U.S. patent application number 09/995010 was filed with the patent office on 2003-06-05 for formulation of amino acids and riboflavin useful to reduce toxic effects of cytotoxic chemotherapy.
Invention is credited to Burzynski, Stanislaw R..
Application Number | 20030105104 09/995010 |
Document ID | / |
Family ID | 25541300 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105104 |
Kind Code |
A1 |
Burzynski, Stanislaw R. |
June 5, 2003 |
Formulation of amino acids and riboflavin useful to reduce toxic
effects of cytotoxic chemotherapy
Abstract
Pharmaceutical compositions effective in alleviating or reducing
the effects of fatigue and weakness associated with cancer and
cytotoxic cancer chemotherapy are disclosed. The pharmaceutical
compositions of the present invention comprise riboflavin,
effectors of the urea cycle in free form or pharmacologically
acceptable salts thereof, and amino acids selected from the groups
of essential and non-essential amino acids, in free form or
pharmaceutically acceptable salts thereof, suitably combined with
appropriate carriers, diluents, or excipients. Also disclosed are
methods of alleviating or reducing the effects of fatigue and
weakness associated with cancer and cytotoxic cancer chemotherapy
by administration of pharmaceutical compositions of the present
invention.
Inventors: |
Burzynski, Stanislaw R.;
(Houston, TX) |
Correspondence
Address: |
HOWREY SIMON ARNOLD & WHITE
750 Bering Drive
Houston
TX
77057-2198
US
|
Family ID: |
25541300 |
Appl. No.: |
09/995010 |
Filed: |
November 27, 2001 |
Current U.S.
Class: |
514/251 ;
514/553; 514/561; 514/565 |
Current CPC
Class: |
A61K 31/198 20130101;
A61P 35/04 20180101; A61K 31/195 20130101; A61P 39/02 20180101;
A61K 31/525 20130101; A61P 41/00 20180101; A61P 43/00 20180101;
A61P 35/00 20180101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 31/525 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/251 ;
514/565; 514/561; 514/553 |
International
Class: |
A61K 031/525; A61K
031/198; A61K 031/185 |
Claims
What is claimed is:
1. A method for alleviating or reducing the toxic, nutritional and
metabolic disturbances associated with cancer and cancer
chemotherapy comprising: administering to a patient a composition
comprising an effective amount of riboflavin, an effector of the
urea cycle, and the amino acids alanine, glycine, serine, taurine,
threonine and valine.
2. A method according to claim 1 wherein the effector of the urea
cycle is arginine, omithine or citrulline.
3. The method of claim 1 wherein the amino acids are in free form
or pharmacologically acceptable salts.
4. The method of claim 1, wherein the concentration of riboflavin
is about 5 to about 300 mg/L.
5. The method of claim 1, wherein the concentration of the effector
of the urea cycle is about 2 to about 120 mg/L.
6. The method of claim 1, wherein the concentration of alanine is
about 1 to about 90 mg/L, the concentration of glycine is about 1
to about 75 mg/L, the concentration of serine is about 1 to about
75 mg/L, the concentration of taurine is about 0.5 to about 30
mg/L, the concentration of threonine is about 1 to about 90 mg/L
and the concentration of valine is about 1 to about 50 mg/L.
7. The method of claim 1, wherein said composition is administered
enterally or parenterally.
8. The method of claim 1, wherein composition is administered
intravenously.
9. The method of claim 1, wherein said composition further
comprises at least one pharmaceutically-acceptable carrier,
diluent, or excipient.
10. The method of claim 1, wherein the composition consists of
riboflavin, arginine, alanine, glycine, serine, taurine, threonine,
valine and a pharmaceutically-acceptable carrier or diluent.
11. The method of claim 10, wherein the concentration of riboflavin
is about 5 to about 300 mg/L, the concentration of arginine is
about 2 to about 120 mg/L, the concentration of alanine is about 1
to about 90 mg/L, the concentration of glycine is about 1 to about
75 mg/L, the concentration of serine is about 1 to about 75 mg/L,
the concentration of taurine is about 0.5 to about 30 mg/L, the
concentration of threonine is about 1 to about 90 mg/L and the
concentration of valine is about 1 to about 50 mg/L.
12. The method of claim 1, wherein the composition consists of
riboflavin, ornithine, alanine, glycine, serine, taurine,
threonine, valine and a pharmaceutically-acceptable carrier or
diluent.
13. The method of claim 12, wherein the concentration of riboflavin
is about 5 to about 300 mg/L, the concentration of ornithine is
about 2 to about 120 mg/L, the concentration of alanine is about 1
to about 90 mg/L, the concentration of glycine is about 1 to about
75 mg/L, the concentration of serine is about 1 to about 75 mg/L,
the concentration of taurine is about 0.5 to about 30 mg/L, the
concentration of threonine is about 1 to about 90 mg/L and the
concentration of valine is about 1 to about 50 mg/L.
14. A pharmaceutical composition for alleviating or reducing the
toxic, nutritional and metabolic disturbances associated with
cancer and cancer chemotherapy comprising: an effective amount of
riboflavin, an effector of the urea cycle, and the amino acids
alanine, glycine, serine, taurine, threonine, and valine.
15. The pharmaceutical composition of claim 14, wherein the
effector of the urea cycle is selected from arginine, omithine or
citrulline, wherein the effector is in free form or a
pharmacologically acceptable salt.
16. The pharmaceutical composition of claim 14 wherein the amino
acids are in free form or pharmacologically acceptable salts.
17. The pharmaceutical composition of claim 14, wherein the
concentration of riboflavin is about 5 to about 300 mg/L.
18. The pharmaceutical composition of claim 14, wherein the
concentration of the effector of the urea cycle is about 2 to about
120 mg/L.
19. The pharmaceutical composition of claim 14, wherein the
concentration of alanine is about 1 to about 90 mg/L, the
concentration of glycine is about 1 to about 75 mg/L, the
concentration of serine is about 1 to about 75 mg/L, the
concentration of taurine is about 0.5 to about 30 mg/L, the
concentration of threonine is about 1 to about 90 mg/L and the
concentration of valine is about 1 to about 50 mg/L.
20. The pharmaceutical composition of claim 14, having a pH of
about 6.0 to about 7.0.
21. The pharmaceutical composition of claim 14, further comprising
at least one pharmaceutically-acceptable carrier, diluent, or
excipient.
22. The pharmaceutical composition of claim 14, consisting of
riboflavin, arginine, alanine, glycine, serine, taurine, threonine,
valine and a pharmaceutically-acceptable carrier or diluent.
23. The pharmaceutical composition of claim 22, wherein the
concentration of riboflavin is about 5 to about 300 mg/L, the
concentration of arginine is about 2 to about 120 mg/L, the
concentration of alanine is about 1 to about 90 mg/L, the
concentration of glycine is about 1 to about 75 mg/L, the
concentration of serine is about 1 to about 75 mg/L, the
concentration of taurine is about 0.5 to about 30 mg/L, the
concentration of threonine is about 1 to about 90 mg/L and the
concentration of valine is about 1 to about 50 mg/L.
24. The pharmaceutical composition of claim 14, consisting of
riboflavin, ornithine, alanine, glycine, serine, taurine,
threonine, valine and a pharmaceutically-acceptable carrier or
diluent.
25. The pharmaceutical composition of claim 24, wherein the
concentration of riboflavin is about 5 to about 300 mg/L, the
concentration of omithine is about 2 to about 120 mg/L, the
concentration of alanine is about 1 to about 90 mg/L, the
concentration of glycine is about 1 to about 75 mg/L, the
concentration of serine is about 1 to about 75 mg/L, the
concentration of taurine is about 0.5 to about 30 mg/L, the
concentration of threonine is about 1 to about 90 mg/L and the
concentration of valine is about 1 to about 50 mg/L.
26. A method for alleviating or reducing the toxic, nutritional and
metabolic disturbances associated with cancer and cancer
chemotherapy comprising: administering to a patient a composition
comprising an effective amount of riboflavin, an effector of the
urea cycle comprising arginine and omithine, and the amino acids
alanine, glycine, serine, threonine and valine.
27. The method of claim 26, wherein the composition further
comprises 3-phenylacetylamino-2,6-piperidinedione.
28. The method of claim 26, wherein the composition consists of
0.01-10 wt % riboflavin, 1-15 wt % arginine, and 1-15 wt %
ornithine, 1-15 wt % alanine, 1-15 wt % glycine, 1-15 wt serine,
1-15 wt % threonine 1-15 wt % valine, and 25-75 wt %
3-phenylacetylamino-2,6-piperidinedione.
29. A pharmaceutical composition for alleviating or reducing the
toxic, nutritional and metabolic disturbances associated with
cancer and cancer chemotherapy comprising: an effective amount of
riboflavin, an effector of the urea cycle comprising arginine and
omithine, and the amino acids alanine, glycine, serine, threonine
and valine.
30. The pharmaceutical composition of claim 29, further comprising
3-phenylacetylamino-2,6-piperidinedione.
31. The pharmaceutical composition of claim 29, consisting of
0.01-10 % riboflavin, 1-15 % arginine, and 1-15 wt % ornithine,
1-15 wt % alanine, 1-15 wt % glycine, 1-15 wt % serine, 1-15 wt %
threonine 1-15 wt % valine, and 25-75 wt %
3-phenylacetylamino-2,6-piperidinedione.
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to the fields of
pharmaceutical chemistry and formulation. More particularly, it
concerns the use of an effective amount of riboflavin and amino
acids, in any combination, in the alleviation of the nutritional,
metabolic and toxic symptoms of cancer and cancer chemotherapy in
diagnosed cancer patients.
DESCRIPTION OF RELATED ART
[0002] In spite of the progress which has been made over the years
in the areas of cytotoxic chemotherapy, immunotherapy, and
radiation therapy in the treatment of patients with a variety of
malignant and nonmalignant disorders, most of the commonly used
antineoplastic drugs produce immediate toxicities in the organs
composed of self-renewing cell populations such as the
gastrointestinal tract epithelium. As a result, many patients
suffer such toxic effects as pancytopenia, alopecia, nausea and
vomiting, as well as a variety of other physical distresses. In
fact, it has been shown in numerous studies (Vachon, M. L. S. et
al., J. Pain Symptom Management, 10, 142-150 (1995); Coyle, N. et
al., J. Pain Symptom Management, 5, 83-93 (1990)) that outside of
pain, the most common symptoms reported by patients diagnosed with
cancer and/or undergoing chemotherapy treatment for cancer are
fatigue, weakness, and appetite disturbances, the latter of which
directly contributes to the other symptoms.
[0003] Moreover, these symptoms are so common that they are
frequently neglected by the physicians, and patients may be told
that there is nothing that can be done to remedy these
side-effects. In some patients, correction of anemia, reduced
concentrations of sodium, potassium, calcium, and glucose in the
blood, dehydration, and enhanced function of major organs may
provide a relief. Adjustment of the dosages of medications, which
may contribute to fatigue and weakness, including analgesics,
muscle relaxants, and anti-depressants may also provide temporary
relief. Pharmacological management of fatigue includes the use of
psychostimulatory agents such as methylphenidate, pemoline and
corticosteroids, as described by Brietbart, W. et
al.(Psychosomatics, 33, 352-356 (1992)) Unfortunately, in most
patients such measures are short-lasting or not effective.
[0004] When total parenteral nutrition (TPN) was introduced, it was
speculated that improvement of the patient's nutrition would treat
several emergency situations related to cancer and the side effects
of therapy, as well as reduce weakness and tiredness.
Unfortunately, this was not observed in most cancer patients
receiving TPN, and the efficacy of TPN to improve patient
nutritional status and survival remains questionable (Koretz, R. L.
J. Clinical Oncology, 2: 534-538 (1984); McGeer, A. J.; Detsky, A.
S.; O'Rourke, K. Ann. Internal Med., 110: 734-736 (1989)). A
variety of studies have been conducted since the inception of TPN,
with an array of conflicting reports. In some of them, TPN
facilitated cancer progression through supply of large quantities
of nutrients necessary for cancer growth, suggesting that the broad
use of TPN in cancer patients could be deleterious at worst or
ineffective at best. While it has been clearly shown that exogenous
substrates have a distinct effect on both host and cancer
metabolism, the characteristics of the substrates, such as caloric
intake and the kind of amino acids used appear to be crucial for a
selective response. As a result, fatigue and weakness are currently
not indicators for the use of TPN in cancer patients.
[0005] In spite of such seemingly conflicting reports, several
amino acids have indicated promise as nutritional supplements in
the treatment of a variety of disorders, including cancer. Key
amongst these are arginine, glycine, ornithine and taurine. The
amino acid arginine has properties which suggest that it may be of
value both nutritionally and immunologically when administered as a
dietary supplement. In fact, research has shown that a retardation
in tumor growth, tumor regression, decreased tumor incidence, or a
combination of all three can be affected by the administration of
dietary arginine. Additionally, mixtures which contain arginine as
well as a variety of other amino acids, sugars, vitamins, and
nucleobases have exhibited potentially cytotoxic effects against
several cancer cell lines. The non-essential amino-acid glycine has
been shown to inhibit hepatocyte proliferation, and may have
general anticancer properties as a dietary supplement.
[0006] In addition to amino acids, a variety of vitamins and their
analogs have been tested for potential cancer therapeutic effects
as part of TPN regimens, but for the most part the results have
been inadequate to confirm or deny the benefits, and the evidence
relating to cancer is weak or conflicting. However, several
vitamins, most notably Vitamins A, B, C, and D have shown
preliminary promise for use in cancer therapy.
[0007] There accordingly exists a need for a process to alleviate
the side effects of cytotoxicity associated with cancer and cancer
chemotherapy, specifically a decrease of fatigue and weakness, an
increase of energy, and the reduction of toxicity of chemotherapy
regimens. Simultaneously, improving the nutritional status of
cancer patients unlikely to have a curative response to existing
therapeutic regimens has potential for decreasing the size of the
tumors within the patient.
SUMMARY OF THE INVENTION
[0008] The present invention provides a method for the treatment or
alleviation of cancer chemotherapy toxicity, involving
administering to a patient a pharmaceutical composition comprising
therapeutically-effective amounts of riboflavin, a component of the
urea cycle, and effective amounts of the amino acids alanine,
glycine, serine, taurine, threonine, and valine.
[0009] It is thus an object of the invention to provide a method
for treatment of fatigue and weakness by administering to a subject
a composition comprising riboflavin, an effector of the urea cycle,
and one or more amino acids.
[0010] A further aspect of the present invention is to provide a
pharmaceutically acceptable agent for the alleviation of the
symptoms of fatigue and weakness associated with cancer and cancer
cytotoxicity, comprising a therapeutically effective amount of
riboflavin, an effector of the urea cycle, and one or more amino
acids selected from a group of essential and non-essential amino
acids, wherein the latter two constituents are in free form or
pharmacologically acceptable salts. A preferred composition
consists of the six amino acids, alanine, glycine, serine, taurine,
threonine, and valine; an effector of the urea cycle selected from
L-arginine, L-omithine, and L-citrulline; riboflavin; and a
pharmaceutically acceptable diluent.
[0011] These and other objects will be more readily understood upon
consideration of the following detailed descriptions of embodiments
of the invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0012] The invention is described below in terms of the preferred
embodiments known at the time of filing of this application. These
embodiments represent the best mode presently contemplated by the
inventor for preparing the pharmaceutical compositions and their
method of use.
[0013]
[0014] A. Preparation of Pharmaceutical Compositions
[0015] Riboflavin, used within the present invention, can be
obtained from a commercial source (e.g., Spectrum Laboratory
Products, Inc., Gardena, Calif.) or can be prepared synthetically
by any known technique in the art, e.g. by condensation of a
ribitylxylidine azo derivative with barbituric acid (Yoneda, F. et
al., J. Chem. Soc., Perkin Trans. I, 348 (1978); U.S. Pat. No.
2,807,611). For pharmaceutical use, riboflavin is preferably
obtained from a fermentation process of any number of bacteria, or
through a combination of synthetic and biotechnology techniques
described in the art (U.S. Pat. No. 6,150,364; U.S. Pat. No.
5,589,355).
[0016] Similarly, the amino acids used within the present invention
can be obtained from a commercial source (e.g., Kyowa Hakko Kogyo
Co., LTD., Tokyo, Japan), by fermentation methods, or can be
prepared synthetically using any number of techniques in the art,
e.g. through the displacement reactions on .alpha.-halo acids. For
pharmaceutical use, the amino acids are preferably prepared
synthetically. The amino acids used within the present invention
are all of the L-(levorotatory), stereochemical series and are all
proteinogenic .alpha.-amino acids except for glycine, which does
not have optic isomers and taurine, which is an .beta.-amino acid
and does not have optic iosomers.
[0017] The compounds of the present invention can also exist in
different stereoisomeric forms by virtue of the presence of one or
more asymmetric centers in the compound. The present invention
contemplates L- stereoisomeric forms of the compounds, as well as
mixtures thereof, including racemic mixtures. Individual
stereoisomers may be obtained commercially, or by methods known in
the art, such as the separation of stereoisomers in chiral
chromatographic columns.
[0018] Further, the compounds of the present invention can exist in
unsolvated as well as solvated forms with
pharmaceutically-acceptable solvents such as water, ethanol, and
the like. In general, solvated forms of the compounds are
considered to be equivalent to the unsolvated forms for the
purposes of the present invention.
[0019] The use of the term "pharmaceutically-acceptable salts"
means salts which have the biological activity of the parent
compound while lacking any toxic activity at the selected
administration level. Determination of whether a salt is
pharmaceutically-acceptable salt can be determined readily by
methods known to those of skill in the art. Pharmaceutically
acceptable salts include, but are not limited to, organic
diethanolamine, cyclohexylamine and amino acid salts, and inorganic
sodium, potassium, and ammonium salts.
[0020] The term "amino acid of the invention", as used hereinafter,
is meant to refer to glycine, alanine, serine, valine, threonine
and/or taurine, in free amino acid form and/or pharmacologically
acceptable salt form.
[0021] As used herein, the term "urea cycle effector" includes any
of the amino acids comprising the urea cycle wherein such a cycle
serves as a metabolic pathway for disposing of cellular breakdown
products containing nitrogen. Such effectors are selected from the
group comprising arginine, omithine, and citrulline.
[0022] As used herein, the term "patient" refers to human
patients.
[0023] The term "unit dosage form", or alternatively "unit dosage
levels" as used herein refers to physically discrete units suitable
as unitary dosages for human subjects, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical diluent, carrier, or vehicle. The specifications for
the novel unit dosage forms of this invention are dictated by and
are directly dependent upon (a) the unique characteristics of the
active material and the particular therapeutic effect to be
achieved, and (b) the limitation inherent in the art of compounding
such an active material for therapeutic use in humans, as disclosed
in this specification, these being features of the present
invention. Examples of suitable unit dosage forms in accordance
with this invention are tablets, capsules, troches, powder packets,
wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls,
ampules, vials, I.V. bags, segregated multiples of any of the
foregoing, and other forms as described herein.
[0024] The present invention therefore provides the use of the
amino acid(s) of the invention, namely alanine, glycine, serine,
taurine, threonine and valine, in combination with riboflavin and
an effector of the urea cycle in minimizing the effects of fatigue
and weakness in cancer patients resulting from cancer and cancer
chemotherapy toxicity; compositions containing the amino acids of
the invention in combination with riboflavin and an effector of the
urea cycle; the use of the composition of the invention in the
manufacture of compositions for minimizing and alleviating the
effects of fatigue and weakness in cancer patients resulting from
cancer and cancer chemotherapy toxicity; and a method of minimizing
and alleviating the effects of fatigue and weakness in cancer
patients resulting from cancer and cancer chemotherapy
cytotoxicity. Typical compositions contain the selected effector of
urea cycle (L-arginine, L-ornithine or L-citrulline) in an amount
from about 50 to about 3000 times the molar concentration of
riboflavin. Further, each of the amino acids is generally provided
in a molar amount from about 0.1 to about 3.0 of the selected
effector of the urea cycle.
[0025] One embodiment of the present invention (AVA) is
particularly well suited for patients who have normal kidney
function. An alternative embodiment of the present invention (AVB)
is particularly well suited for those patients who have kidney
insufficiency or urological abnormalities. These formulations were
initially used for patients who require additional parenteral
nutrition. It was observed that even after a few days of
administration, many patients had experienced an increased energy
level and a decrease in fatigue and weakness. The patients were
also able to tolerate standard cytotoxic chemotherapy without
significant side effects. Since this time, both formulations AVA
and AVB have been used. Typical formulations are shown below.
1 AVA AVB Component Amount (g/L) Component Amount (g/L) L-Alanine
4.46 L-Alanine 4.46 Glycine 5.25 Glycine 5.25 L-Serine 5.25
L-Serine 5.25 Taurine 1.88 Taurine 1.88 L-Threonine 5.96
L-Threonine 5.96 L-Valine 3.51 L-Valine 3.87 L-Arginine 8.71
L-Ornithine 8.43 Riboflavin (B.sub.2) 0.05 Riboflavin (B.sub.2)
0.05
[0026] To prepare a pharmaceutical composition of solution AVA
according to the present invention, an aqueous solution of
L-arginine and riboflavin in about a 500:1 molar ratio is prepared
such that the concentration of L-arginine in solution is about 2
mg/mL to about 120 mg/mL. The solution also contains the amino
acids L-alanine, L-serine, and L-threonine in a 1:1 molar ratio
with L-arginine in a concentration of about 1 mg/mL to about 90
mg/mL; the amino acid glycine in a 1.4:1 molar ratio with
L-arginine in a concentration of about 1 mg/mL to about 75 mg/mL;
the beta-amino acid taurine in a 0.3:1 molar ratio with L-arginine
in a concentration of about 0.5 mg/mL to about 30 mg/mL; and the
amino acid L-valine in a 0.6:1 molar ratio with L-arginine in a
concentration of about 1 mg/mL to about 50 mg/mL. Preparation of
the AVA solution can be performed using any technique known to
those skilled in the art. It is to be noted that the solution is to
be made sterile, and the pH is to be adjusted to a value at or near
the physiological pH of 7.4, e.g. 6.8, using sodium hydroxide and
hydrochloric acid as needed.
[0027] To prepare a pharmaceutical composition of solution AVB
according to the present invention, an aqueous solution of
L-ornithine and riboflavin in about a 500:1 molar ratio is prepared
such that the concentration of L-ornithine in solution is about 2
mg/mL to about 120 mg/mL. The solution also contains the amino
acids L-alanine, L-serine, and L-threonine in a 1:1 molar ratio
with L-ornithine in a concentration of about 1 mg/mL to about 90
mg/mL; the amino acid glycine in a 1.4:1 molar ratio with
L-ornithine in a concentration of about 1 mg/mL to about 75 mg/mL;
the beta-amino acid taurine in a 0.3:1 molar ratio with L-ornithine
in a concentration of about 0.5 mg/mL to about 30 mg/mL; and the
amino acid L-valine in a 0.7:1 molar ratio with L-ornithine in a
concentration of about 1 mg/mL to about 50 mg/mL. Preparation of
the AVB solution can be performed using any technique known to
those skilled in the art. It is to be noted that the solution is to
be made sterile, and the pH is to be adjusted to a value at or near
the physiological pH of 7.4, e.g. 6.8, using sodium hydroxide and
hydrochloric acid as needed.
[0028] An alternative embodiment of the present invention (AVC) is
useful for the prevention of breast, lung and liver cancers as well
as for reducing the toxic effects of cytotoxic chemotherapy. A
pharmaceutical composition AVC according to the present invention
typically comprises 0.01-10 wt % riboflavin, 1-15 wt % arginine,
and 1-15 wt % ornithine, 1-15 wt % alanine, 1-15 wt % glycine, 1-15
wt % serine, 1-15 wt % threonine 1-15 wt % valine, and 25-75 wt %
3-phenylacetylamino-2,6-piperi- dinedione. A typical AVC
formulation is shown below.
2 AVC Component % Composition L-Alanine 7.0 Glycine 7.0 L-Serine
7.0 Taurine 0.00 L-Threonine 7.0 L-Valine 7.0 L-Arginine 7.6
L-Ornithine 7.0 Riboflavin (B.sub.2) 1.4
3-phenylacetylamino-2,6-piperidinedione 49.0
[0029] The sterile pharmaceutical compositions AVA, AVB and AVC
should be stored at room temperature (15-30 .degree. C.) without
refrigeration or freezing. They should be stored in such a manner
that they are protected from light until the time of usage.
[0030] The dosage administered of the present composition will be
dependent upon a combination of the identity of the neoplastic
disease; the type of host involved, including its age, health, and
weight; the type of concurrent treatment, if any; the frequency of
treatment and the therapeutic ratio.
[0031] Illustratively, typical daily dosage levels of the compounds
of the present invention will be in the range of from about 7
mg/kg/d (low end) to about 4000 mg/kg/d (high end) of host body
weight. Preferred daily doses shall generally be in the range of
1000 mg/kg/d of host body weight. Dosages will depend upon method
of administration.
[0032] The compositions of the present invention can be prepared
for administration to humans in unit dosage forms by a variety of
routes, including, but not limited to, oral, subcutaneous,
bronchial, pharyngolaryngeal, intranasal and intravenous. Preferred
method of administration of AVA and AVB is as intravenous solution.
AVC is particularly suitable for formulation as a solid for
encapsulation in gel caps.
[0033] The pharmaceutical compositions of the present invention are
preferably presented for administration to humans in unit dosage
forms known to those skilled in the art, such as tablets, capsules,
pills, granules, sterile parenteral solutions or suspensions, and
oral solutions or suspensions and the like, containing suitable
quantities of the active ingredients. Examples are given in the
following paragraphs. One or more ingredients, other than
riboflavin, an effector of the urea cycle, and selected amino
acids, may be present as diluents, carriers, or excipients in any
composition of the present invention.
[0034] For intravenous administration, the pharmaceutical
composition can be formulated as an intravenous solution of sodium
salts in water suitable for injection.
[0035] For oral administration, either solid or fluid unit dosage
forms can be prepared. Formulation can be as a tablet, capsule,
powder, spirit, or elixir, among others.
[0036] Fluid unit dosage forms for oral administration such as in
syrups, elixirs and suspensions can be prepared wherein each
teaspoonful of composition contains a predetermined amount of
active ingredients for administration. The water-soluble forms can
be dissolved in an aqueous vehicle together with sugar, flavoring
agents and preservatives to form a syrup. An elixir is prepared by
using a hydroalcoholic vehicle with suitable sweeteners together
with a flavoring agent. Suspensions can be prepared of the
insoluble forms with a suitable vehicle with the aid of a
suspending agent such as acacia, tragacanth, methylcellulose and
the like.
[0037] For parenteral administration, fluid unit dosage forms are
prepared utilizing an active ingredient and a sterile vehicle,
water being preferred. The active ingredients, depending on the
form and concentration used, can be either suspended or dissolved
in the vehicle. In preparing solutions, the water-soluble active
ingredients can be dissolved in water for injection and filter
sterilized before filling into a suitable vial or ampule and
sealing. Advantageously, adjuvants such as a local anesthetic,
preservative and buffering agents can be dissolved in the vehicle.
Parenteral suspensions are prepared in substantially the same
manner except that an active ingredient is suspended in the vehicle
instead of being dissolved and sterilization cannot be accomplished
by filtration. The active ingredient can be sterilized by exposure
to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the
composition to facilitate uniform distribution of the active
ingredient.
[0038] Powders are prepared quite simply by comminuting the active
ingredients to a suitably fine size and mixing with a similarly
comminuted dilutent. The diluent can be an edible carbohydrate
material such as lactose or starch. Advantageously, a sweetening
agent or sugar is present as well as a flavoring oil.
[0039] Capsules are produced by preparing a powder mixture as
hereinbefore described and filling into formed gelatin sheaths.
Advantageously, as an adjuvant to the filling operation, a
lubricant such as talc, magnesium stearate, calcium stearate and
the like is added to the powder mixture before the filling
operation.
[0040] Soft gelatin capsules are prepared by machine encapsulation
of a slurry of the active ingredients with an acceptable vegetable
oil, light liquid petolatum or other inert oil or triglyceride.
[0041] Tablets are made by preparing a powder mixture, granulating
or slugging, adding a lubricant and pressing into tablets. The
powder mixture is prepared by mixing an active ingredient, suitably
comminuted, with a diluent or base such as starch, lactose, kaolin,
dicalcium phosphate, and the like. The powder mixture can be
granulated by wetting with a binder such as corn syrup, gelatin
solution, methylcellulose solution or acacia mucilage and forcing
through a screen. As an alternative to granulating, the powder
mixture can be slugged, i.e. run through a tablet machine and the
resultant imperfectly formed tablets broken into pieces (slugs).
The slugs can be lubricated to prevent sticking to the
tablet-forming dies by means of the addition of stearic acid, a
stearic salt, talc or mineral oil. The lubricated mixture is then
compressed into tablets.
[0042] Advantageously, the tablet can be provided with a protective
coating consisting of a sealing coat or enteric coat of shellac, a
coating of sugar and methylcellulose and a polish coating of
carnauba wax.
[0043] For intranasal instillation, a fluid unit dosage form is
prepared using active ingredients and a suitable pharmaceutical
vehicle, preferably P.F. water, wherein a dry powder can be
formulated when insufflation is the administration of choice.
[0044] For the use as aerosols, the active ingredients can be
packaged in a pressurized aerosol container together with a gaseous
or liquified propellant, for example dichlorofluoromethane, carbon
dioxide, nitrogen, propane, and the like, with the usual adjuvants
such as cosolvents and wetting agents as necessary or
desireable.
[0045] Optionally, all compositions according to the present
invention can include other agents, such as buffering compounds,
glucose, or other sugars, preservatives, and the like suitable for
use in pharmaceutical compositions prepared for intravenous
administration, as are known in the art.
[0046] B. Method of Administration of Pharmaceutical
Compositions
[0047] A pharmaceutical composition of the present invention can be
administered via the appropriate route for its formulation as
described above. The pharmaceutical compositions of the present
invention are preferrably administered intravenously. If it is
formulated as an intravenous solution, it shall be administered
through a single-channel infusion pump and IV catheter. The
catheter will be a single-lumen Broviac, Groshong, or equivalent.
The regimen for injections will vary depending upon age and the
concentration of arginine in their plasma, as outlined below.
Methods of intravenous administration are widely known in the
art.
[0048] Regimen for Patients Older than 16 Years of Age
[0049] Day 1
[0050] Perform skin tests with 0.2 mL of the injection. If the skin
test is negative, thirty minutes after the skin test administer 10
mL of injection at 50 mL/h. Check the blood pressure and heart rate
before and after completion of the injection.
[0051] Thirty minutes later, administer 50 mL of the injection at a
rate of 100 mL/h. Check the blood pressure and heart rate at the
beginning of the injection and every 15 minutes during the course
of the injection.
[0052] If no side effects are observed after the administration of
50 mL of the injection, thirty-minutes later administer 440 mL of
the requisite injection at 250 mL/h (the remainder of the 500 mL IV
bag). Check the blood pressure and heart rate of the patient before
the injection, 15 minutes after the beginning of the injection, one
hour after beginning the injection, immediately after completion of
the injection, and 30 minutes after completion of the
injection.
[0053] Day 2
[0054] If no side effects have been noticed after the completion of
Day 1, administer 500 mL of the requisite injection at 250 mL/h.
Check the blood pressure and heart rate before the injection, every
hour during the injection, and 30 minutes after completion of the
injection.
[0055] Proceed with the administration of an additional 500 mL of
the injection at a rate of 250 mL/h, unless otherwise modified by
the treating physician. Check the blood pressure and heart rate
before the injection, every hour during the injection, and 30
minutes after completion of the injection.
[0056] Day 3 and All Following Days
[0057] If no side effects have been noticed following the
administration of 1000 mL of solution on Day 2, administer 1000 mL
of the injection at a rate of 250 mL/h. Check the blood pressure
and heart rate of the patient before the injection, after 1 hour
from the beginning of the injection, immediately following
completion of the injection, and 30 minutes after the completion of
the injection.
[0058] Regimen for Patients Between 4 and 16 Years of Age
[0059] Day 1
[0060] Perform skin tests on the patient with 0.2 mL of the
appropriate injection. If the skin test is negative, thirty minutes
after the test administer 10 mL of the injection at a rate of 50
mL/h. Check the blood pressure and heart rate both before and after
the completion of the injection.
[0061] Thirty minutes later, administer 50 mL of the appropriate
injection at a flow rate of 100 mL/h. Check the blood pressure and
heart rate of the patient at the beginning of the injection and
every 15 minutes during the course of the injection.
[0062] If no side effects were observed after the administration of
50 mL of solution, thirty minutes later administer 440 mL of the
injection at a flow rate of between 100 mL/h and 200 mL/h,
depending upon the patient's age and tolerance according to the
chart below. Check the blood pressure and heart rate before the
injection, 15 minutes after the beginning of the injection, 1 hour
after initiating the injection, immediately after completion of the
injection, and 30 minutes after completion of the injection.
3 Age of Patient (years) Flow Rate of Administration of Solution
(mL/h) 4-7 100 7-10 150 10-16 200
[0063] Day 2
[0064] If no side effects were noticed following Day 1, as
described above, administer 500 mL of the appropriate injection at
the flow rate recommended for the patient's age, as shown in the
chart above. Check the blood pressure and heart rate before the
injection, every hour during the injection, and 30 minutes
following the completion of the injection.
[0065] For patients older than 10 years of age, proceed with the
administration of an additional 500 mL of the appropriate injection
at 200 mL/h, but only if ordered by the treating physician. Check
the blood pressure and heart rate at the same interval as after the
injection of the first 500 mL.
[0066] Day 3 and Following Days
[0067] If no side effects were noticed after the administration of
500 mL of the solution on day 2, administer 500 mL or 1000 mL of
the appropriate injection, if ordered by the treating physician, at
the flow rate recommended for the patient's age. Check the blood
pressure and heart rate before the injection, after 1 hour from the
initiation of the injection, immediately after the completion of
the injection, and 30 minutes following the completion of the
injection.
[0068] The treatment regimen described above is useful in the
treatment of patients suffering from a variety of neoplastic
disease, including cancers, both of the hard tissue and soft tissue
types, as well as malignant and benign tumors. In particular,
neoplastic diseases that are advantageously susceptible to
treatment using the disclosed treatment regimen of this invention
include carcinoma of the adrenal gland, carcinoma of the bladder,
carcinoma of the breast, high grade glioma, glioblastoma
multiforme, astrocytoma including anaplastic and low grade
astrocytoma, brain stem glioma, primitive neuroectodermal tumors
including medulloblastoma and pinealoblastoma, rhabdoid tumor of
the central nervous system, oligodendroglioma, mixed glioma,
neurofibroma, schwannoma, visual pathway glioma, ependymoma, germ
cell tumors, meningioma, carcinoma of the colon and rectum,
carcinoma of the esophagus, primary and metastatic liver cancer,
carcinoma of the head and neck, adenocarcinoma of the lung, large
cell undifferentiated carcinoma of the lung, bronchio-alveolar
carcinoma of the lung, squamous cell carcinoma of the lung,
non-small cell carcinoma of the lung, non-Hodgkin's lymphomas,
chronic leukemias, mesothelioma, malignant melanoma, malignant
fibrous histiocytoma, multiple myeloma, neuroblastoma,
neuroendocrine tumros, carcinoma of the ovary, carcinoma of the
pancreas, primitive neuroectodermal tumors outside the central
nervous system, adenocarcinoma of the prostate, carcinoma of the
kidney, sarcomas, carcinoma of the small intestine, carcinoma of
the stomach, carcinoma of the uterus, carcinoma of the vulva, and
carcinoma of an unknown primary. Additionally, the described
treatment regimen is useful for alleviation of symptoms and toxic
effects associated with standard chemotherapeutic regimens, as well
as for restoring patient nutritional status. The duration of the
therapeutic regime may be for only as much time as is required in
order to alleviate the symptoms and side-effects of the cancer
chemotherapy treatment. Alternatively, the duration of the
therapeutic administration may be for any or all of the length of
time following initial cancer treatment.
[0069] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention. The following case histories illustrate successful
methods of treatment employing AVA or AVB for the treatment of
adenocarcinoma, non-Hodgkin's lymphoma, and metastatic transitional
cell carcinoma.
EXAMPLE 1
Treatment of 53-Year Old Female Diagnosed with Adenocarcinoma of
the Colon using AVA Formulation
[0070] A composition comprising a sterile solution of six amino
acids, L-arginine, and riboflavin, hereinafter referred to as AVA
was tested for its ability to alleviate the symptoms of cancer
chemotherapy and improve the nutritional status of a middle-aged
cancer patient.
[0071] A fifty-three-year old Caucasian female, diagnosed with
adenocarcinoma of the sigmoid colon was treated surgically by lower
anterior resection and anastomosis between the descending colon and
the rectum. Following recovery, she was started on a daily
intravenous administration of AVA. This was followed closely by the
initiation of a combination chemotherapy regimen involving
intravenous infusions of methotrexate and 5-fluorouracil (5-FU).
Following weekly administration of the chemotherapy cocktail for
fifty-two weeks, the chemotherapy was discontinued, and shortly
thereafter the AVA treatment was discontinued.
[0072] Following the first two weeks of chemotherapy treatment in
combination with AVA treatment, the patient reported a recovery of
her strength and did not experience the side of effects typically
associated with this treatment (tiredness, loss of appetite,
mucositis, diarrhea, and myelosuppression). Over the next year of
treatment, the patient had regained the weight lost during the year
previous to diagnosis. Follow-up evaluations involving physical
examination, blood count, biochemical profile, urinalysis,
electrolyte level tests, and appropriate CT scans indicated no
cancer recurrence.
[0073] The results of the intravenous AVA treatment in conjunction
with standard cancer chemotherapy regimens indicate that the
pharmaceutical formulations of the present invention, and
variations thereon, can act to alleviate the symptoms and improve
the nutritional status of cancer patients.
EXAMPLE 2
Treatment of 70-Year Old Female Diagnosed with Ductal
Adenocarcinoma of the Breast using AVA Formulation
[0074] A composition comprising a sterile solution of six amino
acids, L-arginine, and riboflavin, hereinafter referred to as AVA
was tested for its ability to alleviate the symptoms of cancer
chemotherapy and improve the nutritional status of an elderly
cancer patient.
[0075] A 70-year old Caucasian female, diagnosed with infiltrating
ductal adenocarcinoma, was treated surgically, then started on a
nine-cycle chemotherapy regime using a cocktail of Cytoxan
(cyclophosphamide), methotrexate, and 5-FU, followed by two months
of radiation therapy in conjunction with tamoxifen. The tamoxifen
treatment was discontinued due to side effects. Two years later,
the patient developed a cancerous nodule behind the left axilla,
confirmed by biopsy. Immediately thereafter, the patient was
started on Taxol and received twenty-one treatments, whereup CT
analysis of the chest indicated three nodules in the lungs and one
in the liver. The patient was then started on daily intravenous
infusions of AVA. Two months later, she was started on tamoxifen
hormonal treatment, which continued for fourteen months. After
discontinuation of tamoxifen, combination chemotherapy was begun
with weekly injections of methotrexate and 5-FU in combination with
Aromasin.
[0076] During the course of the current treatment, the patient
showed a gradual improvement in her condition and exhibited an
absence of fatigue and weakness and a gradual weight recovery.
Follow-up evaluations involving physical examination, blood count,
biochemical profile, urinalysis, electrolyte level tests, and CT
scans of the chest and abdomen indicated two pulmonary and one
liver lesion; the third pulmonary nodule was no longer visible. Of
the two pulmonary lesions, one of those still present was larger in
size in comparison with the baselines studies, and the second was
notably smaller, indicating a remission of two of the lesions.
[0077] The treatment with daily infusions of AVA in combination
with a battery of chemotherapeutic agents has resulted in a
decrease in the size, as well as the complete disappearance of
tumors. In addition, symptoms such as substantial cytotoxicity and
related side effects preventing utilization of a particular
therapeutic agent were alleviated and the nutritional status of the
cancer patient undergoing the extreme therapeutic regimen was
notably improved.
[0078] The patient is continuing a maintenance treatment with AVA,
phenylbutyrate sodium, methotrexate, 5-FU and Aromasin, and
continues to show improvement.
EXAMPLE 3
Treatment of 52-Year Old Female Diagnosed with Non-Hodgkin's
Lymphoma using AVA Formulation
[0079] A composition comprising a sterile solution of six amino
acids, L-arginine, and riboflavin, hereinafter referred to as AVA
was tested for its ability to alleviate the symptoms of cancer
chemotherapy and improve the nutritional status of an elderly
cancer patient.
[0080] A 52-year-old Caucasian female, diagnosed with low-grade
non-Hodgkin's lymphoma, was treated initially with CHOP
(combination of Cyclophosphamide, Doxorubicin/hydroxydoxorubicin,
and Vincristine along with the corticosteroid Prednisolone)
chemotherapy for a period of six months. CT scans indicated no
measurable disease. One year later, the low-grade non-Hodgkin's
lymphoma had returned to the patient's neck, chest, abdomen and
pelvis. Treatment was begun using daily intravenous infusions of
AVA. The AVA infusions were continued for four months, during which
time the patient reported no symptoms typical of the cytotoxicity
expected from the chemotherapeutic regimen involved. Shortly
afterwards, she began treatment involving subcutaneous injections
of Intron-A. Five months later, chemotherapy with Cytoxan was
begun, and was continued for five months. During this time,
chemotherapy using Rituxan was begun, but soon discontinued.
EXAMPLE 4
Treatment of 72-Year-Old Female Diagnosed with Transitional Cell
Carcinoma of the Bladder using AVB Formulation
[0081] A composition comprising a sterile solution of six amino
acids, L-ornithine, and riboflavin, hereinafter referred to as AVB
was tested for its ability to alleviate the symptoms of cancer
chemotherapy and improve the nutritional status of an elderly
cancer patient.
[0082] A 72-year-old Caucasian female was diagnosed with
transitional cell carcinoma, papillary and invasive, grade 3,
within the bladder wall. Due to two lymph nodes out of two being
positive for metastatic transitional cell carcinoma of the bladder,
cystectomy was not persued. The patient underwent urinary diversion
and ileal conduit to relieve voiding symptoms, but no radiation
therapy or chemotherapy regimen was initiated. Shortly thereafter,
the patient was started on intravenous infusions of AVB. One week
later, she began combination chemotherapy with methotrexate and
5-FU, the latter of which was given intravenously once a week..
[0083] Almost immediately after the start of the AVB infusions, and
during the course of the treatments, the patient reported good
appetite and energy levels and tolerated the chemotherapy very
well. After 11 months, treatment with AVB was discontinued.
Follow-up evaluation with CT scans of the chest, abdomen and pelvis
seven months after the initiation of treatment showed complete
remission of the enlarged mediastinal lymph node. The CT scan also
revealed a decrease in the size of the lymph nodes in the pelvis
and abdomen, as well as in the size of the left and right adrenal
glands.
[0084] All of the compositions disclosed and claimed herein can be
made and executed without undue experimentation in light of the
present disclosure. While the compositions and methods of this
invention have been described in terms of preferred embodiments, it
will be apparent to those of skill in the art that variations may
be applied to the compositions and in the steps or in the sequence
of steps of the method described herein without departing from the
concept, spirit and scope of the invention. More specifically, it
will be apparent that certain agents which are both chemically and
physiologically related may be substituted for the agents described
herein while the same or similar results would be achieved. All
such similar substitutes and modifications apparent to those
skilled in the art are deemed to be within the spirit, scope and
concept of the invention as defined by the appended claims.
* * * * *