U.S. patent application number 11/146883 was filed with the patent office on 2005-09-29 for treatment method against side-effects of chemotherapy.
Invention is credited to Ford, John P..
Application Number | 20050215514 11/146883 |
Document ID | / |
Family ID | 34520566 |
Filed Date | 2005-09-29 |
United States Patent
Application |
20050215514 |
Kind Code |
A1 |
Ford, John P. |
September 29, 2005 |
Treatment method against side-effects of chemotherapy
Abstract
A method and composition is provided for organ rescue wherein a
specific counter-measure is applied locally to a tissue at risk for
or exhibiting an adverse side effect of a cancer treatment. More
particularly, the method and composition is directed at controlling
Hand-Foot Syndrome, a painful redness and cracking of the skin of
the hands and feet which can occur with systemic treatment with
5-fluorouracil or a precursor thereof. Uracil ointment is applied
to the skin of the hands and feet to prevent Hand-Foot Syndrome
which can occur from systemic administration of 5-fluorouracil (or
precursor thereof) as cancer treatment.
Inventors: |
Ford, John P.; (Unadilla,
NY) |
Correspondence
Address: |
DECHERT LLP
P.O. BOX 10004
PALO ALTO
CA
94303
US
|
Family ID: |
34520566 |
Appl. No.: |
11/146883 |
Filed: |
June 6, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11146883 |
Jun 6, 2005 |
|
|
|
10684203 |
Oct 10, 2003 |
|
|
|
10684203 |
Oct 10, 2003 |
|
|
|
10364383 |
Feb 12, 2003 |
|
|
|
60355764 |
Feb 12, 2002 |
|
|
|
Current U.S.
Class: |
514/49 ;
514/269 |
Current CPC
Class: |
A61K 31/337 20130101;
A61K 31/505 20130101; A61K 31/7072 20130101; A61P 35/00 20180101;
A61K 31/555 20130101; A61K 31/337 20130101; A61K 31/704 20130101;
A61K 31/513 20130101; A61K 31/513 20130101; A61K 31/7072 20130101;
A61K 31/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/555 20130101;
A61K 31/704 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/049 ;
514/269 |
International
Class: |
A61K 031/7072; A61K
031/513 |
Claims
What is claimed is:
1. A method for organ rescue from toxicity of chemotherapeutic
treatment, the method comprising topically applying a rescue agent
composition to an area of the body at risk of or exhibiting adverse
side effects from the cancer treatment, the rescue agent operative
to reverse the efficacy of the cancer treatment due to its high
local concentration in the tissues to be rescued; the rescue agent
being present in a negligible amount that systematically allows the
chemotherapeutic treatment to attack cancer in an unabated
manner.
2. A method for organ rescue from toxicity of cancer treatment, the
method comprising topically applying a composition comprising a
rescue agent to an area of a human body at risk of or exhibiting
adverse side effects from the cancer treatment.
3. A method according to claim 2 wherein the adverse side effects
include Hand-Foot Syndrome.
4. A method according to claim 2 wherein the side effects are
conditions selected from pain, numbness, tingling feeling,
swelling, redness and combinations thereof in palms of a cancer
patient's hands or soles of a cancer patient's feet.
5. A method according to claim 2 wherein the cancer treatment
applies an anti-cancer active which is 5-fluorouracil or a
precursor thereof.
6. A method according to claim 2 wherein the rescue agent is
uracil.
7. A method according to claim 6 wherein the rescue agent is
delivered in a pharmaceutically acceptable carrier selected from
the group comprising emollients, water, inorganic powders, foaming
agents, emulsifiers, microspheres, and combinations thereof.
8. A method for reducing Hand-Foot Syndrome (HFS) resulting from a
chemotherapeutic treatment through systemic treatment with
5-fluorouracil or a precursor thereof, the method comprising
topically applying to a body surface affected by HFS or at risk of
HFS, a composition comprising uracil in an effective amount to
reduce the Hand-Foot Syndrome.
9. A composition for treating Hand-Foot Syndrome comprising about
0.01 to about 60% by weight of uracil in a pharmaceutically
acceptable carrier.
10. A composition according to claim 9 wherein the uracil is
present in an amount from about 0.5 to about 5% by weight in a
pharmaceutically acceptable carrier.
11. A method of reducing stomititis due to 5FU or a 5FU precursor
by applying a topical uracil composition to the oral/rectal mucosa.
Description
CROSS-REFERENCES
[0001] This application is a continuation-in-part application of
Ser. No. 10/364,383 filed Feb. 12, 2003, and which claims benefit
from Provisional Application Ser. No. 60/355,764, filed Feb. 12,
2002.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention concerns reducing side-effects of certain
chemotherapy, and particularly, side-effects manifested topically
in areas of the hands and feet.
[0004] 2. The Related Art
[0005] Chemotherapy can result in predictable toxicity to organs.
An important chemotherapy is the use of 5-fluorouracil (5FU), and
its precursors, such as capecitabine available as Xeloda.RTM., a
drug produced by Roche Pharmaceuticals. Xeloda.RTM. and 5FU can
induce a skin side effect called "Hand-Foot Syndrome" (HFS). This
syndrome can cause pain, a loss of feeling (numbness), a tingling
feeling, swelling and redness in the palms of your hands and/or
soles of feet. Some patients also get a rash, discolored skin, nail
problems, and hair loss. Severe cases of HFS can be very painful,
cause skin of the hands and feet to blister and peel.
[0006] Compilations relevant to this field include the
following.
[0007] Mackean M, Planting A, Twelves C et al: Phase 1 and
pharmacologic study of intermittent twice-daily oral therapy with
capecitabine in patients with advanced and/or metastatic cancer. J.
Clin Oncol 16:2977-2985, 1998.
[0008] Cao S, Frank C, Shirasaka et al: 5-fluorouracil pro drug:
role of anabolic and catabolic pathway modulation in therapy of
colorectal cancer. Clin Can Res 1:839-845, 1995.
[0009] Hoff, P: The tegafur-based dehydropyrimidine dehydrogenase
inhibitory fluoropyrimidines, UFT/Leucoverin (Orzel) and S-1: a
review of their clinical development and therapeutic potential.
Invest New Drugs 18:331-342, 2000.
[0010] Johnson M, Hageboutros A, Wang K, et al: Life threatening
toxicity in a dihydropyrimidine dehydrogenase-deficient patient
after treatment with topical 5-fluorouracil. Clin Can Res
5:2006-2011, 1999.
SUMMARY OF THE INVENTION
[0011] The present invention introduces the concept of "organ
rescue." By applying locally a uracil ointment, certain adverse
side effects of 5FU and its precursors can be averted. Uracil and
5FU are anabolized by the same enzymes. Uracil and 5FU differ
chemically only in the H (Uracil) or F(5FU) at 5 position. Uracil
is in high concentration when the uracil ointment is applied at the
skin subject to HFS ("rescuing" the skin). After topical
application of the uracil ointment to the hands and feet, uracil
has negligible concentration in the body generally and specifically
in the tumor containing regions of the body. The application of 1%
uracil ointment prevents the anabolism of 5FU into a toxic form in
those tissues, subjacent to the ointment application, where uracil
concentration is high. Adverse side effects of 5FU are countered
while preserving the anti-cancer systemic efficacy of the 5FU. With
application of the uracil ointment to the hands and feet, the
systemic uracil concentration is low. No longer is it necessary to
reduce the systemic dose of 5FU/precursor in efforts to avoid the
HFS side-effect.
[0012] The concept of "organ rescue" can be applied to other organs
and to other chemotherapy agents which have specific organ
toxicities. In each case, the rescue agent is directly applied in
high local concentration to a tissue subject to toxicity thereby
reversing the unwanted side effect of systematically administered
anti-cancer agent. The rescue agent must, in each case,
specifically reverse the local efficacy of the cancer treatment.
The rescue agent must have negligible systemic concentration in the
body to preserve the anti-cancer efficacy of the cancer
treatment.
[0013] Previous work presumed the oral administration of uracil,
systemically together with a precursor of 5FU would increase the
metabolism of the 5FU and decrease its degradation. The resultant
effect was presumed to be an increase in toxicity. This oral agent
(UFT) is administered systematically at a dose of 1000-2000 mg
uracil (4.times. molar excess over 5FU) per day. It is possible
that the high uracil dose in UFT can counteract the anti-cancer
effect of the 5FU. The 1% uracil ointment is administered at 1-2 cc
or 10-20 mg uracil per day.
[0014] This logic for creating mixtures of uracil and 5FU/precursor
was that the uracil compared to 5FU would be preferentially
degraded and metabolized. Thus, the application of a 1% uracil
ointment might be expected to increase HFS. Yet, quite the opposite
was observed. The 1% uracil ointment eliminated the HFS toxicity of
cancer treatment by 5FU or its precursor.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Use of uracil formulations can be effective as
post-chemotherapy treatment providing benefit to the adverse skin
effects of the chemotherapy chemicals. Among those effects that can
be mitigated include redness (erythema) and cracking.
[0016] Chemotherapy agents applicable to the present treatment and
method include 5-fluorouracil or precursors thereof
[0017] Amounts of uracil as the rescue active in rescue
formulations may range from about 0.01 to about 60%, preferably
from about 0.5 to about 5%, optimally from about 1% by weight.
[0018] Formulations of uracil may be in any convenient format.
These include creams, lotions, aerosol sprays, roll-on liquids,
sticks and pad forms.
[0019] Treatment compositions of the present invention may be
anhydrous or emulsions. Oil and water emulsions are preferred for
the present invention. Whether anhydrous or emulsion type,
compositions of the present invention may further include a variety
of pharmaceutically acceptable carriers and skin actives. Amounts
of the carrier may range from about 1 to about 99%, preferably from
about 5 to about 70%, optimally from about 10 to about 40% by
weight. Among the carriers are emollients, water, inorganic
powders, foaming agents, emulsifiers, fatty alcohols, fatty acids,
and combinations thereof
[0020] Emollients are substances selected from polyols, esters and
hydrocarbons. Polyols suitable for the invention may include
propylene glycol, dipropylene glycol, polypropylene glycol,
polyethylene glycol, sorbitol, hydroxypropyl sorbitol, hexylene
glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, glycerin,
ethoxylated glycerin, propoxylated glycerin, xylitol and mixtures
thereof.
[0021] Esters useful as emollients include:
[0022] (1) Alkyl esters of fatty acids having 10 to 20 carbon
atoms. Methyl, isopropyl, and butyl esters of fatty acids are
useful herein. Examples include hexyl laurate, isohexyl laurate,
isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl
oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate,
diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate,
diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl
lactate. Particularly preferred are C12-C15 alcohol benzoate
esters.
[0023] (2) Alkenyl esters of fatty acids having 10 to 20 carbon
atoms. Examples thereof include oleyl myristate, oleyl stearate and
oleyl oleate.
[0024] (3) Ether-esters such as fatty acids esters of ethoxylated
fatty alcohols.
[0025] (4) Polyhydric alcohol esters. Ethylene glycol mono and
di-fatty acid esters, diethylene glycol mono- and di-fatty acid
esters, polyethylene glycol (200-6000) mono- and di-fatty acid
esters, polyglycerol poly-fatty esters, ethoxylated glyceryl
monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol
distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty
acid esters, and polyoxyethylene sorbitan fatty acid esters are
satisfactory polyhydric alcohol esters.
[0026] (5) Wax esters such as beeswax, spermaceti, myristyl
myristate, stearyl stearate.
[0027] (6) Sterol esters, of which cholesterol fatty acid esters
are examples thereof
[0028] Illustrative hydrocarbons are mineral oil, polyalphaolefins,
petrolatum, isoparaffin, polybutenes and mixtures thereof.
[0029] Inorganic powders are useful carriers. Examples include
clays (such as Montmorillonite, Hectorite, Laponite and Bentonite),
talc, mica, silica, alumina, zeolites, sodium sulfate, sodium
bicarbonate, sodium carbonate, calcium sulfate and mixtures
thereof.
[0030] Aerosol propellants may also be used as carriers.
Propellants are normally based on volatile hydrocarbons such as
propane, butane, isobutene, pentane, isopropane and mixtures
thereof Philipps Petroleum Company is a source of such propellants
under trademarks including A31, A32, A51 and A70. Halocarbons
including fluorocarbons and dimethyl ether are further widely
employed propellants.
[0031] Emulsifiers may constitute at least a portion of the carrier
for compositions according to the present invention. These may be
selected from nonionic, anionic, cationic, or amphoteric
emulsifying agents. They may range in amount anywhere from about
0.1 to about 20% by weight. Illustrative nonionic emulsifiers are
alkoxylated compounds based on C10-C22 fatty alcohols and acids and
sorbitan. These materials are available, for instance, from the
Shell Chemical Company under the Neodol trademark. Copolymers of
polyoxypropylenepolyoxyethylene sold by the BASF Corporation under
the Pluronic trademark are sometimes also useful. Alkyl
polyglycosides available from the Henkel Corporation may also be
utilized for purposes of this invention.
[0032] Anionic type emulsifiers include fatty acid soaps, sodium
lauryl sulphate, sodium lauryl ether sulphate, alkyl benzene
sulphonate, mono- and di-alkyl acid phosphates, sarcosinates,
taurates and sodium fatty acyl isethionate.
[0033] Amphoteric emulsifiers include such materials as
dialkylamine oxide and various types of betaines (such as
cocamidopropyl betaine).
[0034] Preservatives such as methyl paraben and propyl paraben are
useful to prevent microbial contamination.
[0035] Another system for delivering uracil and similar rescue
agents may be microsphere technology. Typical of this technology is
use of a high surface area polymethacrylate impregnated with the
rescue agent.
[0036] Except in the operating and comparative examples, or where
otherwise explicitly indicated, all numbers in this description
indicating amounts of material ought to be understood as modified
by the word "about."
[0037] The following examples will more fully illustrate the
embodiments of this invention. All parts, percentages and
proportions referred to herein and in the appended claims are by
weight unless otherwise illustrated.
[0038] All documents mentioned in this application should be
considered as being incorporated herein by reference.
EXAMPLE 1
[0039] A patient being treated with orally administered Xeloda had
to discontinue the routine after only 5 of 14 days of planned
treatment. Discontinuance was the result of severe Hand-Foot
Syndrome. Tumor measurements on the original date and after 21 days
subsequent to Hand-Foot Syndrome recovery are recorded in Table 1
below as "initial" and "Day 21," respectively. After two courses of
treatment with Xeloda.RTM. and a concurrent topical application of
1% uracil ointment based on a vanishing cream base (applied four
times a day to the hands and feet), the patient had no symptoms of
the syndrome. See "Day 35."
1TABLE 1 Original Day Day Tumor Date 21 35 Breast mass 7 .times. 7
cm 9 .times. 9 cm 8.5 .times. 8.5 cm Left supraclavicular 1 .times.
1 cm 2 .times. 2 cm 1.5 .times. 1.5 cm node Right axillary mass 2
.times. 2 cm 3 .times. 3 cm 2 .times. 2 cm
[0040] The administration of the uracil ointment both prevented the
Hand-Foot Syndrome as well as restored the anti-tumor activity of
the Xeloda.RTM..
[0041] This 48 year old female patient exhibited metastatic breast
cancer. She had refused mastectomy and had previously failed
adriamycin and cytoxan, weekly taxol, weekly navelbine. She was
then placed on Xeloda.RTM. together with 1% uracil ointment applied
to the hands and feet. The 1% uracil ointment was used starting
with cycle 5 of treatment with Xeloda.RTM.. Table 2 below
summarizes results on this patient.
2 TABLE 2 Course q3 wk 1 2 3 4 5 6 7 8 Xeloda dose 1250 same D/C
1000 1250 same same same 14/21 days mg/m2 after mg/m2 mg/m2 bid
.times. 14 4 days bid .times. 14 bid .times. 14 Taxotere 75 mg/m2 +
+ + + + + + + Marker tumor size 12 .times. 12 8 .times. 8 7 .times.
7 7 .times. 7 9 .times. 9 8.5 .times. 8.5 8 .times. 8 8.5 .times.
8.5 cm-prior to rx progression on lower dose Xeloda 1% uracil
ointment 0 0 0 0 + + + + Hand-foot syndrome ND* ND ++++ ++ 0 0 0 0
*Not described
[0042] The 1% uracil ointment allowed a reescalation of the dose of
Xeloda.RTM. The results show recovered anti-tumor activity at the
higher dose of Xeloda.RTM.. The 1% uracil ointment did not
interfere with the anti-cancer activity of the Xeloda.RTM.. Neither
did the 1% uracil ointment have any discernible toxicity.
EXAMPLE 2
[0043] Another patient, a 68 year old white female diagnosed with
metastatic colon cancer, was treated with Xeloda.RTM. and
thalidomide. Hand-Foot Syndrome developed. Complete reversal of the
syndrome occurred after topical treatment with a 1% uracil
ointment. The efficacy of the Xeloda.RTM. and thalidomide treatment
was unaffected by the concurrent use if the 1% uracil ointment.
There were no dose reductions of chemotherapy or treatment
delays.
EXAMPLE 3
[0044] A 60 year old white female with metastatic colon cancer was
treated with 5FU, Leucovocin.RTM., and Oxaliplatin, a very common
regime of treatment for this form of cancer. The patient developed
hand-foot syndrome. Topical application of 1% uracil ointment
resulted in complete resolution of the syndrome. The anti-cancer
treatment remained efficacious. No side-effects were noted as a
result of the uracil ointment applications. There were no dose
reductions of chemotherapy or treatment delays.
[0045] The foregoing description and examples illustrate selected
embodiments of the present invention. In light thereof, variations
and modifications will be suggested to one skilled in the art, all
of which are within the spirit and purview of this invention.
* * * * *