE 42 ) TPA+LoW D o s e s o f A r a - C :

The t r e a t m e n t o f HL-60 c e l l s W i t h loW d o s e s o f TPA 2 0n g / m l ) o r A r a - C ( 1 0 0 n g / m l ) d e m o n s t r a t e d t h a t A r a - C c o u l di n d u c e c e l l d i f f e r e n t i a t i o n , a n d TPA t loW c o n c e n t r a t i o n i sa Weak e l l d i f f e r e n t i a t i o n - i n d u c i n g a g e n t . The c o m b i n a t i o nt r e a t m e n t o f HL-60 c e l l s W i t h TPA nd Ara-C i n d u c e d t h eHL-60 c e l l s t o d i f f e r e n t i a t e s y n e r g i s t i c a l l y .

EXAMPLEE f f e c t o f TPA n M i c e I n j e c t e d W i t h S 1 8 0 ( S a r c o m a 1 8 0 )Tumor C e l l s :E i g h t g r o u p s o f KWen-Ming m i c e c o n t a i n i n g 7 m i c e p e r

g r o u p Were u s e d i n t h e f o l l o W i n g e x p e r i m e n t . TWo g r o u p sWere u n t r e a t e d a n d s i x g r o u p s r e c e i v e d t h e d r u g .

Each KWen-Ming mouse Was i n j e c t e d W i t h 5 > < 1 0 6 S180c e l l s a t t h e u n d e r - a r m p o s i t i o n . A f t e r 24 o r 72 , t h e a n i m a l sWere g i v e n TPA . p . o r l o c a l l y a t t h e t u m o r s i t e . The i n j e c t e dd o s e s o f TPA e r e 5 0 , 1 0 0 a n d 200 g / k g / d f o r 7 d a y s . Thea n i m a l s Were s a c r i ? c e d 2 4 h r s a f t e r t h e ? n a l TPA r e a t m e n tand t h e tumors Were Weighed t o c a l c u l a t e t h e e x t e n t o f t h et u m o r g r o W t h i n h i b i t i o n . The s t u d y shoWed t h a t t h e t u m o rg r o W t h Was i n h i b i t e d by 4 1 . 7 , 54.8 a n d 3 0 . 4 ,r e s p e c t i v e l y , i n m i c e t h a t W e r e i n j e c t e d ip W i t h 5 0 , 1 0 0 o r2 0 0 p i g / k g TPA d a i l y f o r 7 d a y s . The t u m o r g r o W t h Wasi n h i b i t e d b y 3 5 . 5 , 4 9 . 3 a n d 5 9 . 2 , r e s p e c t i v e l y , i n m i c et h a t W e r e i n j e c t e d d a i l y f o r 7 d a y s W i t h 5 0 , 1 0 0 o r 200 i g / k gTPA l o c a l l y a t t h e tumor s i t e i n c o m p a r i s o n t o t h e c o n t r o lm i c e . P a t h o l o g i c a l s t u d i e s shoWed t h a t t h e tumor c e l l s Wered i f f e r e n t i a t e d a f t e r t h e TPA r e a t m e n t .

EXAMPLEE f f e c t o f TPA n Mice I n j e c t e d W i t h B16 Tumor C e l l s :

F o u r g r o u p s o f C57 m i c e W e r e u s e d i n t h e e x p e r i m e n t .Each group c o n t a i n e d 7 mice and one group Was u n t r e a t e d .Each C57 mouse Was i n j e c t e d W i t h 0 . 2 m l o f s u p e r n a t a n t o fa 1 : 6 W/v homogenate o f B16 e l l s a t t h e u n d e r - a r m p o s i t i o n .On t h e t h i r d d a y , e a c h t r e a t m e n t g r o u p Was g i v e n TPA . p .a t 5 0 , 100 o r 200 p g / k g / d f o r 8 d a y s . The a n i m a l s Weres a c r i ? c e d a f t e r t h e t r e a t m e n t , t h e tumors Were W e i g h e d , a n dt h e r a t e s o f i n h i b i t i o n o f tumor groWth Were 40.0 , 59.4a n d 3 2 . 1 , r e s p e c t i v e l y , W h i c h W e r e a l l s t a t i s t i c a l l y d i f f e re n t from t h e c o n t r o l g r o u p .

EXAMPLEE f f e c t o f TPA on t h e P e r i p h e r a l White Blood C e l l s (WBC)a n d H e m o g l o b i n ( H b ) C o u n t s i n S 1 8 0 C e l l - I n j e c t e d M i c e :S180 c e l l s Were i n j e c t e d i n t o m i c e . On t h e t h i r d d a y , t h em i c e Were g i v e n TPA . p . a t 5 0 , 1 0 0 o r 200 p g / k g / d f o r 7d a y s . On t h e s e c o n d d a y a f t e r t h e t r e a t m e n t Was c o m p l e t e d ,b l o o d s a m p l e s Were t a k e n from t h e t a i l s o f t h e t r e a t e d micef o r WBC n d Hb a n a l y s e s . The WBC o u n t s f o r t h e t r e a t e dg r o u p s ( 5 0 , 1 0 0 , o r 2 0 0 u g / k g / d f o r 7 d ) W e r e 1 6 1 1 7 . 4 ,1 8 7 1 3 . 0 a n d 2 0 . 7 1 3 . 4 > < 1 0 9 / L , r e s p e c t i v e l y ; t h e WBC o u n tf o r t h e c o n t r o l g r o u p Was 1 3 . 6 1 1 . 8 > < 1 0 9 / L . The Hb o f t h et r e a t e d g r o u p s Were 1 3 6 1 1 1 , 149112 and 149110 g / L , a n dt h e Hb o f t h e c o n t r o l g r o u p Was 134115 g / L . The r e s u l t si n d i c a t e t h a t ip n j e c t i o n o f TPA o u l d i n c r e a s e t h e p e r i p he r a l WBC o u n t s i n mice i n a d o s e - d e p e n d e n t manner,Whereas t h e Hb l e v e l s Were n o t g r e a t l y a f f e c t e d i n TPAt r e a t e d m i c e When compared t o t h e c o n t r o l m i c e .

EXAMPLEStudy on t h e C l i n i c a l Use o f TPA n Hum ans1 . D o s e R a n g i n g S t u d y .Due t o t h e s t r o n g l o c a l i r r i t a t i o n c a u s e d by TPA


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6 , 0 6 3 , 8 1 47

2 . The T o x i c i t y a n d S i d e E f f e c t s o f D i f f e r e n t TPA DosesA d m i n i s t e r e d C l i n i c a l l y :

1 ) TPA g i v e n a t 1 m g / p a t i e n t / W e e k :One mg TPA n s o l u t i o n Was m ixed W e l l W i t h 200 m l o f

s a l i n e f o r i v . i n f u s i o n Which Was completed i n 1 h t t h e r a t eo f 1 6 p i g / m i n . One h o u r a f t e r TPA a d m i n i s t r a t i o n , p a t i e n t ss t a r t e d t o h a v e c h i l l s Which l a s t e d f o r a b o u t 30 m i n , f o ll o W e d b y f e v e r , t h e p a t i e n t s t e m p e r a t u r e r e a c h e d3 7 . 5 3 9 . 5 C . Which l a s t e d f o r 35 h , t h e n r e t u r n e d t on o r m a l ) W i t h l i g h t t o h e a v y p e r s p i r a t i o n . T h e a b o v e sympt o m s c o u l d b e a l l e v i a t e d b y g i v i n g t h e p a t i e n t s g l u c o c o r t ic o i d s . TPA t t h i s d o s e c a u s e d a m i n o r i t y o f p a t i e n t s t ob l e e d , s e v e r a l p a t i e n t s s u f f e r e d f o r a s h o r t p e r i o d o f t i m ed i f ? c u l t y i n b r e a t h i n g , a n d Hb Was d e t e c t e d i n t h e u r i n e .HoWever, t h e s e s i d e e f f e c t s Were s h o r t l i v e d a n d r e v e r s i b l e .The c a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n s W e r e a l lfound t o be n o r m a l .

2 ) TPA g i v e n a t 0 . 5 m g / p a t i e n t > < 2 / W e e k : ( t W o d o s e s aW e e k )0 . 5 mg f TPA n s o l u t i o n Was miXed W e l l W i t h 200 m l o f

s a l i n e f o r i v . i n f u s i o n Which Was completed i n 1 h t t h e r a t eo f 8 p i g / m i n . The r e a c t i o n s a f t e r a d m i n i s t r a t i o n Were s i m i l a rt o t h a t o f t h e 1 mg TPA o s a g e , b u t t o a l e s s e r e X t e n t t h a nt h e 1 mg o s e . The p a t i e n t s t o l e r a t e d t h e l o W e r d o s e moree a s i l y . O c c a s i o n a l l y , Hb Was d e t e c t e d i n p a t i e n t s u r i n e .D i f ? c u l t y i n b r e a t h i n g Was n o t o b s e r v e d . The c a r d i a c ,h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n s W e r e a l l n o r m a l .

3 ) TPA g i v e n a t 0 . 2 5 m g / p a t i e n t > < 4 / W e e k :0 . 2 5 mg f TPA n s o l u t i o n Was miXed W e l l W i t h 200 m l

o f s a l i n e f o r i v . i n f u s i o n Which Was completed i n 1 h a t t h er a t e o f 4 p i g / m i n . A f t e r t h e a d m i n i s t r a t i o n , symptoms s u c h a sc h i l l s and f e v e r Were a l s o o b s e r v e d , b u t t o a m u c h l e s s e re X t e n t t h a n W i t h t h e h i g h e r d o s a g e s . No H b Was d e t e c t e d i nt h e u r i n e , a n d n o p a t i e n t s u f f e r e d d i f ? c ul t y i n b r e a t h i n g . T h ec a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n s W e r e a l ln o r m a l .

A f t e r comparing t h e a b o v e t h r e e d o s a g e s , 0 . 2 5m g / p e r s o n > < 4 / W e e k a n d 0 . 5 m g / p e r s o n > < 2 / W e e k a r e c o n s i de r e d t o b e p r e f e r r e d d o s a g e s o f T P A .

EXAMPLEThe r e s u l t s o b t a i n e d upon t r e a t m e n t o f p a t i e n t s W i t h TPA

a s p r e s e n t e d i n t a b u l a r f o r m a n d i n s u b s e q u e n t e x a m p l e s .TABLE

C l i n i c a lSummary o f C l i n i c a l E ? i c a c y o f TPA n t h e F i v e C a s e s

R e p r e s e n t i n g C h r o n i c M y e l o c y t i c L e u k e m i a H a v i n g P r o g r e s s e d t o A c u t eM y e l o c y t i c L e u k e m i a B e f o r e TPA d m i n i s t r a t i o n S u b j e c t s 1 - 5 )

a n d F i v e C a s e s o f O t h e r L e u k e m i a s ( S u b j e c t s 6 1 0 )Bone marr oW M y e l o b l a s t a n d p r o m y e l o c y t e

S u b j e c t p e r c e n t o f t o t a l c e l l sNo. Before TPA A f t e r TPA

1 30 2 . 52 36 3 . 03 90 2 . 04 6 7 . 5 4 . 55 2 7 . 5 1 . 56 48 37 16 108 8 0 . 8 179 A p l a s t i c a n e m i a ) ( T P A t e r m i n a t e d )

1 0 (9 e a r l y i n TPA 0

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8TABLE 2

C l i n i c a lSummary o f TPA i n d u c e d W h i t e B l o o d C e l l C h a n g e s (WBC) i nP a t i e n t s W i t h S o l i d T u m o r s U n d e r g o i n g C h e m o t h e r a p y

S u b j e c t WBC X 1 0 9 / l i t e rNo. B e f o r e TPA Peak a f t e r TPA1 1 0 . 7 6 . 812 3 . 0 4 . 513 0 . 9 2 . 514 3 . 8 8 . 015 2 . 4 7 . 116 2 . 4 5 . 217 2 . 0 4 . 418 2 . 4 4 . 019 2 . 9 5 . 120 0 . 7 2 . 721 1 . 1 1 . 52 2 1 . 9 7 . 623 2 . 3 3 . 924 1 . 1 5 . 325 2 . 1 6 . 426 3 . 6 5 . 6

EXAMPLE 10I n t h e s u b j e c t s i d e n t i ? e d a s 1 ) t h r o u g h 5 ) b e l o W , c h r o n i cm y e l o c y t i c l e u k e m i a h a d p r o g r e s s e d t o a c u t e m y e l o c y t i c

leukemia b e f o r e t r e a t m e n t W i t h TPA.S u b j e c t N o . 1 ) TS, m a l e , 3 2 , p a t i e n t N o . 2 8 8 7 9 . B l o o d

p r o ? l e b e f o r e TPA r e a t m e n t : H b : 2 8 g / L ; WBC: 1 . 0 > < 1 0 9 /L , p l a t e l e t : 1 3 5 > < 1 0 9 / L . Bone mar roW p r o ? l e b e f o r e TPAt r e a t m e n t : m y e l o b l a s t + p r o m y e l o c y t e : 30 . TPA r e a tm e n t : 1 m g / W e e k ( 0 . 2 5 m g a d m i n i s t e r e d f o u r t i m e s ) f o rtWo W e e k s . Blood p r o ? l e a f t e r t r e a t m e n t : H b : 8 6 g / L ;WBC: 2 . 8 > < 1 0 9 / L , p l a t e l e t : 2 8 3 x 1 0 9 / L . Bone mar roW r o? l e a f t e r TPA r e a t m e n t : m y e l o b l a s t + p r o m y e l o c y t e : 2 . 5 .

S u b j e c t N o . 2 ) C . J . , m a l e , 3 0 , p a t i e n t N o . 2 9 9 2 6 . D i a g n o s i s :c h r o n i c m y e l o c y t i c l e u k e m i a became a c u t e m y e l o c y t i cl e u k e m i a b e f o r e t r e a t m e n t . Blood p r o ? l e b e f o r e TPAt r e a t m e n t : H b : 9 4 g / L ; WBC: . 8 > < 1 0 9 / L , p l a t e l e t : 6 3 x 1 0 9 /L . S p l e e n : 3 cm eloW t h e r i b c a g e . Bone marro W p r o ? l eb e f o r e TPA t r e a t m e n t : m y e l o b l a s t + p r o m y e l o c y t e : 36 .TPA t r e a t m e n t : 1 mg/Week f o r 5 W e e k s . B l o o d p r o ? l ea f t e r t r e a t m e n t : H b : 1 0 4 g / L ; WBC: 4 . 9 > < 1 0 9 / L , p l a t e l e t :8 0 x 1 0 9 / L . S p l e e n : 0 . 5 c m beloW t h e r i b c a g e . Bonema rroW p r o ? l e a f t e r TPA t r e a t m e n t : myeloblast+p r o m y e l o c y t e : 3 .

S u b j e c t N o . 3 ) Z . K . , m a l e , 4 2 , p a t i e n t N o . 1 8 1 0 2 . D i a g n os i s : c h r o n i c m y e l o c y t i c l e u k e m i a became a c u t e m y e l oc y t i c l e u k e m i a b e f o r e t r e a t m e n t . B l o o d p r o ? l e b e f o r e TPAt r e a t m e n t : H b : 7 0 g / L ; WBC: 2 7 . 5 > < 1 0 9 / L , p l a t e l e t :2 1 > < 1 0 9 / L . Bone marroW p r o ? l e b e f o r e TPA r e a t m e n t :myeloblast+promyelocyte: 90 . TPA t r e a t m e n t : 1mg/Week f o r 7 W e e k s . B l o o d p r o ? l e a f t e r t r e a t m e n t : H b :9 6 g / L ; WBC: 2 2 > < 1 0 9 / L , p l a t e l e t : 7 0 > < 1 0 9 / L . Bone m a rroW pro?le a f t e r TPA t r e a t m e n t : myeloblast+p r o m y e l o c y t e : 2 .

S u b j e c t N o . 4 ) W . F . m a l e , 2 5 , p a t i e n t N o . 2 1 3 1 5 . D i a g n o s i s :c h r o n i c m y e l o c y t i c l e u k e m i a became a c u t e m y e l o c y t i cl e u k e m i a b e f o r e t r e a t m e n t . Blood p r o ? l e b e f o r e TPAt r e a t m e n t : H b : 8 7 g / L ; WBC: 1 9 > < 1 0 9 / L , p l a t e l e t : 1 5 0 > < 1 0 9 / L , p l a t e l e t : 2 9 0 > < 1 0 9 / L . B o n emarroW p r o ? l e b e f o r e TPA t r e a t m e n t : m y e l o b l a s t +p r o m y e l o c y t e : 2 7 . 5 . TPA t r e a t m e n t : 1 mg/Week f o r 2W e e k s . B l o o d p r o ? l e a f t e r t r e a t m e n t : H b : 84 g / L ; WBC:2 7 . 3 > < 1 0 9 / L , p l a t e l e t : 1 7 0 > < 1 0 9 / L . B o n e m a r r o W p r o ? l ea f t e r TPA r e a t m e n t : m y e l o b l a s t + p r o m y e l o c y t e : 1 . 5 .A l l t h e a b o v e p a t i e n t s h a d r e c e i v e d v a r i o u s r e g i m e n s o f

c h e m o t h e r a p y p r i o r t o t h e TPA t r e a t m e n t , i n c l u d i n gh y d r o X y u r e a , b u s u l f a n , and A r a - C , e t c . b u t none Was e f f e ct i v e a t t h e s t a r t o f TPA r e a t m e n t . Before t h e a d m i n i s t r a t i o no f T P A , p a t i e n t s r e c e i v e d i n j e c t i o n o f 6 > < 1 0 5 u n i t s o f v i t a m i nD3 ( V D 3 ) / p e r s o n f o r 2 d a y s ; a f t e r t h e TPA d m i n i s t r a t i o n ,p a t i e n t s r e c e i v e d i v . i n f u s i o n o f 40 m g o f A r a - C / d > < 3 . A f t e rt h e t r e a t m e n t , t h e p a t i e n t s a l l a c h i e v e d c l i n i c a l r e m i s s i o n i nbone marroW p a r a m e t e r s i n a s h o r t t i m e . I n a d d i t i o n , d u r i n gand a f t e r t h e treatment, t h e r e W a s no bone m a r r o Ws u p p r e s s i o n , n o r i n f e c t i o n o r b l e e d i n g . T h e s e p a t i e n t s h a v ebeen i n c l i n i c a l r e m i s s i o n f o r o v e r 6 months.

EXAMPLE 1O t h e r T y p e s o f L e u k e m i a :S u b j e c t N o . 6 ) YR, m a l e , 5 7 . D i a g n o s e d a s AML-M3.S y m p t o m s b e g a n i n J a n u a r y , 1 9 9 5 . B l o o d p r o ? l e : H b : 6 0g / L , WBC: 0 . 4 > < 1 0 9 / L , p l a t e l e t : 4 0 > < 1 0 9 / L . B o n e m a r r o W

p r o ? l e : m y e l o b l a s t + p r o m y e l o c y t e : 4 8 . T h e TPA r e a tment p e r i o d Was 1 mg/Week f o r t h r e e W e e k s , a n d 6 > < 1 0 5u n i t s V D 3 / d > < 3 W e r e i n j e c t e d p r i o r t o t h e t r e a t m e n t . A f t e rt h e ? r s t t r e a t m e n t p e r i o d , b l o o d p r o ? l e : H b : 1 1 8 g / L ,WBC: 4 . 1 > < 1 0 9 / L , p l a t e l e t : 8 0 x 1 0 9 / L . Bone marro W p r o? l e : m y e l o b l a s t + p r o m y e l o c y t e : 3 , Which met t h e s t a nd a r d f o r AML-M3 r e m i s s i o n . The p a t i e n t h a s b e e n i nr e m i s s i o n a f t e r t r e a t m e n t f o r a t l e a s t 6 m o n t h s .S u b j e c t N o . 7 ) M . W . , m a l e , 6 7 . D i a g n o s i s : MDS-REABa c c o m p a n i e d b y a n i n c r e a s e d number o f m o n o c y t e s . F o u rmonths o f o r a l VP16 a d m i n i s t r a t i o n f a i l e d t o p r o d u c er e s u l t s . The p a t i e n t s t a r t e d t o r e c e i v e a c o m b i n a t i o nt r e a t m e n t o f 1 , 2 5 - ( O H ) 2 V D3 +TPA+loW d o s e A r a - C .TPA d o s a g e : 0 . 2 5 0 . 5 m g 1 m g p e r W e e k ) f o r e l e v e nW e e k s . Blood p r o ? l e b e f o r e TPA r e a t m e n t : H b : 3 6 g / L ;WBC: 4 . 0 > < 1 0 9 / L , p l a t e l e t : 2 9 > < 1 0 9 / L . M y e l o b l a s t : 2 ,P r o m y e l o c y t e : 4 , M y e l o c y t e : 3 , N e u t r o p h i l : 6 0 ,L y m p h o c y t e : 2 5 , M o n o c y t e 6 . B o n e m a r r o W p r o ? l eb e f o r e t r e a t m e n t : a c t i v e i n p r o l i f e r a t i o n , m y e l o b l a s t : 8 ,p r o m y e l o c y t e : 8 . S p l e e n : 3 c m beloW h e r i b c a g e . A f t e rt h e t r e a t m e n t : S p l e e n : 0 . 5 cm beloW t h e r i b c a g e . Bloodp r o ? l e : H b : 4 2 g / L ; WBC: 1 0 . 2 > < 1 0 9 / L , p l a t e l e t : 3 4 > < 1 0 9 /L . N e u t r o p h i l : 8 0 , L y m p h o c y t e : 1 9 , M o n o c y t e 1 .Promyelocytes Were n o t d e t e c t e d . Bone marroW p r o ? l e :a c t i v e i n p r o l i f e r a t i o n , m y e l o b l a s t : 4 , p r o m y e l o c y t e :6 .

S u b j e c t N o . 8 ) L . Q . , m a l e , 3 6 . D i a g n o s i s : AML-M3. r e a tment W i t h r e t i n o i c a c i d (RA) a t 80 m g / d a y > < 5 0 Was n o ts u c c e s s f u l . Blood p r o ? l e b e f o r e t h e t r e a t m e n t W i t h TPA:H b : 4 5 g / L , WBC: 1 . 0 > < 1 0 9 / L , p l a t e l e t : 3 5 > < 1 0 9 / L . B o n emarroW p r o ? l e : v e r y a c t i v e i n p r o l i f e r a t i o n , m y e l o b l a s t +p r o m y e l o c y t e : 8 0 . 8 . B l o o d p r o ? l e a f t e r t h e TPA r e a tm e n t : H b : 6 6 g / L , WBC: 2 . 2 > < 1 0 9 / L , p l a t e l e t : 2 2 3 > < 1 0 9 / L .Bone mar roW p r o ? l e : a c t i v e i n p r o l i f e r a t i o n , m y e l o b l a s t +p r o m y e l o c y t e : 1 7 .

S u b j e c t N o . 9 ) Z . H. , f e m a l e , 2 1 . D i a g n o s i s : b o n e m a r r o Ws u p p r e s s i o n a f t e r r e c e i v i n g c h e m o t h e r a p y f o r c h r o n i cm y e l o c y t i c l e u k e m i a , s e c o n d a r y a p l a s t i c a n e m i a . T h e

1 0? l e : a p l a s t i c a n e m i a . TPA d o s a g e : 0 . 2 5 m g > < 2 . B l o o dp r o ? l e a f t e r t h e TPA r e a t m e n t : H b : 3 2 g / L , WBC: . 9 > < 1 0 9 / L . Due o s e v e r e a n e m i a , t h e TPAtreatment Was terminated.5 S u b j e c t N o . ( 1 0 ) L . N . , f e m a l e , 2 6 . D i a g n o s i s : CML. T h e

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p a t i e n t h a d b e e n t r e a t e d W i t h c h e m o t h e r a p y u s i n g t h ec o m b i n a t i o n o f h o m o h a r ri n g t o m i n e a n d A r a - C . B l o o dp r o ? l e b e f o r e TPA r e a t m e n t : H b : 9 8 g / L ; WBC: 2 . 0 > < 1 0 9 /L , p l a t e l e t : 1 0 2 x 1 0 9 / L . 0 . 2 5 m g TPA d m i n i s t e r e d t o t h ep a t i e n t o n c e . B l o o d p r o ? l e a f t e r t r e a t m e n t : H b : 9 6 g / L ;WBC: . 0 > < 1 0 9 / L , p l a t e l e t : 1 1 2 > < 1 0 9 / L . On h e s e c o n d d a ya f t e r TPA t r e a t m e n t : m y e l o b l a s t + p r o m y e l o c y t e : 4 ,m y e l o c y t e 5 . On t h e ? f t h d a y a f t e r t h e TPA r e a t m e n t ,t h e s e t y p e s o f b l o o d c e l l s c o m p l e t e l y d i s a p p e a r e d .

EXAMPLE 12P a t i e n t s u n d e r g o i n g c h e m o t h e r a p y f o r t h e t r e a t m e n t o f

s o l i d t u m o r s .S u b j e c t N o . 1 1 ) L . X . , f e m a l e , 5 0 . D i a g n o s i s : m a l i g n a n tl y m p h o m a . T h e p a t i e n t h a d r e c e i v e d a d r a m y c i n ,v i n c r i s t i n e , a n d hormonal t r e a t m e n t . The b l o o d c e l lc o u n t s Were d e c r e a s e d t o : H b : 78 g / L , WBC: . 7 > < 1 0 9 / L ,p l a t e l e t : 245 < 1 0 9 / L . 0 . 2 5 mg TPA as a d m i n i s t e r e d t o t h ep a t i e n t 4 t i m e s . The b l o o d c e l l c o u n t s improved o : H b : 7 6g / L , WBC: 6 . 8 > < 1 0 9 / L , p l a t e l e t : 3 3 1 x 1 0 9 / L . Chemot h e r a p y Was t h e n c o n t i n u e d f o r 5 more d a y s , a n d f o l l o W e dby one dose o f 0 . 5 mg TPA. The WBC count Wasm a i n t a i n e d a t 3 . 0 > < 1 0 9 / L . T h e p a t i e n t i s s t i l l r e c e i v i n gtreatment.

S u b j e c t N o . 1 2 ) Y . G . , f e m a l e , 4 5 . D i a g n o s i s : b r a i n t u m o r .B l o o d p r o ? l e a f t e r c h e m o t h e r a p y W a s : H b : 1 1 9 g / L ,WBC: 3 . 0 > < 1 0 9 / L , p l a t e l e t : 3 9 9 x 1 0 9 / L . 0 . 2 5 m g TPA Wasg i v e n t o t h e p a t i e n t o n c e . On t h e d a y a f t e r t h e TPAt r e a t m e n t , t h e b l o o d p r o ? l e Was H b : 1 2 3 g / L , WBC:4 . 5 > < 1 0 9 / L , p l a t e l e t : 4 3 6 x 1 0 9 / L . T h e p a t i e n t r e c e i v e d f u rt h e r c h e m o t h e r a p y .

S u b j e c t N o . 1 3 ) G . F . , m a l e , 6 0 . D i a g n o s i s : l u n g c a n c e r .A f t e r c h e m o t h e r a p y , h i s blood e l l c o u n t s Were d e c r e a s e dt o : H b : 7 6 g / L , WBC: 0 . 9 > < 1 0 9 / L , p l a t e l e t : 1 0 0 > < 1 0 9 / L .0 . 2 5 mg TPA Was g i v e n t o t h e p a t i e n t t W i c e . On t h e d a ya f t e r t h e TPA t r e a t m e n t , H b : 7 4 g / L , WBC: 2 . 5 > < 1 0 9 / L ,p l a t e l e t : 1 1 0 > < 1 0 9 / L . T h e p a t i e n t i s s t i l l r e c e i v i n g t r e a tment.

S u b j e c t N o . ( 1 4 ) Z . R . , f e m a l e , 4 4 . D i a g n o s i s : b r e a s t c a n c e r .The WBC f t e r c h e m o t h e r a p y Was 3 . 8 > < 1 0 9 / L . 0 . 2 5 mg fTPA a s g i v e n t o t h e p a t i e n t o n c e . The WBC n t h e daya f t e r t h e TPA r e a t m e n t Was 8 . 0 > < 1 0 9 / L .

S u b j e c t N o . 1 5 ) OZ, f e m a l e , 7 5 . D i a g n o s i s : E s o p h a g e a lC a n c e r . S u r g e r y Was p e r f o r m e d , f o l l o W e d b y chemot h e r a p y u s i n g c i s p l a t i n , 5 - ? u o r o u r a c i l . B l o o d p r o ? l eb e f o r e T P A ) : WBC: 2 . 4 > < 1 0 9 / L ; n e u t r o p h i l : 8 3 , l y mp h o c y t e : 1 7 ; p l a t e l e t : 1 5 0 > < 1 0 9 / L ; R B C : 3 . 4 3 > < 1 0 1 2 / L ;H b : 1 0 7 g / L . TPA o s a g e : 0 . 25 m g . B l o o d p r o ? l e ( o n e d a ya f t e r T P A ) : WBC: 7 . 1 > < 1 0 9 / L ; n e u t r o p h i l : 9 4 ; l y m p h oc y t e : 6 ; p l a t e l e t : 7 7 > < 1 0 9 / L ; R B C : 3 . 3 3 > < 1 0 1 2 / L ; H b : 1 0 9g / L . B l o o d p r o ? l e 4 d a y s a f t e r T P A ) : WBC: 4 . 4 > < 1 0 9 / L ;n e u t r o p h i l : 9 7 ; l y m p h o c y t e : 3 ; p l a t e l e t : 1 0 5 > < 1 0 9 / L ;RBC: 3 . 3 6 > < 1 0 1 2 / L , H b : 1 1 2 g / L . Symptoms a f t e r T P A :C h i l l , f e v e r , l o c a l i r r i t a t i o n a n d s l i g h t h e a d a c h e . T h ec a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n s W e r en o r m a l .

S u b j e c t N o . 1 6 ) X . H . , f e m a l e , 6 0 . D i a g n o s i s : E s o p h a g e a lC a n c e r . S u r g e r y Was p e r f o r m e d , f o l l o W e d b y chemot h e r a p y u s i n g V P 1 6 , MTX, MMC n d c i s p l a t i n . TPA


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6 , 0 6 3 , 8 1 41 1o n e d a y a f t e r T P A ) : WBC: 5 . 2 > < 1 0 9 / L ; n e u t r o p h i l : 8 7 ;l y m p h o c y t e : 1 3 ; p l a t e l e t 6 0 x 1 0 9 / L ; R B C : 3 . 7 6 > < 1 0 1 2 / L ;H b : 1 2 2 g / L . B l o o d p r o ? l e ( 2 d a y s a f t e r TPAa d m i n i s t r a t i o n ) . WBC: 4 . 5 > < 1 0 9 / L ; n e u t r o p h i l 8 0 ; l y mp h o c y t e : 2 0 ; p l a t e l e t : 6 4 > < 1 0 9 / L ; R B C : 2 . 9 9 > < 1 0 1 2 / L ;

H b : 1 0 9 g / L . Symptoms a f t e r T P A : c h i l l s , f e v e r , l o c a li r r i t a t i o n , c a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y W e r en o r m a l .

S u b j e c t N o . 1 7 ) Y . Z . , f e m a l e , 3 7 . D i a g n o s i s : b r e a s t c a n c e r .S u r g e r y W a s p e r f o r m e d , f o l l o W e d b y c h e m o t h e r a p y u s i n gCTX, MTX, a n d 5 - F U . TPA d o s e : 0 . 2 5 m g > < 2 ( S e c o n dd o s e Was 4 d a y s a f t e r 1 s t d o s e ) . B l o o d p r o ? l e ( b e f o r eT P A ) : WBC: 2 . 0 > < 1 0 9 / L ; n e u t r o p h i l : 8 5 ; l y m p h o c y t e :1 5 ; p l a t e l e t : 1 0 6 x 1 0 9 / L ; R B C : 3 . 2 4 > < 1 0 1 2 / L ; H b : 1 0 7g / L . B l o o d p r o ? l e 3 d a y s a f t e r ? r s t TPA o s e ) : WBC:2 . 9 > < 1 0 9 / L ; n e u t r o p h i l 8 3 ; l y m p h o c y t e : 1 7 ; p l a t e l e t :1 2 2 > < 1 0 9 / L ; RBC: 3 . 3 6 > < 1 0 1 2 / L ; H b : 1 0 7 g / L . B l o o d p r o? l e 2 d a y s a f t e r s e c o n d TPA o s e ) : WBC: 3 . 8 > < 1 0 9 / L ;n e u t r o p h i l : 8 4 ; l y m p h o c y t e : 1 6 ; p l a t e l e t : 8 4 x 1 0 9 / L ;R B C : 3 . 4 7 > < 1 0 1 2 / L . B l o o d p r o ? l e 4 d a y s a f t e r s e c o n dTPA o s e ) : WBC: 4 . 4 > < 1 0 9 / L ; n e u t r o p h i l : 8 6 ; l y m p h oc y t e : 1 4 ; p l a t e l e t 1 9 3 > < 1 0 9 / L ; R B C : 3 . 4 9 > < 1 0 1 2 / L ; H b :1 1 2 g / L . Symptoms a f t e r T P A : p a t i e n t s t a r t e d t o h a v ec h i l l s W h i c h l a s t e d f o r 2 h r s f o l l o W e d by f e v e r , t e m p e r at u r e r e a c h e d 3 8 C . Which l a s t e d 4 h r s and l o c a l i r r i t a t i o n .T h e c a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n s W e r en o r m a l .

S u b j e c t N o . ( 1 8 ) HR, m a l e , 5 6 . D i a g n o s i s : C o l o n c a n c e r .S u r g e r y W a s p e r f o r m e d , f o l l o W e d b y c h e m o t h e r a p y u s i n gC i s p l a t i n , V P 1 6 , a n d 5 - F U . TPA o s e : 0 . 2 5 m g > < 2 ( 2 n dTPA o s e Was a d m i n i s t e r e d 24 h r s a f t e r 1 s t TPA o s e ) .B l o o d p r o ? l e b e f o r e T P A ) : WBC: . 4 > < 1 0 9 / L ; n e u t r o p h i l :6 3 ; l y m p h o c y t e : 3 7 ; p l a t e l e t : 2 0 8 x 1 0 9 / L ; R B C : 4 . 0 x1 0 1 2 ; H b : 1 0 4 g / L . B l o o d p r o ? l e ( o n e d a y a f t e r 2 n d TPAd o s e ) : WBC: 4 . 0 > < 1 0 9 / L ; n e u t r o p h i l : 6 0 ; l y m p h o c y t e :4 0 ; p l a t e l e t : 1 9 8 x 1 0 9 / L ; R B C : 4 . 1 > < 1 0 1 2 ; H b : 1 1 2 g / L .Symptoms a f t e r T P A : c h i l l s , f e v e r , l o c a l i r r i t a t i o n . C a rd i a c h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n s W e r e n o r m a l .

S u b j e c t N o . 1 9 ) Z . T . , m a l e , 6 6 . D i a g n o s i s : l u n g c a n c e rm e t a s t a s i Z e d t o a d r e n a l g l a n d . S u r g e r y Was p e r f o r m e d ,f o l l o W e d b y c h e m o t h e r a p y u s i n g MMC, VCR, a n d C T X .TPA o s a g e : 0 . 2 5 m g > < 2 ( 2 n d TPA o s e Was a d m i n i s t e r e d2 4 h r s a f t e r 1 s t TPA o s e ) . B l o o d p r o ? l e b e f o r e T P A ) :WBC: 2 . 9 > < 1 0 9 / L ; n e u t r o p h i l : 7 6 ; l y m p h o c y t e : 2 4 ;p l a t e l e t : 2 2 7 > < 1 0 9 / L ; R B C : 3 . 3 3 > < 1 0 1 2 / L ; H b : 1 0 0 g / L .B l o o d p r o ? l e ( o n e d a y a f t e r s e c o n d TPA o s e ) : WBC:5 . 1 > < 1 0 9 / L ; n e u t r o p h i l : 8 2 ; l y m p h o c y t e : 1 8 ; p l a t e l e t :N / A ; RBC: N / A ; H b : 9 3 g / L . B l o o d p r o ? l e 2 d a y s a f t e r2 n d TPA o s e ) : WBC: 5 . 0 > < 1 0 9 / L ; n e u t r o p h i l : 8 0 ; l y mp h o c y t e : 2 0 ; p l a t e l e t : N / A ; R B C : 3 . 2 5 > < 1 0 1 2 ; H b : 1 0 1g / L . Symptoms a f t e r T P A : c h i l l s , f e v e r , l o c a l i r r i t a t i o n .C a r d i a c , h e p a t i c r e n a l a n d p u l m o n a r y f u n c t i o n s W e r en o r m a l .S u b j e c t N o . 2 0 ) J . Z . , m a l e , 6 8 . D i a g n o s i s : e s o p h a g e a lc a n c e r m e t a s t a s i Z e d t o l i v e r , l u n g a n d b r a i n . The p a t i e n tr e c e i v e d c h e m o t h e r a p y u s i n g T a X o l , c i s p l a t i n , 5 - F U a n dS e m u s t i a l . T o t a l TPA o s a g e : 2 m g . B l o o d p r o ? l e b e f o r eT P A ) : WBC: 0 . 7 > < 1 0 9 / L ; n e u t r o p h i l : 2 9 ; l y m p h o c y t e :7 1 ; p l a t e l e t : N / A ; RBC: 2 . 8 2 > < 1 0 1 2 / L ; H b : 8 7 g / L . TPAt r e a t m e n t s c h e d u l e . On t h e ? r s t a n d t h i r d d a y , 0 . 2 5 mgWas g i v e n a n d on t h e 5 t h , 7 t h a n d 9 t h d a y 0 . 5 mg f TPAW a s g i v e n . B l o o d p r o ? l e a t d a y 2 ) : WBC: 0 . 9 > < 1 0 9 / L ;n e u t r o p h i l : 6 6 ; l y m p h o c y t e : 3 4 ; p l a t e l e t : 8 2 x 1 0 9 / L ;R B C : 2 . 1 7 > < 1 0 1 2 / L ; H b : 7 2 g / L . B l o o d p r o ? l e a t d a y 4 ) :

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1 2l y m p h o c y t e : 5 ; p l a t e l e t : 4 3 > < 1 0 9 / L ; R B C : 1 . 9 > < 1 0 1 2 ; H b :7 0 g / L . B l o o d p r o ? l e a t d a y 8 ) : WBC: 2 . 3 > < 1 0 9 / L ; n e ut r o p h i l : 9 1 ; l y m p h o c y t e : 9 ; p l a t e l e t : 9 0 > < 1 0 9 / L ; R B C :1 . 7 1 > < 1 0 1 2 / L ; H b : 6 1 g / L . B l o o d p r o ? l e a t 1 1 t h d a y ) :WBC: 2 . 7 > < 1 0 9 / L ; n e u t r o p h i l : 8 5 ; l y m p h o c y t e : 1 5 ;p l a t e l e t : 3 7 . 6 > < 1 0 9 / L ; R B C : 2 . 9 1 > < 1 0 1 2 / L ; H b : 6 1 g / L .B l o o d p r o ? l e a t d a y 1 3 ) : WBC: 1 . 9 > < 1 0 9 / L ; n e u t r o p h i l :9 0 ; l y m p h o c y t e : 1 0 ; p l a t e l e t : 3 2 > < 1 0 9 / L ; R B C : 1 . 7 3 > < 1 0 9 / L ; n e u t r o p h i l :7 3 ; l y m p h o c y t e : 2 7 ; p l a t e l e t : 1 4 4 > < 1 0 9 / L ; R B C : 4 . 1 5 > < 1 0 9 / L ; n e u t r o p h i l : N / A ; l y m p h o c y t e : N / A ; p l a t e l e t :6 9 > < 1 0 9 / L ; RBC: 4 . 1 5 > < 1 0 1 2 / L : H b : 1 1 7 g / L . B l o o d p r o ? l ea t d a y 4 ) : WBC: 0 . 6 > < 1 0 9 / L ; n e u t r o p h i l : 2 8 ; l y m p h oc y t e : 7 2 ; p l a t e l e t : 6 8 x 1 0 9 / L ; R B C : 3 . 9 5 > < 1 0 1 2 / L ; H b :1 0 9 g / L . B l o o d p r o ? l e a t d a y 7 ) : WBC: 0 . 8 > < 1 0 9 / L ;n e u t r o p h i l : 8 8 ; l y m p h o c y t e : 1 2 ; p l a t e l e t : 6 0 > < 1 0 9 / L ;R B C : 4 . 2 2 > < 1 0 1 2 / L ; H b : 1 1 0 g / L . B l o o d p r o ? l e a t d a y 9 ) :WBC: 1 . 5 > < 1 0 9 / L ; n e u t r o p h i l : 8 0 ; l y m p h o c y t e : 2 ;p l a t e l e t : 6 9 > < 1 0 9 / L ; R B C : 4 . 0 2 > < 1 0 1 2 / L ; H b : 1 1 2 g / L .Symptoms a f t e r T P A : No c h i l l s a n d f e v e r , o n l y l o c a li r r i t a t i o n . C a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y f u n c t i o n ssame a s b e f o r e TPA r e a t m e n t . S i n c e t h i s p a t i e n t s lymp ho m a c e l l s h a d m e t a s t a s i Z e d t o t h e b o n e m a r r o W , s h er e q u i r e d a h i g h d o s e o f TPA 2 . 5 mg) a n d a l o n g e rt r e a t m e n t t i m e ( 9 d a y s ) i n o r d e r t o i n d u c e a v e r y loW l e v e lo f WBC.S u b j e c t N o . 2 2 ) X . Y . , f e m a l e , 3 4 . D i a g n o s i s : N a s o p h a r y ng e a l c a r c i n o m a m e t a s t a s i Z e d t o n e c k lymph n o d e . Thep a t i e n t Was r e a t e d W i t h c h e m o t h e r a p y u s i n g 5 - F U , A DM ,a n d MMX r i o r t o t r e a t m e n t W i t h TPA. Blood r o ? l e a f t e rc h e m o t h e r a p y b u t b e f o r e TPA t r e a t m e n t ) : WBC: 1 . 9 > < 1 0 9 / L ; n e u t r o p h i l : 7 9 ; l y m p h o c y t e : 2 1 ; H b :1 1 6 g / L . Blood p r o ? l e ( t h r e e d a y s a f t e r TPAa d m i n i s t r a t i o n ) : WBC. . 9 > < 1 0 9 / L ; n e u t r o p h i l : 7 3 ; l y mp h o c y t e : 2 7 ; H b : 1 2 3 g / L . B l o o d p r o ? l e 7 d a y s a f t e rTPA d m i n i s t r a t i o n ) : WBC: 7 . 6 > < 1 0 9 / L ; n e u t r o p h i l : 8 2 ;l y m p h o c y t e : 1 8 ; H b : 1 1 8 g / L . Symptoms a f t e r T P A :C h i l l s , f e v e r 3 9 . 2 C . ) c o n t i n u e d f o r 4 h r s . L i v e r , k i d n e y ,h e a r t a n d l u n g W e r e f u n c t i o n i n g n o r m a l l y .

S u b j e c t N o . 2 3 ) J . H . , m a l e , 5 5 . D i a g n o s i s : s t o m a c h c a r d i a )c a n c e r , r e o c c u r r e d a f t e r p r i o r s u r g e r y . The p a t i e n t h a dr e c e i v e d 5-FU and MMC. b e f o r e t r e a t m e n t W i t h TPA.B l o o d p r o ? l e b e f o r e TPA a d m i n i s t r a t i o n ) : WBC: 2 . 3 > < 1 0 9 / L ; n e u t r o p h i l : 5 3 ; l y m p h o c y t e : 4 7 ;H b : 1 2 3 g / L . B l o o d p r o ? l e f o u r d a y s a f t e r T P A ) : WBC:3 . 9 > < 1 0 9 / L ; n e u t r o p h i l : 4 4 ; l y m p h o c y t e : 5 6 ; H b : 1 2 9g / L . B l o o d p r o ? l e ( s e v e n d a y s a f t e r T P A ) : WBC: 3 . 7 >


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TPA d m i n i s t r a t i o n ) : WBC: 1 . 1 > < 1 0 9 / L ; n e u t r o p h i l : 7 3 ;l y m p h o c y t e : 2 7 ; H b : 1 1 2 g / L . B l o o d p r o ? l e o n e d a ya f t e r a d m i n i s t r a t i o n o f 0 . 2 5 m g T P A ) : WBC: 5 . 3 > < 1 0 9 / L ;n e u t r o p h i l : 6 0 ; l y m p h o c y t e : 4 0 ; H b : 1 3 9 g / L . Symptoms a f t e r TPA: No h i l l s , no f e v e r , no l o c a l i r r i t a t i o n .L i v e r , k i d n e y , h e a r t a n d l u n g W e r e f u n c t i o n i n g n o r m a l l y.S u b j e c t N o . ( 2 5 ) TL, f e m a l e , 4 2 . D i a g n o s i s : b r e a s t c a n c e r .T h e p a t i e n t r e c e i v e d c h e m o t h e r a p y t r e a t m e n t u s i n g CTX,MMC, a n d 5 - F U . B l o o d p r o ? l e b e f o r e T P A ) : WBC:2 . 1 > < 1 0 9 / L ; n e u t r o p h i l : 7 2 ; l y m p h o c y t e : 2 8 ; H b : 1 2 6g / L . B l o o d p r o ? l e ( o n e d a y a f t e r a d m i n i s t r a t i o n o f 0 . 2 5m g f T P A ) : WBC: 6 . 4 > < 1 0 9 / L ; n e u t r o p h i l : 9 0 ; l y m p h oc y t e : 1 0 ; H b : 1 2 6 g / L . Symptoms a f t e r TPA a d m i n i st r a t i o n : No h i l l s , no f e v e r . I n j e c t i o n s i t e Was r e d , s W o l l e ni n a p p e a r a n c e a n d p a i n f u l p r o b a b l y c a u s e d b y t h e i n f u s i o nn e e d l e . T h e symptoms d i s a p p e a r e d t h e s e c o n d d a y a f t e rt h e y a p p e a r e d . L i v e r , k i d n e y , h e a r t a n d l u n g W e r e f u n ct i o n i n g n o r m a l l y .

S u b j e c t N o . 2 6 ) Q . W . , m a l e , 5 6 . D i a g n o s i s : e s o p h a g e a lc a n c e r Which had m e t a s t a s i Z e d t o t h e l i v e r a f t e r s u r g e r y .T h e p a t i e n t h a d r e c e i v e d c h e m o t h e r a p y u s i n g c i s p l a t i na n d t a X o l . TPA d o s a g e : 0 . 2 5 m g . B l o o d p r o ? l e ( b e f o r eTPA d m i n i s t r a t i o n ) : WBC: . 6 > < 1 0 9 / L ; n e u t r o p h i l : 8 0 ;l y m p h o c y t e : 2 0 ; H b : 1 2 4 g / L . B l o o d p r o ? l e o n e d a ya f t e r TPA d m i n i s t r a t i o n ) : WBC: 4 . 2 > < 1 0 9 / L ; n e u t r o p h i l :8 3 ; l y m p h o c y t e : 1 7 ; H b : 1 2 0 g / L . B l o o d p r o ? l e 2d a y s a f t e r T P A ) : WBC: 5 . 6 > < 1 0 9 / L ; n e u t r o p h i l : 8 1 ;l y m p h o c y t e : 1 9 ; H b : 1 1 6 g / L . Symptoms a f t e r TPAa d m i n i s t r a t i o n : t e m p e r a t u r e r e a c h e d 3 9 C . Which l a s t e d3 h r . Stomach a c h e a n d d i a r r h e a ( W h i c h d i s a p p e a r e d s o o na f t e r ) . T h e c a r d i a c , h e p a t i c , r e n a l a n d p u l m o n a r y f u n ct i o n s Were normal.A b b r e v i a t i o n sV P 1 6 , E t o p o s i d e ; MMC, M i t o m y c i n C ; MTX, M e t h o t re X a t e ; 5 F U , 5 - ? u o r o u r a c i l ; C T X , C y c l o p h o s p h a m i d e ; C P ,C i s p l a t i n ; V D 3 , v i t a m i n D 3 ; MDS-RAEB, M y e l o d y s p l a s t i c

s y n d r o m e - r e f r a c t o r y a n e m i a W i t h e X c e s s o r b l a s s t ; A r a - C ,c y t a r a b i n e ; AML, A c u t e m y e l o c y t i c l e u k e m i a ; M l , AMLW i t h o u t d i f f e r e n t i a t i o n ; M2, AML i t h m a t u r a t i o n ; M3,A c u t e p r o m y e l o c y t i c l e u k e m i a ; M 4 , A c u t e m y e l o m o n o c y t i cl e u k e m i a ; M 5 , A c u t e m o n o c y t i c l e u k e m i a ; R T , R e t e n t i o nt i m e ; WBC, W h i t e b l o o d c e l l s ; H b , H e m o g l o b i n .

What i s c l a i m e d i s :1 . Amethod o f t r e a t i n g l e u k e m i a W h i c h c o m p r i s e s a d m i n

i s t r a t i n g p a r e n t e r a l l y t o p a t i e n t s a f f l i c t e d W i t h l e u k e m i a , a ne f f e c t i v e amount o f a compound o f t h e Formula

o r isomers t h e r e o f

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o r s u b st i t u t e d d e r i