NZ731599B2 - Phorbol ester compositions and methods for treating or reducing the duration of cytopenia - Google Patents
Phorbol ester compositions and methods for treating or reducing the duration of cytopenia Download PDFInfo
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- NZ731599B2 NZ731599B2 NZ731599A NZ73159915A NZ731599B2 NZ 731599 B2 NZ731599 B2 NZ 731599B2 NZ 731599 A NZ731599 A NZ 731599A NZ 73159915 A NZ73159915 A NZ 73159915A NZ 731599 B2 NZ731599 B2 NZ 731599B2
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- phorbol
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- phorbol ester
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- 239000002644 phorbol ester Substances 0.000 title claims abstract description 121
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001663 sulfanilamide Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- CGVXVPQJMYMMIH-HKDZDBKOSA-N tigliane Chemical compound C1[C@H](C)C[C@H]2[C@@H]3C(C)(C)[C@@H]3C[C@@H](C)[C@@H]2[C@@H]2C[C@H](C)C[C@H]21 CGVXVPQJMYMMIH-HKDZDBKOSA-N 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherols Natural products 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000224 toxic side effect Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000000717 tumor promoter Substances 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin D3 Drugs 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Abstract
Methods and compositions containing a phorbol ester of Formula I or a derivative thereof in combination with G-CSF (Granulocyte-colony stimulating factor) or in combination with EPO (erythropoetin), are provided for the treatment of cytopenia in mammalian subjects. The compositions and methods also reduce the duration of cytopenia such as neutropenia, thrombocytopenia, and/or anemia. reduce the duration of cytopenia such as neutropenia, thrombocytopenia, and/or anemia.
Description
Phorbol Ester Compositions and Methods of Use for Treating or Reducing the Duration
of Cytopenia
Technical Field
The present invention relates to the use of phorbol esters for the treatment of
cytopenia. Specifically, the present invention relates to the use of phorbol esters, such as
12-O-tetradecanoylphorbolacetate (TPA) or phorbolmyristate (PMA), and G-
CSF in the treatment and reduction of neutropenia and thrombocytopenia in patients with
a neoplastic disease. The present invention also relates to the use of phorbol esters, such
as TPA and erythropoeitin (EPO) for the treatment of anemia in patients.
Background
Plants have historically served many medicinal purposes. The World Health
Organization (WHO) estimates that 4 billion people, 80% of the world population,
presently use herbal medicine for some aspect of primary health care. (WHO Fact sheet
Fact sheet N°134 December 2008) However, it can be difficult to isolate the specific
compound that has the medicinal effect and to reproduce it on a commercial scale.
Additionally, while active compounds may be isolated from a plant, the other parts of a
plant such as the minerals, vitamins, volatile oils, glycosides, alkaloids, bioflavanoids,
and other substances may also be involved in the functioning of the active ingredient or
the medicinal effect for which the plant is known, making the use, purification and
commercialization of plant based pharmaceutical agents a challenge.
Phorbol is a natural, plant-derived organic compound of the tigliane family of
diterpenes. It was first isolated in 1934 as a hydrolysis product of croton oil derived from
the seeds of Croton tiglium, a leafy shrub of the Euphorbiaceae family that is native to
Southeastern Asia. Various esters of phorbol have important biological properties
including the reported ability to mimic diacylglycerols and activate protein kinase C
(PKC); and to modulate downstream cell signaling pathways including the mitogen-
activated protein kinase (MAPK) pathways. Phorbol esters are additionally thought to
bind to chimaerins, the Ras activator RasGRP, and the vesicle-priming protein Munc-13
(Brose N, Rosenmund C., J Cell Sci;115:4399–411 (2002)). Some phorbol esters also
induce nuclear factor-kappa B (NF-κB). The most notable physiological property of
phorbol esters is their reported capacity to act as tumor promoters. (Blumberg, 1988;
Goel, G et al., Int, Journal of Toxicology 26, 279-288 (2007)).
12-O-tetradecanoylphorbolacetate (TPA), also called phorbolmyristate-
13-acetate (PMA), is a phorbol ester used in models of carcinogenesis as an inducer for
differentiation and/or apoptosis in multiple cell lines and primary cells. TPA has also
been reported to cause an increase in circulating white blood cells and neutrophils in
patients whose bone marrow function has been depressed by chemotherapy (Han Z. T. et
al. Proc. Natl. Acad. Sci. 95, 5363-5365 (1998)). However, due to a variety of factors,
including caustic reactions when contacted with the skin and concerns for its potential
toxicity, TPA has not been shown to be an effective adjuvant to chemotherapy. Indeed,
as phorbol esters play a key role in activation of protein kinase C, which triggers various
cellular responses resulting in inflammatory responses and tumor development (Goel et
al., Int, Journal of Toxicology 26, 279-288 (2007)), phorbol esters would generally be
excluded from possible treatment candidates for neoplasms including cancer.
Cancer is one of the leading causes of death worldwide accounting for 7.6 million
deaths (around 13% of all deaths) in 2008 (GLOBOCAN 2008 (IARC) ( Section of
Cancer Information (8/12/2011)). Globally, 12,662,600 new cases were diagnosed in
2008. (2008 (GLOBOCAN 2008 (IARC). In the U.S. alone, 1,596,670 new cases of
cancer were diagnosed in 2011 (Cancer Facts & Figures – 2011, American Cancer
Society (ACS), Atlanta, Georgia, 2011).
Cancer treatments generally involve a combination of surgery, chemotherapy,
hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient.
However, current therapeutics for neoplasms have a number of drawbacks including
insufficient potency and intolerable side effects. Surgery, for example, may be
contraindicated due to the health of a patient. Additionally, it may be difficult to obtain
clear margins around a tumor, resulting in some neoplastic tissue being left behind and an
increased chance of recurrence of the disease.
Generally, chemotherapeutics act by killing cells that divide rapidly, one of the
main properties of most cancer cells. However, they also harm normal cells that divide
rapidly such as cells in bone marrow, the digestive tract and hair follicles. They
frequently have significant side effects including severe nausea, bone marrow depression,
and immunosuppression.
Ionizing radiation works by damaging the DNA of exposed tissue. However,
while targeted, it can still damage normal cells as well as neoplasms and can have side
effects such as anemia, nausea and vomiting, poor appetite, weight loss, constipation,
diarrhea, hair loss, and infertility.
For many patients, the toxic side effects of current therapies diminish their quality
of life to such an extent they simply stop taking their medications. For others, therapeutic
schedules are so complicated and inconvenient that compliance is limited. Other patients
experience excellent results initially, but suffer relapses despite full compliance with
therapeutic regimens. There is clearly a need for new and more effective treatments for
neoplasms and to manage the side effects of current treatments for neoplasms including
cancer. It is an object of the present invention to go some way to meeting this need,
and/or to at least provide the public with a useful choice.
[009a] In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents, or such sources of information, is not to
be construed as an admission that such documents, or such sources of information, in any
jurisdiction, are prior art, or form part of the common general knowledge in the art.
Summary of the Invention
The present invention relates to compositions containing phorbol esters of
Formula I in combination with G-CSF. Methods of using phorbol esters of Formula I in
combination with G-CSF are described herein. The compositions and methods described
herein are effective in treating and reducing the duration of neutropenia and
thrombocytopenia in patients with neoplastic conditions.
[010a] More specifically, in a first aspect, the present invention provides use of a phorbol
ester of Formula I, pharmaceutically-acceptable salt, enantiomer, solvate, hydrate, or
polymorph thereof, in the manufacture of a medicament for treating or reducing the
duration of neutropenia and/or thrombocytopenia in a subject in need thereof, in
combination with a granulocyte-colony stimulating factor (G-CSF),
Formula I
wherein R and R are selected from the group consisting of hydrogen, hydroxyl,
, wherein the alkyl group contains 1 to 15 carbon atoms,
, wherein the lower alkenyl group contains 2 to 7 carbon atoms,
, and , R is selected from hydrogen, and
, wherein the lower alkyl group contains 1 to 7 carbon atoms,
wherein said medicament is formulated for administration of an amount comprising
between about 10 and 1500 µg of said phorbol ester of Formula I; and
wherein the G-CSF is formulated for administration to said subject in a coordinate
administration protocol, simultaneously with, prior to, or after administration of said
medicament comprising said phorbol ester of Formula I.
[010b] In a further aspect, the present invention provides use of a phorbol ester of
Formula I, pharmaceutically-acceptable salt, enantiomer, solvate, hydrate, or polymorph
thereof, in the manufacture of a medicament for treating or reducing the duration of
anemia in a subject in need thereof, in combination with an erythropoietin (EPO),
Formula I
wherein R and R are selected from the group consisting of hydrogen, hydroxyl,
, wherein the alkyl group contains 1 to 15 carbon atoms,
, wherein the lower alkenyl group contains 2 to 7 carbon atoms,
, and , R is selected from hydrogen, and
, wherein the lower alkyl group contains 1 to 7 carbon atoms,
wherein said medicament is formulated for administration of an amount comprising
between about 10 and 1500 µg of said phorbol ester of Formula I; and
wherein the EPO is formulated for administration to said subject in a coordinate
administration protocol, simultaneously with, prior to, or after administration of said
medicament comprising said phorbol ester of Formula I.
[010c] In a still further aspect, the present invention provides a composition for treating
or reducing the duration of neutropenia and/or thrombocytopenia in a mammalian
subject in need thereof comprising a phorbol ester of Formula I, pharmaceutically-
acceptable salt, enantiomer, solvate, hydrate, or polymorph thereof
Formula I
wherein R and R are selected from the group consisting of hydrogen, hydroxyl,
, wherein the alkyl group contains 1 to 15 carbon atoms,
, wherein the lower alkenyl group contains 2 to 7 carbon atoms,
, and , R is
selected from hydrogen, and , wherein the lower alkyl group contains 1 to 7
carbon atoms; and a granulocyte-colony stimulating factor (G-CSF),
wherein said composition comprises said phorbol ester of Formula I in an amount from
to 1500 µg, and said G-CSF in an amount from 150 µg to 400 µg.
[010d] In another aspect, the present invention provides a composition for treating or
reducing the duration of anemia in a mammalian subject in need thereof comprising a
phorbol ester of Formula I, pharmaceutically-acceptable salt, enantiomer, solvate,
hydrate, or polymorph thereof
Formula I
wherein R and R are selected from the group consisting of hydrogen, hydroxyl,
, wherein the alkyl group contains 1 to 15 carbon atoms,
, wherein the lower alkenyl group contains 2 to 7 carbon atoms,
, and , R is selected from hydrogen, and
, wherein the lower alkyl group contains 1 to 7 carbon atoms; and
an erythropoietin (EPO),
wherein said composition comprises said phorbol ester of Formula I in an amount from
to 1500 µg, and said EPO in an amount selected from the group consisting of from 75
IU/kg to 900 IU/kg of EPO, from 2,000 to 40,000 units of EPO, and from 40,000 to
60,000 units of EPO.
Described herein is a method of treating cytopenia comprising administering to a
mammalian subject in need thereof, a phorbol ester of Formula I (as described herein),
pharmaceutically-acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or
prodrug thereof, wherein R and R are selected from the group consisting of hydrogen,
hydroxyl, , and
substituted derivatives thereof, R is selected from hydrogen, and
substituted derivatives thereof; in combination with a granulocyte-colony stimulating
factor (G-CSF).
Described herein is a method of treating neutropenia and/or thrombocytopenia
comprising administering to a mammalian subject in need thereof, a combination of a
phorbol ester of Formula I, pharmaceutically-acceptable salt, isomer, enantiomer, solvate,
hydrate, polymorph or prodrug thereof; in combination with a granulocyte-colony
stimulating factor (G-CSF).
Described herein is a method of treating cytopenia comprising administering to a
mammalian subject in need thereof, a phorbol ester of Formula I, pharmaceutically-
acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof; in
combination with an erythropoietin (EPO).
Described herein is a method of treating anemia comprising administering to a
mammalian subject in need thereof, a phorbol ester of Formula I, pharmaceutically-
acceptable salt, isomer, enantiomer, solvate, hydrate, polymorph or prodrug thereof; in
combination with an erythropoietin (EPO).
In methods described herein, R or R of Formula I is
the remaining R or R is and R of Formula I is hydrogen.
1 2 3
In particular, in the methods described herein, the phorbol ester is phorbol 13-
butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol
13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13-
didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12-
myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13-
angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12-
deoxyphorbol 13-isobutyrateacetate, 12-deoxyphorbol 13-phenylacetate, 12-
deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol
12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13-
acetate.
In a preferred embodiment, the phorbol ester is 12-O-tetradecanoylphorbol
acetate (TPA).
The methods described herein, may further comprise administering at least one
secondary or adjunctive therapeutic agent.
In certain embodiments, G-CSF is administered to said subject in a coordinate
administration protocol, simultaneously with, prior to, or after, administration of said
phorbol ester of Formula I.
In certain embodiments, EPO is administered to said subject in a coordinate
administration protocol, simultaneously with, prior to, or after, administration of said
phorbol ester of Formula I.
The methods described herein involve administering the phorbol ester of Formula
I in an effective amount comprising between about 10 and 1500 µg of said phorbol ester
of Formula I every day or every other day.
In certain embodiments, the methods described herein involve administering the
phorbol ester of Formula I in an effective amount comprising between about 150 to 500
µg of said phorbol ester or derivative compound of Formula I every day or every other
day.
In preferred embodiment, the combination of the phorbol ester of Formula I and
G-CSF increases absolute neutrophil count (ANC) of the mammalian subject to above
1500/mm .
In another preferred embodiment, the combination of the phorbol ester of Formula
I and G-CSF increases platelet levels of the mammalian subject to above 100,000/µl.
In a certain preferred embodiment, the combination of the phorbol ester of
Formula I and EPO increases a complete blood count (CBC) level measured in a
complete blood count by at least 10%.
In another preferred embodiment, wherein the combination of the phorbol ester of
Formula I and EPO increases a hemoglobin level of the mammalian subject to above a
normal hemoglobin level.
In a preferred embodiment, the methods described herein involve treating or
reducing cytopenia such as neutropenia, thrombocytopenia and/or anemia, in a human
with acute myeloid leukemia (AML).
In another embodiment, the present invention relates to compositions containing a
phorbol ester of Formula I and G-CSF.
In a preferred embodiment, the phorbol ester of Formula I is present in an
effective amount sufficient to treat or reduce the duration of cytopenia, such as
neutropenia and/or thrombocytopenia.
In a preferred embodiment, the compositions of the present invention contain
TPA as the phorbol ester, and the TPA and G-CSF are present in an effective amount to
treat or reduce the duration of cytopenia, such as neutropenia and/or thrombocytopenia.
In a particularly preferred embodiment, the effective amount may be a synergistically
effective amount to treat or reduce the duration of neutropenia and/or thrombocytopenia.
The present invention also relates to compositions containing a phorbol ester of
Formula I and EPO.
In a preferred embodiment, the phorbol ester of Formula I is present in an
effective amount sufficient to treat or reduce the duration of cytopenia, such as anemia.
In a preferred embodiment, the compositions of the present invention contain
TPA as the phorbol ester, and the TPA and EPO are present in an effective amount to
treat or reduce the duration of cytopenia, such as anemia. In a particularly preferred
embodiment, the effective amount may be a synergistically effective amount to treat or
reduce the duration of anemia.
In another embodiment, the neutropenia, thrombocytopenia and/or anemia is
related to treatment of neoplasms. Such neoplasms may be malignant or benign. In some
embodiments, neoplasms may be solid or non-solid cancers. In other embodiments, the
neoplasms may be relapses. In another embodiment, the neoplasms may be refractory.
Exemplary neoplasms include, but are not limited to, hematologic
malignancies/bone marrow disorders, including, but not limited to, leukemia, including
acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic myeloid
leukemia blast crisis, myelodysplasia, and myeloproliferative syndrome; lymphoma,
including Hodgkin’s and non-Hodgkin’s lymphoma; subcutaneous adenocarcinoma;
ovarian teratocarcinoma; liver cancer; breast cancer; bone cancer; lung cancer; pancreatic
cancer; non-small cell lung cancer; and prostate cancer. Other neoplastic conditions
amenable to treatment using the methods and compositions as described herein include
other cancer disorders and conditions, including solid tumors of various types.
In yet another embodiment, the phorbol esters and derivatives of phorbol esters as
described herein may be used to modulate cell signaling pathways. Such modulation may
have a variety of results, for example, in some embodiments, the use of compositions
containing phorbol esters and derivatives of phorbol esters may increase white blood cell
counts in mammalian subjects. In another embodiment, compositions containing phorbol
esters and/or phorbol ester derivatives may alter the release of Th1 cytokines in
mammalian subjects. In a further embodiment, compositions containing phorbol esters
and/or phorbol ester derivatives may alter the release of interleukin 2 (IL-2) in
mammalian subjects. In an additional embodiment, compositions containing phorbol
esters and/or phorbol ester derivatives may alter the release of interferon in mammalian
subjects. In yet another embodiment, compositions containing phorbol esters and/or
phorbol ester derivatives may alter the rate of ERK phosphorylation.
The invention achieves the foregoing and satisfies additional objects and
advantages by providing novel and surprisingly unexpected compositions useful for
treating or reducing the duration of cytopenia, such as neutropenia, thrombocytopenia,
and anemia. Novel and surprisingly unexpected methods useful for treating or reducing
the duration of cytopenia, such as neutropenia, thrombocytopenia, and anemia are
described herein.
[037a] In the description in this specification reference may be made to subject matter
which is not within the scope of the appended claims. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice
the invention as defined in the appended claims.
Description of the Drawings
The patent or application file contains at least one drawing executed in color.
Copies of this patent or patent application publication with color drawing(s) will be
provided by the Office upon request and payment of the necessary fee.
Figure 1 illustrates the synergistic effect achieved by the combination of TPA and
GCSF. TPA stimulates upstream stem cells to differentiate into downstream stem cells,
while GCSF stimulates the downstream stem cells. TPA also stimulates downstream
stem cells. Neutrophils are one type of granulocyte.
Figure 2 illustrates the combination of TPA and GCSF generates stronger
stimulating effects than TPA or G-CSF alone. The below abbreviations are used in
Figure 2 and throughout the present disclosure with respect to the following terminology.
BFU-E Burst forming unit erythroid
The forgoing and additional objects, features, aspects and advantages of the present
invention will become apparent from the following detailed description.
Detailed Description of the Invention
Definitions
For convenience, before further description of the present invention, certain terms
employed in the specification, examples and appended claims are collected here. These
definitions should be read in light of the remainder of the disclosure and understood as by
a person of skill in the art. Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as would be understood by a person of ordinary skill
in the art.
"G-CSF" or "GCSF" is known as granulocyte-colony stimulating factor or
colony-stimulating factor 3 ("CSF3"), and may be used interchangeably herein. "G-
CSF," "GCSF," or "CSF3" is a glycoprotein that stimulates the bone marrow to produce
granulocytes and stem cells and release them into the bloodstream.
"EPO" is known as erythropoietin, which is a glycoprotein hormone that controls
erythropoiesis, or red blood cell production.
Induction therapy is used herein to mean the first phase of treatment for a disease,
typically, cancer. For example, the goal of induction therapy for acute myeloid leukemia
is to produce a complete remission in the bone marrow and return to normal blood
counts.
Consolidation therapy is used herein to mean treatment(s) given after cancer has
disappeared following initial treatment, and is given to prevent recurrence of cancer.
Consolidation therapy is used to kill any cancer cells that may be left in the body.
Cytopenia is used herein to mean a reduction in the number of blood cells, and
includes low red blood cell count (anemia), low white blood cell count (leukopenia or
neutropenia), low platelet count (thrombocytopenia), or a combination thereof
(pancytopenia), and low granulocyte count (granulocytopenia).
Red blood cell count (RBC) is the number of red blood cells capable of carrying
hemoglobin in a mm of blood. The normal RBC for men is 4.5 to 6 million mm ; for
women, 4 to 5.5 million per mm . See cytopenia-
cancertype.blogspot.ca/2007/12/diagnosis-of-cytopenia.html.
White blood cell count (WBC) is the total number of all five types of white blood
cells. The normal WBC for men and women is 5,000 to 10,000 per mm of blood. See
cytopenia-cancertype.blogspot.ca/2007/12/diagnosis-of-cytopenia.html.
The articles "a" and "an" are used herein to refer to one or to more than one (i.e.
to at least one) of the grammatical object of the article. By way of example, "an element"
means one element or more than one element.
The terms "comprise" and "comprising" are used in the inclusive, open sense,
meaning that additional elements may be included.
The term "consisting essentially of" is used to limit the elements to those
specified and those that do not materially affect the basic and novel characteristics of the
material or steps.
The term "including" is used herein to mean "including but not limited to."
"Including" and "including but not limited to" are used interchangeably.
A "patient," "subject" or "host" to be treated by the subject method may mean
either a mammal such as a human, or non-human mammal.
The term "pharmaceutically-acceptable carrier" is an art-recognized term and
refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid
or solid filler, diluent, excipient, solvent or encapsulating material. Such carrier must be
"acceptable" in the sense of being compatible with the subject composition and its
components and not injurious to the patient. Examples include, but are not limited to,
binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings,
preservatives, buffers, wetting agents, disintegrants, effervescent agents and other
conventional excipients and additives.
The term "treating" is an art-recognized term and refers to curing as well as
ameliorating or reducing at least one symptom of any condition or disorder.
The term "therapeutic agent" or "drug" is an art-recognized and refers to any
chemical moiety that is a biologically, physiologically, or pharmacologically active
substance that acts locally or systemically in a subject. For example, therapeutic agents
or drugs, are described in the Merck Index, the Physicians' Desk Reference, and The
Pharmacological Basis of Therapeutics.
The term "effective amount" is therapeutically effective, in single or multiple unit
dosage form. The effective amount is an amount that is sufficient to provide a
therapeutic effect in a mammal, including a human. For example, an effective amount
may be an amount sufficient to measurably treat or reduce/shorten the duration of
neutropenia and/or thrombocytopenia in a subject. Another example of an effective
amount is an amount sufficient to measurably treat or reduce/shorten the duration of
anemia. Dosage levels or amounts of the particular therapeutic agent or drug used to
provide a therapeutically effective amount vary depending on factors including, but not
limited to, age, weight, gender, medical condition of the mammal/human, and the route of
administration. Effective amounts of a phorbol ester compound or related or derivative
compound of Formula I (e.g., a unit dose comprising an effective concentration/amount
of TPA, or of a selected pharmaceutically acceptable salt, isomer, enantiomer, solvate,
polymorph and/or prodrug of TPA), of G-CSF, or of EPO, will be readily determined by
those of ordinary skill in the art, depending on clinical and patient-specific factors. A
therapeutically effective amount according to the present invention may include a
synergistically effective amount.
Cytopenia has traditionally been classified as a deficiency related (i.e., nutritional
or hormonal deficiency), immune mediated, BM failure based, or idiopathic cytopenias.
See Valent, P., Hematology: 485-491 (2012), the disclosure of which is herein
incorporated by reference in its entirety.
Diagnosis of cytopenia in a cancer patient requires a complete blood count (CBC)
and the identification of any blood and bone marrow abnormalities, such as anemia,
neutropenia, or thrombocytopenia. See cytopenia-
cancertype.blogspot.ca/2007/12/diagnosis-of-cytopenia.html.
Chemotherapeutic agents adversely affect bone marrow cells, and a complete
blood count (CBC) is necessary prior to each treatment. The effects on bone marrow are
temporary and normal functioning usually returns within 4-10 days, but white blood cells
have a life span of 1 to 3 days; so although those WBCs in circulation remain unaffected,
the slow production of new leukocytes creates a period of increased risk for infection.
See cytopenia-cancertype.blogspot.ca/2007/12/diagnosis-of-cytopenia.html. If white
blood cell production does not recover before the next treatment, treatment is delayed
until the cell count increases sufficiently. Id. Mature red blood cells have a relatively
long life (120 days), cell production usually resumes before symptoms of deficiency
develop. Id.
Anemia is a deficiency in erythrocytes that reduces the amount of oxygen
reaching all cells in the body, so that all tissue and organ function is impaired. Anemia
produces symptoms including severe fatigue, confusion, dizziness, headache,
lightheadedness, loss of concentration, pallor (pale skin, nail beds, gums, linings of
eyelids), rapid heart rate (tachycardia), and shortness of breath (dyspnea). See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-signs-and-symptoms.html. Individuals with
anemia are advised to rest and eat foods high in iron, and treatment may include
medication that helps restore the red blood supply (such as erythropoietin) and a
transfusion of packed red blood cells. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-treatment.html. The Food and Drug
Administration (FDA) in March 2007 issued a warning about these medications in
response to studies indicating that they may increase the risk for blood clots, strokes, and
heart attacks in some patients (e.g., patients who have kidney disease). Id.
Neutropenia is a white blood cell deficiency with symptoms including frequent
and/or severe bacterial, viral, and/or fungal infections; fever; and mouth and throat ulcers.
See cytopenia-cancertype.blogspot.ca/2007/12/cytopenia-signs-and-symptoms.html. A
colony-stimulating factor (CSF), may be prescribed to speed the development of white
blood cells and shorten the period of susceptibility to infection. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-treatment.html.
Thrombocytopenia is a platelet deficiency that causes patients to bruise and bleed
easily, and is characterized by symptoms including bleeding in the mucous membranes
lining the mouth, nose, colon, and vagina. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-signs-and-symptoms.html. It is characterized
by a below normal platelet count of 15,000 to 300,000 per milliliter and the risk of
increased bleeding usually peaks 10 to 14 days following a course of chemotherapy. Id.
A persistently decreased platelet count may be treated with a transfusion of platelets. See
cytopenia-cancertype.blogspot.ca/2007/12/cytopenia-treatment.html.
Growth factors (such as Epoetin alpha (Procrit®, Epogen®), G-CSF (granulocyte
colony-stimulating factor; e.g., filgrastim [Neupogen®), and GM-CSF (granulocyte-
macrophage colony-stimulating factor)) are synthetic versions of substances involved in
stimulating red and white blood cell production, but caution is exercised when
prescribing these medications for people with tumors that involve the bone marrow,
because growth factors might stimulate malignant cell growth. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-treatment.html. The side effects associated
with these growth factors include fever, fatigue, dizziness, diarrhea, nausea, vomiting,
weakness, and paresthesia (prickling sensation) (with epoetin alpha); and bone pain with
(G-CSF). Id.
Chemotherapy and radiation therapy both reduce the number of blood-forming
stem cells in cancer patients, but chemotherapeutic agents have a greater adverse effect
because they suppress bone marrow function in several ways - the extent of damage is
related to the particular drug(s) and the dose used. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-causes-and-risk-factors.html.
Deficiencies in blood cell types can be caused by chemotherapeutic agents which
damage blood-forming stem cells, suppress the kidneys’ production of erythropoietin
(hormone that stimulates blood cell production), and trigger red cell destruction
(hemolysis) by inducing an immune response that causes the body to mistakenly identify
erythrocytes as foreign bodies and destroy them. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-causes-and-risk-factors.html. However,
anemia, thrombocytopenia, and neutropenia caused by cancer treatment are usually
resolved once the course of treatment is over. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-treatment.html.
Malignant tumors can also cause anemia and other cytopenias when they directly
invade bone marrow and suppress marrow function. See cytopenia-
cancertype.blogspot.ca/2007/12/cytopenia-causes-and-risk-factors.html.
The compositions and methods as described herein may be used to treat or
reduce/shorten the duration of anemia, neutropenia and/or thrombocytopenia in
mammalian subjects, including humans. In some embodiment, the mammalian subject is
a human with neoplastic disease.
Compositions and methods of using a phorbol ester of Formula I, below:
Formula I
wherein R and R may be hydrogen; hydroxyl; , wherein the alkyl
group contains 1 to 15 carbon atoms; , wherein a lower alkenyl group
contains between 2 to 7 carbon atoms; ; and
substituted derivatives thereof. R may be hydrogen or and substituted
derivatives thereof; in combination with G-CSF for treatment of cytopenia including but
not limited to, neutropenia and/or thrombocytopenia. The methods described herein and
compositions of the present invention further include any pharmaceutical salts,
enantiomers, isomer, polymorphs, prodrugs, hydrates and solvates of the compositions of
Formula I; in combination with G-CSF for treatment of neutropenia and/or
thrombocytopenia. For example, the combination of phorbol ester of Formula I with G-
CSF is also useful for reducing or shortening the duration of neutropenia and/or
thrombocytopenia.
Compositions and methods of using a phorbol ester of Formula I, below:
Formula I
wherein R and R may be hydrogen; hydroxyl; , wherein the
alkyl group contains 1 to 15 carbon atoms; , wherein a lower alkenyl
group contains between 2 to 7 carbon atoms; ; and
substituted derivatives thereof. R may be hydrogen or and substituted
derivatives thereof; in combination with EPO for treatment of cytopenia, including but
not limited to, anemia. The methods described herein and compositions of the present
invention further include any pharmaceutical salts, enantiomers, isomer, polymorphs,
prodrugs, hydrates and solvates of the compositions of Formula I; in combination with
EPO for treatment of anemia. For example, the combination of phorbol ester of Formula
I with EPO is also useful for reducing or shortening the duration of anemia.
In some embodiments, at least one of R and R are other than hydrogen and R is
1 2 3
hydrogen or and substituted derivatives thereof. In another embodiment,
either R or R is the remaining R or R is a
1 2 1 2
, wherein a lower alkyl is between 1 and 7 carbons, and R is hydrogen.
The alkyl, alkenyl, phenyl and benzyl groups of the formulas herein may be
unsubstituted or substituted with halogens, preferably, chlorine, fluorine or bromine;
nitro; amino; and/or similar type radicals.
Compositions and methods using the same include a combination of a phorbol
ester of Formula II, as 12-O-tetradecanoylphorbolacetate (TPA):
Formula II,
with G-CSF, for treatment of cytopenia, including but not limited to, neutropenia and/or
thrombocytopenia. For example, the combination of TPA with G-CSF is also useful for
reducing or shortening the duration of neutropenia and/or thrombocytopenia
Compositions and methods using the same include a combination of a phorbol
ester of Formula II, as 12-O-tetradecanoylphorbolacetate (TPA):
Formula II,
with EPO, for treating cytopenia, including but not limited to, anemia. For example, the
combination of TPA with EPO is also useful for reducing or shortening the duration of
anemia.
Useful phorbol esters of Formula I and related compounds and derivatives within
the formulations of the invention and methods described herein include, but are not
limited to, other pharmaceutically acceptable active salts of said compounds, as well as
active isomers, enantiomers, polymorphs, glycosylated derivatives, solvates, hydrates,
and/or prodrugs of said compounds. Exemplary forms of phorbol esters for use within
the compositions of the invention and methods described herein include, but are not
limited to, phorbol 13-butyrate; phorbol 12-decanoate; phorbol 13-decanoate; phorbol
12,13-diacetate; phorbol 13,20-diacetate; phorbol 12,13-dibenzoate; phorbol 12,13-
dibutyrate; phorbol 12,13-didecanoate; phorbol 12,13-dihexanoate; phorbol 12,13-
dipropionate; phorbol 12-myristate; phorbol 13-myristate; phorbol 12-myristate
acetate (also known as TPA or PMA); phorbol 12,13,20-triacetate; 12-deoxyphorbol 13-
angelate; 12-deoxyphorbol 13-angelate 20-acetate; 12-deoxyphorbol 13-isobutyrate; 12-
deoxyphorbol 13-isobutyrateacetate; 12-deoxyphorbol 13-phenylacetate; 12-
deoxyphorbol 13-phenylacetate 20-acetate; 12-deoxyphorbol 13-tetradecanoate; phorbol
12-tigliate 13-decanoate; 12-deoxyphorbol 13-acetate; phorbol 12-acetate; and phorbol
13-acetate.
A broad range of mammalian subjects, including human subjects, are amenable to
treatment using the compositions of the invention and methods described herein. These
subjects include, but are not limited to, individuals suffering from diseases or conditions
including but not limited to, neoplastic diseases, side effects from chemotherapy, side
effects from radiation therapy, prostate hypertrophy, urinary incontinence, Myasthemia
gravis, and kidney disease.
Mammalian subjects that are amenable to treatment with phorbol esters of
Formula I, or derivative of the phorbol esters of the Formula I, particularly TPA, in
combination with GCSF or EPO according to the methods described herein include
subjects suffering from anemia, neutropenia and/or thrombocytopenia. Such subjects
amenable to treatment with phorbol esters of Formula I, particularly TPA, in combination
with GCSF or EPO include those suffering from symptoms of diseases or disorders
including but not limited to, neoplastic diseases or effects caused by treatment of the
neoplastic disease.
Additional mammalian subjects, including humans, amenable to treatment with
compositions and methods as described herein, particularly TPA, according to the
methods described herein include subjects or individuals with anemia related diseases or
conditions, including but not limited to, anemia related to kidney failure or disease,
anemia related to pregnancy, anemia related to poor nutrition, pernicious anemia, sickle
cell anemia, , thalassemia, alcoholism, bone marrow-related anemia (such as leukemia or
lymphoma), aplastic anemia (from viral infections), anemia related to medications (such
as cancer medications, HIV medications, seizure medications, transplant medications,
malaria medications, antibiotics, antifungal, and antihistamines), hemolytic anemia,
anemia related to thyroid problems, anemia related to liver disease, and autoimmune
disease (such as lupus).
Additional mammalian subjects, including humans, amenable to treatment with
compositions and methods as described herein, particularly TPA, according to the
methods described herein include subjects or individuals with neutropenia related
diseases or conditions, including but not limited to, congenital neutropenia (such as
Kostmann's syndrome), cyclic neutropenia, idiopathic neutropenia, autoimmune
neutropenia, and drug-induced neutropenia (such as from cancer drugs).
Additional mammalian subjects, including humans, amenable to treatment with
compositions and methods as described herein, particularly TPA, according to the
methods described herein include subjects or individuals with thrombocytopenia related
diseases or conditions, including but not limited to, viral infections (such as parvovirus,
rubella, mumps, varicella, hepatitis C, Epstein-Barr virus, and HIV), severe infections or
sepsis, drug-induced thrombocytopenia (such as from cancer drugs, thiazide, sulfonamide
antibiotics, carbamazepine, digoxin, quinine, quinidine, acetaminophen, heparin, and
ripampin), transfusion reactions, rheumatologic conditions (such as systemic lupus
erythematosus), and idiopathic thrombocytopenia purpura. These and other subjects are
effectively treated prophylactically and/or therapeutically, by administering to the subject
an effective amount of a phorbol ester of Formula I or derivative of a phorbol ester of
Formula I sufficient to treat and/or reduce the duration of anemia, neutropenia and/or
thrombocytopenia in mammalian subjects with a neoplastic disease.
Chemotherapy is the treatment of cancer with an anti-neoplastic drug or
combination of such drugs. Chemotherapy works by impairing the reproduction of
rapidly splitting cells, a property common in cancerous cells. However it does not
actively distinguish between healthy cells that are also rapidly splitting and cancerous
cells and it has a number of side effects such as, but not limited to, neutropenia, anemia,
and thrombocytopenia.
Mammalian subjects amenable to treatment with phorbol esters of Formula I,
particularly TPA, according to the methods described herein additionally include, but are
not limited to, mammalian subjects undergoing chemotherapy.
Mammalian subjects suffering from neoplastic disease include malignant
neoplastic diseases such as solid and non-solid cancers. Non-solid cancers may include,
hematologic malignancies/bone marrow disorders, including, but not limited to,
leukemia, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML),
chronic myeloid leukemia blast crisis, myelodysplasia, myeloproliferative syndrome.
Solid cancers may include, but are not limited to, lymphoma, including Hodgkin’s and
non-Hodgkin’s lymphoma, subcutaneous adenocarcinoma, ovarian teratocarcinoma, lung
cancer; bone cancer; breast cancer; liver cancer; pancreatic cancer; oral cancer; non-small
cell lung cancer and prostate cancer.
Therapeutically useful methods described herein and formulations of the
invention will effectively use a phorbol ester of Formula I in a variety of forms, as noted
above, including any active, pharmaceutically acceptable salts of said compounds, as well
as active isomers, enantiomers, polymorphs, solvates, hydrates, prodrugs, and/or
combinations thereof. TPA of formula II is employed as an illustrative embodiment of
the invention within the examples herein below.
Within additional aspects of the invention, combinatorial formulations are
provided which employ an effective amount of a phorbol ester of Formula I or derivative
of a phorbol ester of Formula I in combination with one or more secondary or adjunctive
active agent(s) that is/are combinatorially formulated or coordinately administered with
the phorbol ester compound of Formula I to yield an effective response in the subject.
Analogous combinatorial methods are described herein.
A phorbol ester compound of Formula I or derivative of the phorbol ester of
Formula I is used in combination with G-CSF. Specifically, G-CSF is used in
combination with a phorbol ester, e.g., TPA.
A phorbol ester compound of Formula I or derivative of the phorbol ester of
Formula I is used in combination with erythropoeitin (EPO). Specifically, EPO is used in
combination with TPA.
A phorbol ester compound of Formula I or derivative of the phorbol ester of
Formula I is used in combination with G-CSF. Specifically, G-CSF is used in
combination with TPA.
Compositions as described herein comprise G-CSF and a phorbol ester compound
of Formula I or derivative compound of phorbol esters of Formula I including
pharmaceutically acceptable salts, enantiomers, isomers, polymorphs, prodrugs, hydrates
and solvates thereof, in an effective amount to treat or reduce the duration of neutropenia
and/or thrombocytopenia.
Compositions as described herein comprise EPO and a phorbol ester compound of
Formula I or derivative compound of phorbol esters of Formula I including
pharmaceutically acceptable salts, enantiomers, isomers, polymorphs, prodrugs, hydrates
and solvates thereof, in an effective amount to treat or reduce the duration of anemia.
The compositions of the invention comprise G-CSF and a phorbol ester
compound of Formula I or derivative compound of phorbol esters of Formula I including
pharmaceutically acceptable salts, enantiomers, isomers, polymorphs, prodrugs, hydrates
and solvates thereof, in a synergistically effective amount or synergistic combination
effective to treat or reduce the duration of neutropenia and/or thrombocytopenia. The
compositions of the invention are synergistically effective in treating or reducing the
duration of neutropenia and/or thrombocytopenia in human and other mammalian
subjects with neoplastic disease. A "synergistically effective amount" as applied to
compositions of the invention comprise G-CSF and a phorbol ester compound of Formula
I or derivative compound of phorbol esters of Formula I including pharmaceutically
acceptable salts, enantiomers, isomers, polymorphs, prodrugs, hydrates and solvates
thereof, is effective for shortening the duration of neutropenia and/or thrombocytopenia,
which is effective in treating or reducing the duration of neutropenia and/or
thrombocytopenia. The effect produced by the combination of the present invention
results in a response greater than G-CSF or a phorbol ester compound of Formula I or
derivative compound of phorbol esters of Formula I, alone or the sum of their individual
effects
A synergistically effective amount of a phorbol ester of Formula I (such as TPA)
with G-CSF or a synergistically effective amount of a combination of a phorbol ester of
Formula I (such as TPA) with EPO, may be administered to a mammal in a single or
multiple unit form either simultaneously or sequentially, in combined or separate
formulation(s), with one or more secondary agents, or one or more adjunctive therapeutic
agents; by an oral method (such as capsules, in liquid form, tablets, etc.), parenteral
method (such as parenteral injection), or by any other methods known in the art suitable
for administering drugs to mammals.
The compositions of the invention comprise EPO and a phorbol ester compound
of Formula I or derivative compound of phorbol esters of Formula I including
pharmaceutically acceptable salts, enantiomers, isomers, polymorphs, prodrugs, hydrates
and solvates thereof, in a synergistically effective amount or synergistic combination
effective to treat or reduce the duration of anemia. In particular, the compositions of the
invention are synergistically effective in treating or reducing the duration of anemia in
human or other mammalian subjects with neoplastic disease.
The compositions of the invention comprise an effective amount or unit dosage of
a phorbol ester compound of Formula I or derivative compound of a phorbol ester of
Formula I, and G-CSF which may be formulated with one or more pharmaceutically
acceptable carriers, excipients, vehicles, emulsifiers, stabilizers, preservatives, buffers,
and/or other additives that may enhance stability, delivery, absorption, half-life, efficacy,
pharmacokinetics, and/or pharmacodynamics, reduce adverse side effects, or provide
other advantages for pharmaceutical use.
Effectiveness of the compositions of the invention and methods described herein
may be demonstrated by a decrease in the duration of anemia, neutropenia and/or
thrombocytopenia.
Compositions of the invention may be coordinately administered (simultaneously
or sequentially, in combined or separate formulation(s)), with one or more secondary
cancer treating agents, or other indicated or adjunctive therapeutic agents, including, but
not limited to, doxorubicin, vitamin D3, cytarabine, cytosine arabinoside, daunorubicin,
cyclophosphamide, gemtuzumab, ozogamicin, idarubicin, mercaptopurine, mitoxantrone,
thioguanine, aldesleukin, asparaginase, carboplatin, etoposide phosphate, fludarabine,
methotrexate, etoposide, dexamethasone, and choline magnesium trisalicylate.
Within the methods described herein and compositions of the invention, a phorbol
ester compound(s) of Formula I (such as TPA) as disclosed herein is/are effectively
formulated or administered with GCSF for treating neutropenia, thrombcytopenia and/or
related disorders. In exemplary embodiments, TPA is demonstrated for illustrative
purposes to be an effective agent in pharmaceutical formulations and therapeutic
methods, in combination with GCSF. The present disclosure further provides additional,
pharmaceutically acceptable phorbol ester compounds (such as TPA) in the form of a
native or synthetic compound, including complexes, derivatives, salts, solvates, isomers,
enantiomers, polymorphs, and prodrugs of the compounds disclosed herein, and
combinations thereof, which are effective as therapeutic agents within the methods
described herein and compositions of the invention.
Compositions of the invention may comprise a phorbol ester compound of
Formula I (such as TPA) encapsulated for delivery, separately or together with GCSF or
EPO, in microcapsules, microparticles, or microspheres, prepared, for example, by
coacervation techniques or by interfacial polymerization, for example,
hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacrylate)
microcapsules, respectively; in colloidal drug delivery systems (for example, liposomes,
albumin microspheres, microemulsions, nano-particles and nanocapsules); or within
macroemulsions.
As noted above, in certain embodiments the methods described herein and
compositions of the invention may employ pharmaceutically acceptable salts, e.g., acid
addition or base salts of the above-described phorbol ester compounds of Formula I
and/or related or derivative compounds (such as TPA). Examples of pharmaceutically
acceptable addition salts include inorganic and organic acid addition salts. Suitable acid
addition salts are formed from acids which form non-toxic salts, for example,
hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate,
phosphate, and hydrogen phosphate salts. Additional pharmaceutically acceptable salts
include, but are not limited to, metal salts such as sodium salts, potassium salts, cesium
salts and the like; alkaline earth metals such as calcium salts, magnesium salts and the
like; organic amine salts such as triethylamine salts, pyridine salts, picoline salts,
ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N’-
dibenzylethylenediamine salts and the like; organic acid salts such as acetate, citrate,
lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate,
trifluoroacetate, oxalate, and formate salts; sulfonates such as methanesulfonate,
benzenesulfonate, and p-toluenesulfonate salts; and amino acid salts such as arginate,
asparginate, glutamate, tartrate, and gluconate salts. Suitable base salts are formed from
bases that form non-toxic salts, for example aluminum, calcium, lithium, magnesium,
potassium, sodium, zinc and diethanolamine salts.
Other detailed embodiments, the methods described herein and compositions of
the invention for employ prodrugs of phorbol esters of Formula I. Prodrugs are
considered to be any covalently bonded carriers which release the active parent drug in
vivo. Examples of prodrugs useful within the invention include esters or amides with
hydroxyalkyl or aminoalkyl as a substituent, and these may be prepared by reacting such
compounds as described above with anhydrides such as succinic anhydride.
For instance, in current AML therapeutic regimen, G-CSF has been a common
adjuvant drug for reducing the duration of neutropenia, but not thrombocytopenia, after
chemotherapy. The present invention indicates that G-CSF combined with phorbol esters
such as TPA can treat or reduce the duration of both neutropenia and/or
thrombocytopenia through the following two mechanisms.
1) TPA stimulates the upstream stem cells to differentiate into downstream stem
cells. TPA also stimulates downstream stem cells. GCSF only stimulates the
downstream stem cells.
2) TPA stimulates the growth of stromal cells, which nourish the stem cells.
For example, the duration of neutropenia after high dose chemotherapy and
treatment with GCSF is, for example, about 24±3 days. The combination of TPA and
GCSF reduces the duration of neutropenia to about 15±3 days, or about a 25% to 50%
reduction in the duration of neutropenia.
The combination of TPA and GCSF may result in about a 15% to 70% reduction
in the duration of cytopenia, including but not limited to, neutropenia, thrombocytopenia,
and/or anemia in comparison to treatment with GCSF or TPA alone. More preferably,
the combination results in about at 20% to 60% reduction in the duration of cytopenia;
and most preferably, the combination results in about a 25% to 50% reduction in the
duration of cytopenia.
Likewise, the combination of TPA and EPO may result in about a 15% to 70%
reduction in the duration of cytopenia, including but not limited to, neutropenia,
thrombocytopenia, and/or anemia in comparison to treatment with EPO or TPA alone.
More preferably, the combination results in about at 20% to 60% reduction in the
duration of cytopenia; and most preferably, the combination results in about a 25% to
50% reduction in the duration of cytopenia.
The invention achieves a surprisingly synergistic effect by stimulating upstream
stem cells to differentiate into downstream stem cells, as shown in Figure 1.
Alternatively, effectiveness of the compositions of the invention and methods
described herein may also be demonstrated, for example, by an increase toward normal
levels of red blood cells, white blood cells, neutrophils, and/or platelets. For instance,
effectiveness of the compositions of the invention and methods described herein may be
demonstrated by a decrease in neutropenia, anemia, and/or thrombocytopenia.
Effectiveness may be demonstrated using, for example, a complete blood count
(CBC). The measurements taken in a CBC include a white blood cell count (WBC), a
red blood cell count (RBC), the red cell distribution width, the hematocrit, and the
amount of hemoglobin. An effective amount of a composition of the present invention
will increase the levels measured in a complete blood count by 10%, 20%, 30%, 50% or
greater increase, up to a 75-90%, or 95% or greater. Effective amounts will also move
the blood protein of an individual towards the optimal category for each type of protein.
12 12
A normal erythrocyte (RBC) count is from 4.0 x10 /l to 5.2x x10 /l (in females)
12 12
and from 4.4 x10 /l to 5.7x10 /l (in males). Effectiveness of the compositions and
methods herein will increase the RBC count towards the normal count range.
A normal hemoglobin level is typically from 130 g/l to 175 g/l. Specifically, the
normal hemoglobin level is typically from 140 g/l to 180 g/l in human males, and the
normal hemoglobin level is typically from 120 g/l to 160 g/l in human females. Anemia
is a decrease in the amount of RBCs or hemoglobin in the blood. Anemia in men is
based on a hemoglobin of less than 130 to 140 g/L (13 to 14 g/dL), while anemia in
women is less than 120 to 130 g/L (12 to 13 g/dL). Effectiveness of the compositions
and methods herein will increase the hemoglobin level towards the normal hemoglobin
level.
A normal hematocrit level is from 0.370 to 0.460 (in females) and is from 0.420
to 0.520 (in males). Effectiveness of the compositions and methods herein will increase
the hematocrit level towards the normal range.
A normal WBC count is from 4.0x10 /l to 10.0x x10 /l. Effectiveness of the
compositions and methods herein will increase the WBC count towards the normal count
range.
Effectiveness of the compositions and methods herein may be evaluated using, an
absolute neutrophil count (ANC). A normal ANC is between 1,500 to 8,000/mm .
Individuals suffering from neutropenia have an ANC below 1500/mm , and may even
reach levels below 500/mm Effective amounts of the compositions and methods herein
will increase an individual’s ANC by 10%, 20%, 30%, 50% or greater increase, up to a
75-90%, or 95% or greater. Effective amounts may increase ANC levels above
1500/mm .
Effectiveness of the compositions and methods herein may further be evaluated
using, for example, a platelet count. A platelet count is normally between 150,000 to
450,000 platelets per microliter (x 10–6/Liter). Individuals suffering from
thrombocytopenia may have platelet counts below 100,000 per microliter (100,000/µl).
Effective amounts of the compositions and methods herein will increase an individual’s
platelet count by 10%, 20%, 30%, 50% or greater increase, up to a 75-90%, or 95% or
greater. Effective amounts may increase platelet levels above 100,000 per microliter
Effectiveness of the compositions and methods herein may additionally be
evaluated, for example, by measuring the number of myeloblasts. Myeloblasts normally
represent less than 5% of the cells in the bone marrow but should not be present in
circulating blood. Effective amounts of the compositions and methods herein will
decrease the number of myeloblasts by 10%, 20%, 30%, 50% or more, up to a 75-90%,
96% or greater decrease. Effective amounts may decrease myeloblasts to below 5%.
Effectiveness of the compositions and methods herein may further be evaluated
by examining myeloblasts for the presence of Auer rods. Effective amounts of the
compositions of the present invention will decrease the number of Auer rods visible by
%, 20%, 30%, 50% or more, up to a 75-90%, 96% or greater decrease up to the
complete elimination of Auer rods.
Effectiveness of the compositions of the invention and methods described herein
may be demonstrated by a decrease in the symptoms that accompany cytopenia,
including but not limited to, neutropenia, anemia, and/or thrombocytopenia.
Effective amounts of a phorbol ester compound or related or derivative compound
of Formula I (e.g., a unit dose comprising an effective concentration/amount of TPA, or
of a selected pharmaceutically acceptable salt, isomer, enantiomer, solvate, polymorph
and/or prodrug of TPA) will be readily determined by those of ordinary skill in the art,
depending on clinical and patient-specific factors. Suitable effective unit dosage amounts
of the active compounds for administration to mammalian subjects, including humans,
may range from about 10 to about 1500 µg, about 20 to about 1000 µg, about 25 to about
750 µg, about 50 to about 500 µg, about 150 to about 500 µg, about 125 µg to about 500
µg, about 180 to about 500 µg, about 190 to about 500 µg, about 220 to about 500 µg,
about 240 to about 500 µg, about 260 to about 500 µg, about 290 to about 500 µg. In
certain embodiments, the disease treating effective dosage of a phorbol ester compound
or related or derivative compound of Formula I may be selected within narrower ranges
of, for example, 10 to 25 µg, 30-50 µg, 75 to 100 µg, 100 to 300 µg, or 150 to 500 µg.
These and other effective unit dosage amounts may be administered in a single dose, or in
the form of multiple daily, weekly or monthly doses, for example in a dosing regimen
comprising from 1 to 5, or 2 to 3, doses administered per day, per week, or per month. In
one exemplary embodiment, dosages of 10 to 30 µg, 30 to 50 µg, 50 to 100 µg, 100 to
300 µg, or 300 to 500 µg, are administered one, two, three, four, or five times per day. In
more detailed embodiments, dosages of 50-100 µg, 100-300 µg, 300-400 µg, or 400-600
µg are administered once or twice daily. In a further embodiment, dosages of 50-100 µg,
100-300 µg, 300-400 µg, or 400-600 µg are administered every other day. In alternate
embodiments, dosages are calculated based on body weight, and may be administered,
2 2 2
for example, in amounts from about 0.5µg/m to about 300µg/m per day, about 1 µg/m
2 2 2 2
to about 200 µg/m , about 1 µg/m to about 187.5 µg/m per day, about 1 µg/m per day
2 2 2
to about 175 µg/m per day, about 1 µg/m per day to about 157 µg/m per day about 1
2 2 2 2 2
µg/m to about 125 µg/m per day, about 1 µg/m to about 75 µg/m per day, 1 µg/m to
2 2 2 2 2
about 50/ µg/m per day, 2 µg/m to about 50 µg/m per day, 2 µg/m to about 30 µg/m
per day or 3 µg/m to about 30 µg/m per day.
In other embodiments, dosages may be administered less frequently, for example,
2 2 2 2
0.5µg/m to about 300µg/m every other day, about 1 µg/m to about 200 µg/m , about 1
2 2 2 2
µg/m to about 187.5 µg/m every other day, about 1 µg/m to about 175 µg/m every
2 2 2
other day, about 1 µg/m per day to about 157 µg/m every other day about 1 µg/m to
2 2 2
about 125 µg/m every other day, about 1µg/m to about 75 µg/m every other day, 1
2 2 2 2
µg/m to about 50µg/m every other day, 2 µg/m to about 50 µg/m every other day, 2
2 2 2 2
µg/m to about 30 µg/m per day or 3 µg/m to about 30 µg/m per day. In additional
embodiments, dosages may be administered 3 times/week, 4 times/week, 5 times/week,
only on weekdays, only in concert with other treatment regimens, on consecutive days, or
in any appropriate dosage regimen depending on clinical and patient-specific factors.
Erythropoietin is a glycosylated protein hormone and a haematopoietic growth
factor produced primarily in the kidneys, and for clinical use, is produced by recombinant
DNA technology and the name epoetin is often applied to such material. See
noblood.org/forum/content/179-erythropoietin_-28epo-29. Epoetin alfa, epoetin beta,
epoetin gamma, epoetin omega, and epoetin zeta are recombinant human erythropoietins
derived from a cloned human erythropoietin gene; all of which have the same 165 amino
acid sequence but differ in the glycosylation pattern. Id. Epoetin delta is a recombinant
human erythropoietin derived from a genetically engineered continuous human cell line,
and has the same amino acid sequence and glycosylation pattern as human erythropoietin.
EPO such as EPOETIN® may be given either as an IV or SC injection, as
described at inceptapharma[dot]
com/epoetin/submenu_page_view.php?menu_id=86&submenu_id=223&fs, the
disclosure of which is herein incorporated by reference in its entirety. For instance, the
dosage may be adjusted for each patient to achieve and maintain hemoglobin levels
between 10 to 12 g/dL. Id. For example, if hemoglobin is increasing and approaching 12
g/dL, the dose may be reduced by approximately 25%; if the hemoglobin continues to
increase, the dose may be temporarily withheld until the hemoglobin begins to decrease
and then reinitiated at a dose approximately 25% below the previous dose; or if the
hemoglobin increases by more than 1 g/dL in a 2-week period, the dose may be decreased
by approximately 25%. Id. If the increase in the hemoglobin is less than 1 g/dL over 4
weeks and iron stores are adequate, the dose of EPOETIN® may be increased by
approximately 25% of the previous dose. Further increases may be made at 4-week
intervals until the specified hemoglobin is obtained. Id.
The dose of EPO may be titrated for each patient on chemotherapy or who have
undergone chemotherapy, to achieve and maintain the lowest hemoglobin level sufficient
to avoid the need for blood transfusion and not to exceed the upper safety limit of 12
g/dL. inceptapharma[dot]
com/epoetin/submenu_page_view.php?menu_id=86&submenu_id=223&fs The initial
recommended dose of EPO in adults is 150 Units/kg SC TIW or 40,000 Units SC
Weekly, and the initial recommended dose of EPO in pediatric patients is 600 Units/kg
IV weekly. Id.
Suitable effective unit dosage amounts of erythropoeitin may depend on several
factors and will be within the discretion of the subject's physician. For example, some
patients may be more or less sensitive to the compounds or compositions described
herein, and for those patients compositions providing a higher of a lower plasma or serum
value may be preferred. Also, some subjects may metabolize the compound or may
metabolize it at different rates, and so dosages and/or alternative dosage forms may be
required to provide the desired serum or plasma concentration. Skilled artisans will
appreciate that specific dosages of EPO in compositions of the present invention may be
adjusted depending on conditions of disease, the age, body weight, general health
conditions, sex, and diet of the subject, dose intervals, administration routes, excretion
rate, and combinations of active compounds.
The dosing regimen for EPO may include doses such as 75 to 150 IU for every
kilogram (u/kg) of body weight given daily or every other day; 600 u/kg given once a
week; or 300 u/kg three or four times a week; as described at
noblood.org/forum/content/179-erythropoietin_-28epo-29 is a suggested dosing guide,
the disclosure of which is herein incorporated by reference in its entirety. For instance,
for a 70 kg patient, 60,000 IU per week may be ordered. Id.
Suitable effective unit dosage amounts of EPO may include a range from 450
IU/kg to 900 IU/kg, given daily or every other day, or given once, twice, three times or
four times a week. See noblood.org/forum/content/179-erythropoietin_-28epo-29
Suitable effective unit dosage amounts of EPO-beta may include 1000 IU/0.3mL,
2000 IU/0.3mL, 3000IU/0.3mL, 4000 IU/0.3mL, 5000 IU/0.3mL, 6000 IU/0.3mL,
,000 IU/0.6mL, and 30,000 IU/0.6mL solutions; and contains urea, sodium chloride,
sodium phosphate, and water, in pre-filled syringes for injection. See
noblood.org/forum/content/179-erythropoietin_-28epo-29.
Epoetin alfa may be administered by injection of 1 mL of a water-based solution
which may contain a single dose of 2000, 3000, 4000, 10,000, or 40,000 units of epoetin
alfa per single dose, along with other ingredients including albumin, based on treatment
requirements and weight of patient. See noblood.org/forum/content/179-erythropoietin_-
28epo-29. In addition, multidose injections may also be administered with 10,000 units
or 20,000 units per 1 mL of injection solution. Id. This applies to other forms of EPO.
Id. Chronic diseases, such as renal failure, heart disease, diabetes, and inflammatory
diseases like rheumatoid arthritis, all contribute to anemia and produce a blunted
response to EPO therapy - in all such cases the dosage should be increased. Id.
Dosages of EPO alfa (rch) or EPREX may be administered as described at
medsafe.govt.nz/profs/datasheet/e/eprexinj.pdf, the disclosure of which is herein
incorporated by reference in its entirety. For example, EPO alfa may be administered
subcutaneously with 150 units/kg 3 times weekly, or 40,000 units weekly, and/or 300
units/kg 3 times weekly or 60,000 units weekly. See drugs.com/ppa/epoetin-alfa-
erythropoietin-epo.html, the disclosure of which is herein incorporated by reference in its
entirety.
The dosage of EPO may include high doses as described in U.S. Patent No.
7,232,797, the disclosure of which is herein incorporated by reference. For instance, U.S.
Patent No. 7,232,797 describes a dosage of EPO of 5000 IU/kg weekly or 17,000~25,000
IU/kg (biweekly or triweekly).
The dosage of EPO may include low doses as described in CA2418531, the
disclosure of which is herein incorporated by reference. For instance, the CA2418531
patent describes dosage of EPO from about 1 to about 90 IU/kg per week; as well as an
initial treatment dose of about 75 to about 120 IU/Kg per week and maintenance dose of
about 20 to about 75 IU/Kg per week. In addition, CA2418531 describes administration
of recombinant Epoetin Omega at a dose of 5-150 IU/Kg, one to three times per week.
An effective dose or multi-dose treatment regimen for the instant disease treating
(alternatively, “neutrophil stimulating,” “erythropoiesis stimulating,” or “platelet
stimulating”) formulations of the invention will ordinarily be selected to approximate a
minimal dosing regimen that is necessary and sufficient to substantially treat or
reduce/shorten the duration of anemia, neutropenia, and/or thrombocytopenia in the
subject. A dosage and administration protocol will often include repeated dosing therapy
over a course of several days or even one or more weeks or years. An effective treatment
regime may also involve prophylactic dosage administered on a day or multi-dose per
day basis lasting over the course of days, weeks, months or even years.
Effectiveness of the compositions of the invention and methods described herein
may also be demonstrated by a decrease in the symptoms of subjects suffering from
neoplastic disease including, but not limited to, anemia, chronic fatigue; excessive or
easy bleeding, such as bleeding of the nose, gums, and under the skin; easy bruising,
particularly bruising with no apparent cause; shortness of breath; petechiae; recurrent
fever; swollen gums; slow healing of cuts; bone and joint discomfort; recurrent
infections; weight loss; itching; night sweats; lymph node swelling; fever; abdominal
pain and discomfort; disturbances in vision; coughing; loss of appetite; pain in the chest;
difficulty swallowing; swelling of the face, neck and upper extremities; a need to urinate
frequently, especially at night; difficulty starting urination or holding back urine; weak or
interrupted flow of urine; painful or burning urination; difficulty in having an erection;
painful ejaculation; blood in urine or semen; frequent pain or stiffness in the lower back,
hips, or upper thighs; and/or weakness.
Effectiveness of the compositions of the invention and methods described herein
in the treatment of rheumatoid arthritis may also be demonstrated by a change in the
erythrocyte sedimentation rate. An effective amount of the compositions of the invention
would decrease the levels of erythrocyte sedimentation by 10%, 20%, 30%, 50% or more,
up to a 75-90%, 96% or greater decrease over the initial diagnostic levels of erythrocyte
sedimentation. Effectiveness may also be demonstrated by a change in the levels of
rheumatoid factor and anti-cyclic citrullinated antibodies.
The compounds and compositions described herein can be formulated into
pharmaceutically acceptable compositions, which may include one or more
pharmaceutically acceptable carriers. Such compositions may be prepared by mixing one
or more compounds or compositions described herein, including, e.g., pharmaceutically
acceptable salts thereof or stereoisomers thereof, with pharmaceutically acceptable
carriers, excipients, binders, diluents or the like to treat or reduce the duration of
cytopenia such as neutropenia, thrombocytopenia, and/or anemia.
The instant compositions can be formulated for various routes of administration,
for example, by oral, transdermal, parenteral, rectal, nasal, vaginal administration, or via
implanted reservoir or other device such as a stent. Such implants may employ known
inert materials such as silicones and biodegradable polymers. They also may be provided
in combination with delivery vehicles such as in micelles or liposomes, or some other
encapsulating technology. Parenteral or systemic administration includes, but is not
limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intrathecal,
intracranial, and intracerebroventricular injections.
For oral, buccal, and sublingual administration, powders, suspensions, granules,
tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These
can be prepared, for example, by mixing one or more compounds disclosed herein, or
pharmaceutically acceptable salts or stereoisomers thereof, with at least one additive,
including but not limited to, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,
starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins,
collagens, casein, albumin, synthetic or semi-synthetic polymers and glycerides.
Optionally, oral dosage forms can contain other ingredients to aid in administration, such
as an inactive diluent, lubricants such as magnesium stearate, preservatives such as
paraben or sorbic acid, anti-oxidants such as ascorbic acid, tocopherol or cysteine, a
disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or
perfuming agents. Tablets and pills may be further coated with coating materials known
in the art.
Liquid dosage forms for oral administration may be in the form of
pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which
may contain an inactive diluent, such as water. Pharmaceutical formulations and
medicaments may be prepared as liquid suspensions or solutions using a sterile liquid,
including, but not limited to, oil, water, alcohol, and combinations thereof.
Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be
added for oral or parenteral administration.
Injectable dosage forms include aqueous suspensions or oil suspensions which
may be prepared using a suitable dispersant or wetting agent and a suspending agent.
Injectable forms may be in solution phase or in the form of a suspension, which is
prepared with a solvent or diluent, including but is not limited to, sterilized water,
Ringer's solution, or an isotonic aqueous saline solution. For injection, the
pharmaceutical formulation and/or medicament may be a powder suitable for
reconstitution with an appropriate solution, and may optionally contain stabilizers, pH
modifiers, surfactants, bioavailability modifiers and combinations thereof. Examples of
such suitable powders include, but are not limited to, freeze dried, rotary dried or spray
dried powders, amorphous powders, granules, precipitates, or particulates.
Compounds and compositions described herein also may be administered to the
lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for
inhalation include but are not limited to, aqueous and nonaqueous aerosols, solutions,
sprays, dry powders, or aerosols containing any appropriate solvents and optionally other
compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH
modifiers, surfactants, bioavailability modifiers and combinations thereof. Formulations
for inhalation administration may contain excipients including but not limited to, lactose,
polyoxyethylenelauryl ether, glycocholate and deoxycholate. An aqueous aerosol is
made by formulating an aqueous solution or suspension of the compound or composition
together with conventional pharmaceutically acceptable carriers and stabilizers, which
include but are not limited to, nonionic surfactants (Tweens, Pluronics, or polyethylene
glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino
acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols may be prepared
from isotonic solutions, or a nonaqueous suspension (e.g., in a fluorocarbon propellant)
can also be used to deliver embodiments of the compounds and compositions described
herein.
The compounds and compositions of the present invention may be provided in a
spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other
compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH
modifiers, surfactants, bioavailability modifiers and combinations thereof, for nasal
administration.
Compounds and compositions of the present invention may be provided for
sustained or immediate release. Sustained release dosage forms control the rate of
release, and can maintain an effective concentration of the composition over time,
thereby providing the recipient with a therapeutic effect over an extended duration. the
pharmaceutical composition is a dosage form selected from the group consisting of a
tablet, liquid for oral administration, oral spray, intranasal spray, inhalable formulation,
pill, gel, solid, capsule, multi-particulate, transdermal patch, implantable dosage, and
injectable solution including intravenous drip (including in lyophilized and re-constituted
form); as well as dosage forms that swell or unfold so that the dosage form is retained in
the stomach or the upper portion of the small intestine for a period of least 1 hour, at least
2 hours, at least three hours, at least 4 hours, at least 5 hours, at least 6 hours or for a
period of longer than 6 hours. Examples of patents that describe sustained release
compositions include, but are not limited to, U.S. Pat. No. 7,438,927, U.S. Pat. No.
7,413,751, U.S. Pat. No. 7,405,238, U.S. Pat. No. 6,723,340, U.S. Pat. No. 6,682,759,
U.S. Pat. No. 6,635,280, U.S. Pat. No. 6,488,962, U.S. Pat. No. 6,451,808, U.S. Pat. No.
6,340,475, U.S. Pat. No. 5,972,389, U.S. Pat. No. 5,582,837, and U.S. Pat. No.
,007,790.
The following non-limiting examples are provided merely to illustrate various
aspects or embodiments of the present invention.
Examples
Example 1:
In Vitro Study of TPA and GCSF on colony forming cells
The combination of TPA and GCSF generated stronger stimulating effects on colony
forming cells than TPA or G-CSF alone, as shown in Figure 2.
Myelosuppression is the most common adverse reactions of cancer patients who
use chemotherapy drugs, severe bone marrow suppression often makes chemotherapy
difficult to continue as planned, may be bring out the complications, could be life-
threatening. Recently, rhG-CSF, EPO are used widely to treat leukopenia or anemia
which coursed by chemotherapy and radiotherapy. But only rhG-CSF, EPO cannot
recover medullary hematopoiesis in the short term for those who accepted high intensity
or many times chemotherapy, especially for leukemia patients. Because chemotherapy
drugs can hurt the normal hematopoietic cells and microenvironment in the bone marrow,
when they are killing cancer cells. Meanwhile rhG-CSF, EPO play a role in the
downstream of hematopoiesis. Such as G-CSF effects on myeloid progenitor stage,
which stimulate their proliferation, differentiation and promote mature neutrophils to be
released into the peripheral blood. EPO play a role on erythroid progenitor cells stage, to
stimulate erythropoiesis , increase the number of red blood cells in peripheral blood. But
they have no effects on bone marrow microenvironment all. Therefore, it is important to
find a way to quickly restore bone marrow hematopoiesis. It is reported that 12-O-
tetradecanoylphorbolacetate which is called phorbol ester(TPA), not only can induce
a variety of leukemia cells to normal cells, but also TPA have a certain influence on bone
marrow hematopoietic and can increase white blood cell.
To explore the effect of TPA alone or combined rhG-CSF on bone marrow
hematopoietic cells proliferation and colony formation ability which from patients of
acute myeloid leukemia(AML) in the period of bone marrow suppression in vitro and to
observe the effect of TPA on bone marrow stromal cells(BMSCs) proliferation or
inhibition from patients of AML in the period of myelosuppression and the healthy
persons.
Methods:
1) Human bone marrow cells from the same AML patient after chemotherapy were
cultured by methyl cellulose semi-solid culture medium. Groups: Blank, TPA (10
ng/ml), G-CSF (50 ng/ml), TPA(10 ng/ml) + GCSF(50 ng/ml). The experiments
were repeated for 4 times.
2) The stroma cells of bone marrow from the healthy human and the AML patient after
chemotherapy were cultured by methyl cellulose semi-solid culture medium.
Different TPA concentrations were added. Groups: Blank, TPA (0.1 ng/ml), TPA
(1.0 ng/ml), TPA (5 ng/ml), TPA (10 ng/ml), TPA (20 ng/ml), TPA (30 ng/ml).
3) Cultivation of BMSCs from healthy persons and patients of AML in the bone marrow
suppression phase in vitro, added to TPA of different concentrations ,0.1 ng/ml, 1.0
ng/ml, 5 ng/ml, 10 ng/ml, 20 ng/ml, 30 ng/ml, and set up a control to detect cell
proliferation or inhibition with CCK8 method.
Results and Conclusion:
1. Compared the clones of four groups in incomplete medium, in the control
group a small cell clusters can be seen for 24-72 hours, but the cells were dead as time
prolong. Cultivated 14 days, control group have no clones formation, CFU-GM are
dominated for G-CSF group, TPA alone and combination with G-CSF group have
myeloid colony formation, while BFU-E and CFU –GEMM. For G-CSF group, TPA
alone group and combination with G-CSF group, the total number of clones were higher
than control group (both P<0.05), meanwhile the clones for TPA alone group and
combination with G-CSF group are higher than G-CSF group (both P <0.05), the clones
of joint group is higher than that of TPA group (P <0.001).
2. Compared the clones of different concentration of TPA stimulation in
incomplete medium, the total clones of 5 ng/ml, 10 ng/ml, 20 ng/ml group are higher than
other groups, including 10 ng/ml in the highest, there are statistical significance (both
P<0.05).While decreasing or increasing TPA concentration cannot improve the colony
number. The better concentration of TPA to stimulate the colony formation is 5 ~ 20
ng/ml. Cultivated 14 days, except CFU-GM, CFU-GEMM were seen in 1 ng/ml, 5 ng/ml,
ng/ml, 20 ng/ml group , and can be seen fewer BFU-E in 5 ng/ml, 10 ng/ml, 20 ng/ml
group, while the other group concentration did not see the erythroid clones.
3. Compared the clones of different concentration of TPA and G-CSF(50 ng/ml)
stimulation in incomplete medium. Combination with G-CSF the better concentration of
TPA is 1 ~ 10 ng/ml (both P<0.05). Combination with G-CSF the best concentration of
TPA is 5 ng/ml and 1 ng/ml.for CFU-GM and CFU-GEMM. The main clone types are
myeloid clones, CFU-GM, also have CFU-GEMM and fewer BFU-E.
4. Compared the clones of four groups in complete medium, clones can be seen in
four groups including of CFU-GM, CFU-GEMM, BFU-E, CFU-E. The clones of TPA
with G-CSF group are highest compared with TPA group, G-CSF group and control
group, difference have statistical significance (both P<0.05). While TPA group and G-
CSF group the number of clones of TPA group and G-CSF group have no statistical
significance (P = 0.577).
. Experiments show that TPA promote bone marrow stromal cells from healthy
persons proliferation of concentration 5~10 ng/ml (cell number 2 x 105/ml). Decreasing
or increasing the concentration of TPA, it shows that BMSCs are inhibited. Meanwhile,
TPA promote bone marrow stromal cells from the AML patients proliferation of
concentration 5~30 ng/ml (cell number 2 x 105/ml). 5 ng/ml of TPA is the best
concentration of promoting proliferation, and G-CSF had no effect on the growth of
BMSCs from healthy persons or AML patients.
Conclusion:
TPA promoted hematopoietic cell clone formation lonely ,mainly of CFU – GM
for bone marrow of AML patients in the period of bone marrow suppression in vitro ,the
best concentration is 10 ng/ml. TPA promoted the formation of CFU-GM, CFU-GEMM,
and BFU-E at different stages.
TPA and G-CSF have synergistic effects in promoting bone marrow myeloid
clones formation, in addition promote CFU-GEMM and BFU-E formation, the best
concentration of TPA is 5 ng/ml. G-CSF promoted the formation of CFU-GM, but had
no effect on CFU-GEMM and BFU-E.
TPA promoted the growth of the stroma cells of bone marrow (BMSCs) of the
healthy human and the AML patient after chemotherapy, in the bone marrow suppression
phase in vitro. The optimal concentrations were 5ng/ml and 10ng/ml.
As shown in Figure 1, TPA stimulated the upstream stem cells to differentiate into
downstream stem cells. GCSF only stimulated the downstream stem cells. TPA also
stimulates downstream stem cells. Neutrophils are one type of granulocytes.
Example 2:
Project TPA ( PD616 ) for AML
• MOA : Protein kinase C (PKC) activator
• Indication :
1) current protocol: salvage therapy of AML after relapse
2) new strategy: AML supportive care after induction/consolidation
chemotherapy on WBC and platelet recovery.
• Rationale:
(1) Activation of PKC facilitates hematopoietic cells recovery
(2) PKC induces differentiation of leukemia cells
TPA in AML Strength
• To enhance bone marrow recovery in 1L AML after induction and consolidation
chemotherapy
• Well established mechanism of action by activation of PKC
• Well known tolerable toxicity profile from prior clinical studies
• Strong efficacy data in AML patients with potential shortening of neutropenia &
thrombocytopenia duration from 20 to 12 days
➢ Decrease hospital stay
➢ Minimize chance of infection
➢ Decrease the need of blood product support
➢ Reduce AML patient care cost
TPA as a supportive care for white cell & platelets recovery after AML
chemotherapy
• Pitfalls of standard of care (SOC): G-CSF or GM-CSF does not work on early
hematopoietic progenitor cells and with limited efficacy in shortening of the
duration of neutropenia & thrombocytopenia after induction or consolidation
therapy.
• There is no effective approach to facilitate platelet recovery after chemotherapy in
AML induction/consolidation.
• TPA enhances growth of early progenitor cells and potentially helps shorten the
duration of neutropenia and thrombocytopenia
• Annual incidence 14,000 cases of AML, and 80% will receive aggressive chemo
and develop prolonged neutropenia.
• Target:
➢ shortening of duration of neutropenia and hospital stay from 20 to 12 days,
➢ Decrease blood products (PRBC and platelets) support, due to facilitation
of platelet recovery
➢ Decrease infection complication
➢ No negative impact on efficacy, CR rate or duration of response
Indication
Shortening of neutropenia & thrombocytopenia in AML
patients after induction or consolidation chemotherapy. Shortening
of neutropenia and thrombocytopenia.
Administration
TPA IV 3 times per week (M-W-F) until ANC over 1000 and
platelets over 20,000 for at least 2 days at 0.125 mg/m as a single
course starting 24 - 48 hours after completion of chemotherapy
whereas other supportive care remains as SOC.
Efficacy
Decrease the duration of neutropenia by 40%, from 20 days to 12
days. Decrease average hospitalization days by 40%. Decrease
blood product support by 40%.
Safety
All toxicities not significantly worse than common toxicities
associated with standard AML chemotherapy.
Competition
G-CSF and GM-CSF but not very effective
• Phase 2 single arm study of 12 patients, TPA starts at 24 - 48 hours after
completion of standard chemotherapy (6 for induction 3+7 and 6 for consolidation
with 2+5 or high-dose Ara-C ). TPA IV for M-W-F per week until ANC over
1000 and platelet over 20,000 persistently for 2+ days, whereas other supportive
care same as SOC.
• Double-blinded randomized phase 2, TPA+G-CSF vs. G-CSF in 1:1. 20 patients
sample size with ~90% power and alpha 0.1, to detect a decrease of the duration
of neutropenia & thrombocytopenia by 40% ( from 20 days to 12 days )
➢ Primary endpoints: Duration of neutropenia, blood product supports and
hospitalization date all decreased by 40%.
• Target goal of 40% reduction is achieved, and no obvious unfavorable effect to
leukemia therapy.
Additional AML protocol includes starting TPA at 24 - 48 hours after completion of
chemotherapy and watch duration of neutropenia & thrombocytopenia
Randomized phase 2 trial in two cohorts. One for induction chemotherapy, one for
consolidation chemotherapy. Show duration of neutropenia decreased by 40%.
Example 3:
This protocol is induction therapy, and does not include consolidation. This
adjuvant therapy combines TPA and G-CSF(Granulocyte colony stimulating factor).
This is a single-arm, open label study. Ten (10) patients receive standard
induction chemotherapy with idarubicin (12 mg/m2) or daunorubicin (60 mg/m2) on
days 1, 2, 3 and Ara-C continuous (100-200 mg/m2/day) infusion on days 1-7. On Day 8
or 24 hours after completion of all scheduled Ara-C infusion, TPA is started at 0.125
mg/m IV every two days, in addition to G-CSF (400 µg subcutaneously daily) support
until absolute neutrophil count (ANC) above 1000/µL for two consecutive days.”
A Phase 2a study of phorbol ester in shortening the duration of neutropenia and
thrombocytopenia in acute myelocytic leukemia patients who receive induction
chemotherapy.
Phorbol ester (12-O-Tetradecanoylphorbolacetate, TPA) is an agonist of protein
kinase C, and has been shown to increase early hematopoietic progenitor cells by in vitro
studies. In prior Phase 1 dose escalation studies of TPA, TPA is observed to be capable
of shortening the duration of post-chemotherapy neutropenia in acute myelocytic
leukemia (AML) patients. In the recommended Phase 2 dose at 0.125 mg/m daily up to
days a week x 2 weeks, it is well tolerated with only minor adverse events such as
shortness of breath, proteinuria, fever, chills and irritation of vein at infusion site. This
study is designed to examine the efficacy of TPA as a supportive care agent to enhance
bone marrow recovery in AML patients after induction chemotherapy.
Study objectives:
1. Evaluate the safety and tolerability of TPA in AML patients after induction
chemotherapy
2. Evaluate preliminary efficacy in shortening of the duration of neutropenia and
thrombocytopenia in AML patients after induction chemotherapy
3. Evaluate the preliminary Complete Remission (CR) rate after induction
chemotherapy with maintenance TPA after induction therapy.
Eligibility
The inclusion criteria include:
1. Patients diagnosed with AML or advanced myelodysplastic syndrome (MDS,
such as refractory anemia with excess blasts (RAEB), or RAEB with
transformation), if their bone marrow blast count is over 20%.
2. AML should be classified by FAB classification, and all subtypes are allowed
and recorded during enrollment, except patients with M3 or acute
promyelocytic leukemia.
3. AML or advanced MSD patients who are considered suitable to receive 3+7
induction chemotherapy (anthracycline and cytarabine)
4. Age 18-70
. ECOG 0-2
6. No evidence of major organ dysfunctions as defined by Creatinine ≤ 2 mg/dL,
AST/ALT ≤ 5 X ULN, Bilirubin ≤ 2 mg/dL, and no major cardiovascular
problems such as recent acute myocardiac infarction or stroke within 6
months from enrollment.
7. Patients with adequate cardiac function without history of congestive heart
failure as defined by no worse than American Heart Association class I
(Patients with cardiac disease but resulting in no limitation of physical
activity. Ordinary physical activity does not cause undue fatigue, palpitation,
dyspnea or anginal pain).
8. Patients able to give consent for the study
The exclusion criteria include:
1. Patients with other non-AML malignancies within the past 24 months, except
those that are considered curable, such as treated basal cell carcinoma of skin,
resected early stage malignancies such as ductal carcinoma in situ of breast
and other cured cancers.
2. Patients with clinical active or chronic infection and not suitable for standard
AML 3+7 induction therapy
3. Patients with recent major bleeding, surgery and other major medical
problems within 6 months who are not suitable for standard AML 3+7
induction therapy.
4. Patients with chronic COPD who require chronic oxygen supplement to
maintain pulse oxygen saturation above 92%.
. Lactating and pregnant women
6. Patients with known positive HIV infection in the past
Study design
This is a single-arm, open label study. Ten (10) patients receive standard
induction chemotherapy with idarubicin (12 mg/m ) or daunorubicin (60 mg/m ) on days
1, 2, 3 and Ara-C continuous (100-200 mg/m /day) infusion on days 1-7. On Day 9 or 24
hours after completion of all scheduled Ara-C infusion, TPA is started at 0.125 mg/m IV
every morning for 5 days on then 2 days off. Same 5 days on and 2 days off cycle of
TPA administration is repeated once until patients’ absolute neutrophil count (ANC) is
above 1000/µL for two consecutive days. G-CSF at 400 µg subcutaneously or
intravenously daily is started at the same day as the first day TPA starts but is
administered in the afternoon, or approximately 8 hours after the morning dose of TPA.
G-CSF is also stopped when patients’ absolute neutrophil count (ANC) is above 1000/µL
for two consecutive days. This sequential approach of administration of TPA followed
by G-CSF is designed based on TPA stimulation of the proliferation of early progenitors
such as CFU-GM and CFU-GEMM; whereas G-CSF stimulates the proliferation of later
progenitor mainly CFU-GM or CFU-G. Without the expansion of early progenitor
population, G-CSF would not have the target cell population and work effectively to
enhance the recovery of normal white blood cells.
All other supportive care such as IV broad-spectrum antibiotics, anti-viral (such
as anti-herpetic agents), and anti-fungal (such as anti-Candidiasis agents) support follow
the standard practice guideline for AML induction therapy. Blood product support also
follows the standard practice guideline with transfusion of packed red cells (PRBC) when
hematocrit is below 30 and platelet count below 10,000 if no clinical evidence of
bleeding (or 50,000 if clinical evidence of bleeding). All patients are hospitalized for the
whole induction period until ANC and platelet recovery to adequate level without
evidence of active infection. Standard care for neutropenia is adopted.
Study duration
After patients recover from induction therapy, patients may be discharged from
the hospital and return later for subsequent additional chemotherapy such as high dose
Ara-C or considered for bone marrow transplantation per treating physician discretion
based on their risk factors. Patients will be off study after they return for follow-up bone
marrow evaluation for the efficacy of the induction therapy. All further consolidation
therapy will not be considered part of the study.
Safety evaluation
Safety analysis is evaluated based on Common Terminology Criteria for Adverse Events
(CTCAE) vs. 4.0. The commonly observed adverse events includes shortness of breath,
fever, chills and proteinuria. The treatment-related fever and chills are consistent with a
cytokine increase after IV infusion of the study medication, but it is generally transient
and subsides after 24 hours. Acetaminophen is used for symptomatic relief of the fever if
necessary.
Efficacy analysis
Evaluation of neutropenia and thrombocytopenia after induction chemotherapy is done by
daily hematological tests, including complete blood count and differential count. Day 14
bone marrow is routinely done according to the standard clinical practice guideline to
assess any residual blasts 7 days after completion of induction therapy. Flow cytometry
of the aspirated bone marrow is tested to differentiate the recovering normal progenitor
cells versus residual blasts. The duration of neutropenia and thrombocytopenia is
assessed separately and the ANC and platelet counts should be plotted in a diagram for
each patient.
Statistics analysis
The study explores the duration of neutropenia and thrombocytopenia after standard 3+7
induction chemotherapy in AML patients. Usually, 80% of AML patients will have a
duration of neutropenia/thrombocytopenia of 20 ± 3 days (i.e. ANC or platelet recovery
at approximately at Days 24-30 assuming chemotherapy starts at Day 1) and then are
discharged from the hospital if there is no evidence of infection. In the study, TPA
shortens the duration of neutropenia and thrombocytopenia significantly. Duration of
neutropenia or thrombocytopenia for patients treated with TPA is reduced to 12 days
(ANC or platelet recovery at Day 14-24 days) with a standard deviation of 5 days, the
sample size of 10 patients will have 90% power to detect a difference and reject the null
hypothesis.
Example 4:
Male patient, age 25, diagnosed with AML (M2). Patient's bone marrow myeloblast plus
promyelocyte count was about 60%. After he received one standard course of DA
regimen (7 Ara C + 3 Daunorubicin), his peripheral WBC count dropped to 0.8×10 /L.
He was then administered 150μg G-CSF each day. After chemotherapy, it took 12 days
(duration of neutropenia and thrombocytopenia) to bring both his platelet count and WBC
count, including the neutrophil count, back to normal. His bone marrow myeloblast plus
promyelocyte count was about 40%, still way above the normal value (0~5%). Then, he
received his second standard course of DA regimen. After the second course of DA
regimen, his peripheral WBC count and platelet count dropped to 0.6×10 /L and 80 ×
/L respectively. He was then administered TPA plus G-CSF (150μg TPA followed
with 150μg G-CSF) each day of day 1 and day 2. On day 4 and day 5, he was
administered with only 150μg TPA each day. The WBC counts and neutrophil
percentage* in parenthesis were 1.8 ×10 /L (39%) on day 3, 6.5×10 /L (72%) on day 7,
and 5.7×10 /L (77%) on day 14. The estimated duration of neutropenia after
chemotherapy was shortened to about 5 days. The platelet counts were 330x 10 /L on
day 3, 715 ×10 /L on day 7, and 568 ×10 /L on day 14. The estimated duration of
thrombocytopenia after chemotherapy was shortened to less than 3 days. His bone
marrow myeloblast plus promyelocyte count was 2%, falling to the normal value.
*Neutrophils usually make up 60 to 70% of circulating WBC.
Example 5:
Male patient, age 33, was diagnosed with myelodysplastic syndromes (MDS5q-). He had
been treated with therapy which included EPO, G-CSF, thalidomide, and testosterone for
7 months without any improvement. His hematopoietic function was very low, especially
erythropoiesis. His hemoglobin level was 40g/L without blood transfusion. Besides
receiving medication, he also had blood transfusion each month. After blood transfusion,
his hemoglobin level reached 70-80g/L. One to two weeks later, it dropped to 60g/L. By
the end of the month, it dropped to 40g/L again. He had to receive blood transfusion
again. He had suffered a loss of working ability and could not live a normal life. He was
administered TPA+G-CSF+EPO treatment (TPA:150-180µg iv infusion + G-CSF:150µg
im + EPO: 5000 unit im) 5 times. Each time, EPO and G-CSF were given 5 hours after
TPA was given. After the 5 treatments of TPA+G-CSF with EPO, he maintained a
hemoglobin level of 70g/L without blood transfusion. He has ceased blood transfusions
since then. His hemoglobin level continued to increase gradually the following two
months and reached 120g/L in three months after TPA+G-CSF+EPO treatment, close to
the normal hemoglobin level (130-175g/L). His WBC, RBC and platelet counts also
gradually increased to nearly normal levels. He has recovered his daily work and normal
life.
Example 6:
Drug Induced Cytopenia Treated by TPA
Ninety (90) adult mice were randomly assigned to 9 groups (10 mice per group). No
drug was administered in Control group. Model group was given DNR (6 mg/kg)+Ara-C
(150 mg/kg) on Day 0. The rest of the 7 groups were given DNR (6 mg/kg)+Ara-C (150
mg/kg) on Day 0, and each group on Day 7, Day 8, and Day9 was administered with one
of the following drugs: G-CSF (10 μg/kg), EPO (500 IU/kg), TPA (12.5 μg/kg), TPA (25
μg/kg), TPA (50 μg/kg), TPA (12.5 μg/kg)+GCSF (10 μg/kg), or TPA (12.5 μg/kg)+EPO
(500 IU/kg).
Experiment Model (3 days after DNR+Ara-C )
Table 1 The comparison of blood cell counts between each group(n=10)
-1 9 12 9
Group Dose(mg.kg ) WBC(×10 /L) RBC(×10 /L) PLT(×10 /L)
Control - 6.47±0.39 10.05±0.43 1478±125
** **
Model DNR6+Ara- 1.03±0.26 9.91±0.63 342±59
c150
* **
Note: Date represent meansSD. “ ”P <0.05,“ ”P <0.01 vs control group
Table 2 The comparison of blood cell counts between each group(n=10)
(6 days after DNR+Ara-C )
-1 9 12 9
Group Dose(mg.kg ) WBC(×10 /L) RBC(×10 /L) PLT(×10 /L)
Control - 6.72±0.8 9.7±0.48 1432±79
** ** **
Model DNR6+Ara- 2.76±0.61 6.04±0.74 170±51
c150
* **
Note: Date represent meansSD. “ ”P <0.05,“ ”P <0.01 vs control group
Table 3 The comparison of blood cell counts between each group(n=10)
(8 days after DNR+Ara-c, 1 day after 1 TPA or other )
-1 9 12 9
Group Dose(μg.kg ) WBC(×10 /L) RBC(×10 /L) PLT(×10 /L)
Control - 6.70±0.17 10.05±0.24 1439±14.18
①① ①① ①①
Model - 3.30±0.30 5.02±0.14 98±14.8
①②② ①① ①①②②
G-CSF 10 5.3±0.62 4.94±0.42 373±76.27
①① ①①②② ①①②②
EPO 500 3.7±0.69 7.32±0.10 385±19.28
②② ①①②③③④ ①①②②
TPA 12.5 6.4±0.62 6.08±0.49 395±30.41
②② ①①②②③③⑤ ①①②②
TPA 25 6.4±0.35 7.09±0.23 391±20.42
②② ①①②②③③⑤ ①①②②
TPA 50 6.5±0.75 7.10±0.24 413±9.64
①①②②③③⑤ ①①②③③ ①①②②
TPA+GCSF 12.5+10 8.5±0.46 6.22±0.61 405±47.62
②②④④ ①①②②⑤⑤ ①①②②
TPA+EPO 12.5+500 6.8±0.79 8.61±0.27 417±45.3
① ①①
Note: Date represent meansSD. “ ”P <0.05,“ ”P <0.01 vs control group;
② ②② ③ ③③
“ ”P <0.05,“ ”P <0.01 vs model group, “ ” P <0.05, “ ”P <0.01 vs G-CSF group“
④ ④④ ⑤ ⑤⑤
” P <0.05, “ ”P <0.01 vs EPO group“ ” P <0.05, “ ”P <0.01 vs TPA12.5μg.kg
group
Table 4 The comparison of blood cell counts between each group(n=10)
(9 days after DNR+Ara-c, 1 day after 2 TPA or other )
-1 9 12 9
Group Dose(μg.kg ) WBC(×10 /L) RBC(×10 /L) PLT(×10 /L)
Control - 6.72±0.81 9.74±0.48 1432±79.28
① ①① ①①
Model - 5.46±0.49 5.45±0.68 512±42.99
② ①① ①①②②
G-CSF 10
6.95±0.44 5.40±0.46 949±65.88
①① ①①② ①①②②
EPO 500 5.52±0.34 6.75±0.69 935±43.57
② ①①②②③ ①①②②
TPA 12.5
6.84±0.44 7.47±0.55 965±76.23
② ①①②②③ ①①②②
TPA 25
6.72±0.50 7.34±0.87 951±70.29
② ①①②②③ ①①②②
TPA 50 6.86±0.39 7.30±0.49 999±45.67
①①②②③③⑤ ①①②②③ ①①②②
TPA+GCSF 12.5+10 10.74±0.58 7.18±0.38 969±52.86
④ ①②②④④ ①①②②
TPA+EPO 12.5+500 6.78±0.34 8.87±0.29 928±32.72
① ①①
Note: Date represent meansSD. “ ”P <0.05,“ ”P <0.01 vs control group;
② ②② ③ ③③
“ ”P <0.05,“ ”P <0.01 vs model group, “ ” P <0.05, “ ”P <0.01 vs G-CSF group“
④ ④④ ⑤ ⑤⑤
” P <0.05, “ ”P <0.01 vs EPO group“ ” P <0.05, “ ”P <0.01 vs TPA 12.5μg.kg
group
Table 5 The comparison of blood cell counts between each group(n=10)
(10 days after DNR+Ara-c, 1 day after 3 TPA or other )
-1 9 12 9
Group Dose(μg.kg ) WBC(×10 /L) RBC(×10 /L) PLT(×10 /L)
Control - 6.60±0.54 9.96±0.82 1425±52.34
①① ①①
Model - 6.55±0.61 5.17±0.56 730±71.09
①①②② ①① ②②
G-CSF 10
9.14±0.67 5.30±0.34 1456±91.76
③③ ①①②②③③ ②②
EPO 500 6.45±0.41 8.51±0.86 1469±75.67
①①②②④④ ①①②②③③ ②②
TPA 12.5
9.51±0.85 7.59±0.67 1447±78.09
①①②②④④ ①①②②③③ ②②
TPA 25 9.69±0.85 8.26±0.63 1465±72.81
①①②②④④ ①①②②③③ ②②
TPA 50 9.90±0.64 8.18±0.55 1463±80.33
①①②② ①①②②③③ ②②
TPA+GCSF 12.5+10 9.90±0.63 7.47±0.64 1419±89.66
①①②②④④ ②②③④⑤ ②②
TPA+EPO 12.5+500
9.44±0.30 10.18±0.19 1430±71.47
① ①①
Note: Date represent meansSD. “ ”P <0.05,“ ”P <0.01 vs control group;
② ②② ③ ③③
“ ”P <0.05,“ ”P <0.01 vs model group, “ ” P <0.05, “ ”P <0.01 vs G-CSF group“
④ ④④ ⑤ ⑤⑤
” P <0.05, “ ”P <0.01 vs EPO group“ ” P <0.05, “ ”P <0.01 vs TPA12.5μg.kg
group
Conclusion:
1) TPA promoted the production of WBC, RBC, and platelet. It could be useful to treat
different forms of cytopenia, such as anemia, leukopenia, neutropenia, thrombocytopenia,
granulocytopenia, pancytopenia, and hypocytopenia (see https at
en.wikipedia.org/wiki/Cytopenia).
2) TPA combined with G-CSF has a synergistic effect in promoting the production of
WBC.
3) TPA combined with EPO has a synergistic effect in promoting the production of RBC.
4) TPA may promote the hematopoietic pathway on different stages, from upstream
myeloid stem cells to differentiate towards downstream stem cells and then from
downstream stem cells to further differentiate to different blood cells.
Claims (19)
1. Use of a phorbol ester of Formula I, pharmaceutically-acceptable salt, enantiomer, solvate, hydrate, or polymorph thereof, in the manufacture of a medicament for treating or reducing the duration of neutropenia and/or thrombocytopenia in a subject in need thereof, in combination with a granulocyte-colony stimulating factor (G-CSF), Formula I wherein R and R are selected from the group consisting of hydrogen, hydroxyl, , wherein the alkyl group contains 1 to 15 carbon atoms, , wherein the lower alkenyl group contains 2 to 7 carbon atoms, , and , R is selected from hydrogen, and , wherein the lower alkyl group contains 1 to 7 carbon atoms, wherein said medicament is formulated for administration of an amount comprising between about 10 and 1500 µg of said phorbol ester of Formula I; and wherein the G-CSF is formulated for administration to said subject in a coordinate administration protocol, simultaneously with, prior to, or after administration of said medicament comprising said phorbol ester of Formula I.
2. Use of a phorbol ester of Formula I, pharmaceutically-acceptable salt, enantiomer, solvate, hydrate, or polymorph thereof, in the manufacture of a medicament for treating or reducing the duration of anemia in a subject in need thereof, in combination with an erythropoietin (EPO), Formula I wherein R and R are selected from the group consisting of hydrogen, hydroxyl, , wherein the alkyl group contains 1 to 15 carbon atoms, , wherein the lower alkenyl group contains 2 to 7 carbon atoms, , and , R is selected from hydrogen, and , wherein the lower alkyl group contains 1 to 7 carbon atoms, wherein said medicament is formulated for administration of an amount comprising between about 10 and 1500 µg of said phorbol ester of Formula I; and wherein the EPO is formulated for administration to said subject in a coordinate administration protocol, simultaneously with, prior to, or after administration of said medicament comprising said phorbol ester of Formula I.
3. The use according to claim 1or 2, wherein R or R is , wherein the alkyl group contains 1 to 15 carbon atoms, the remaining R or R is , wherein the lower alkyl group contains 1 to 7 carbon atoms, and R is hydrogen.
4. The use according to claim 1 or 2, wherein the phorbol ester is phorbol 13- butyrate, phorbol 12-decanoate, phorbol 13-decanoate, phorbol 12,13-diacetate, phorbol 13,20-diacetate, phorbol 12,13-dibenzoate, phorbol 12,13-dibutyrate, phorbol 12,13- didecanoate, phorbol 12,13-dihexanoate, phorbol 12,13-dipropionate, phorbol 12- myristate, phorbol 13-myristate, phorbol 12,13,20-triacetate, 12-deoxyphorbol 13- angelate, 12-deoxyphorbol 13-angelate 20-acetate, 12-deoxyphorbol 13-isobutyrate, 12- deoxyphorbol 13-isobutyrateacetate, 12-deoxyphorbol 13-phenylacetate, 12- deoxyphorbol 13-phenylacetate 20-acetate, 12-deoxyphorbol 13-tetradecanoate, phorbol 12-tigliate 13-decanoate, 12-deoxyphorbol 13-acetate, phorbol 12-acetate, or phorbol 13- acetate.
5. The use according to claim 1 or 2, wherein the phorbol ester is 12-O- tetradecanoylphorbolacetate (TPA).
6. The use according to claim 1 or 2, wherein the medicament is formulated for administration with at least one secondary or adjunctive therapeutic agent
7. The use according to claim 1 or 2, wherein said medicament is formulated for administration of an amount of said phorbol ester of Formula I between about 10 and 1500 µg of said phorbol ester of Formula I every day or every other day.
8. The use according to claim 1 or 2, wherein said medicament is formulated for administration of an amount of said phorbol ester of Formula I between about 150 to 500 µg of said phorbol ester of Formula I every day or every other day.
9. The use according to claim 1, wherein the combination increases absolute neutrophil count (ANC) of the subject to above 1500/mm .
10. The use according to claim 1, wherein the combination increases platelet levels of the subject to above 100,000/µl.
11. The use according to claim 2, wherein the combination increases a complete blood count (CBC) level of the subject measured in a complete blood count by at least 10%.
12. The use according to claim 2, wherein the combination increases a hemoglobin level of the subject to above a normal hemoglobin level.
13. The use according to claim 1 or 2, wherein the subject has acute myeloid leukemia (AML).
14. The use according to claim 1, wherein said G-CSF is formulated for administration in an amount from 150 µg to 400 µg of G-CSF.
15. The use according to claim 2, wherein said EPO is formulated for administration in an amount selected from the group consisting of from 75 IU/kg to 150 IU/kg of EPO, from 450 IU/kg to 900 IU/kg of EPO, 600 IU/kg once a week of EPO, 300 IU/kg three or four times a week of EPO, from 2,000 to 40,000 units per single dose of EPO, 150 IU/kg three times weekly of EPO, 300 IU/kg three times weekly of EPO, and from 40,000 units weekly to 60,000 units weekly of EPO.
16. A composition for treating or reducing the duration of neutropenia and/or thrombocytopenia in a mammalian subject in need thereof comprising a phorbol ester of Formula I, pharmaceutically-acceptable salt, enantiomer, solvate, hydrate, or polymorph thereof Formula I wherein R and R are selected from the group consisting of hydrogen, hydroxyl, , wherein the alkyl group contains 1 to 15 carbon atoms, , wherein the lower alkenyl group contains 2 to 7 carbon atoms, , and , R is selected from hydrogen, and , wherein the lower alkyl group contains 1 to 7 carbon atoms; and a granulocyte-colony stimulating factor (G-CSF), wherein said composition comprises said phorbol ester of Formula I in an amount from 10 to 1500 µg, and said G-CSF in an amount from 150 µg to 400 µg.
17. A composition for treating or reducing the duration of anemia in a mammalian subject in need thereof comprising a phorbol ester of Formula I, pharmaceutically- acceptable salt, enantiomer, solvate, hydrate, or polymorph thereof Formula I wherein R and R are selected from the group consisting of hydrogen, hydroxyl, , wherein the alkyl group contains 1 to 15 carbon atoms, , wherein the lower alkenyl group contains 2 to 7 carbon atoms, , and , R is selected from hydrogen, and , wherein the lower alkyl group contains 1 to 7 carbon atoms; and an erythropoietin (EPO), wherein said composition comprises said phorbol ester of Formula I in an amount from 10 to 1500 µg, and said EPO in an amount selected from the group consisting of from 75 IU/kg to 900 IU/kg of EPO, from 2,000 to 40,000 units of EPO, and from 40,000 to 60,000 units of EPO.
18. The composition of claim 16, wherein the phorbol ester of Formula I is TPA, and TPA and G-CSF are present in an amount sufficient to treat or reduce the duration of neutropenia and/or thrombocytopenia.
19. The composition of claim 17, wherein the phorbol ester of Formula I is TPA, and TPA and EPO are present in an amount sufficient to treat or reduce the duration of anemia.
Applications Claiming Priority (3)
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US201462074133P | 2014-11-03 | 2014-11-03 | |
US62/074,133 | 2014-11-03 | ||
PCT/US2015/058732 WO2016073416A1 (en) | 2014-11-03 | 2015-11-03 | Phorbol ester compositions and methods for treating or reducing the duration of cytopenia |
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