U.S. patent application number 11/501949 was filed with the patent office on 2006-11-30 for methods for treatment of neuro- and nephro- disorders and therapeutic toxicities using aminothiol compounds.
This patent application is currently assigned to MedImmune Oncology, Inc.. Invention is credited to David S. Alberts, Edward H. Kaplan, Martin Stogniew.
Application Number | 20060270636 11/501949 |
Document ID | / |
Family ID | 25533362 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060270636 |
Kind Code |
A1 |
Stogniew; Martin ; et
al. |
November 30, 2006 |
Methods for treatment of neuro- and nephro- disorders and
therapeutic toxicities using aminothiol compounds
Abstract
The present invention relates to new uses of
S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate,
(amifostine) and other aminothiol compounds to treat and reverse
toxicities caused by therapeutic agents, radiation treatment or
diabetes. In particular, the invention provides a method for
treating neurotoxicity and nephrotoxicity associated with the
administration of chemotherapeutic agents.
Inventors: |
Stogniew; Martin; (Blue
Bell, PA) ; Alberts; David S.; (Tucson, AZ) ;
Kaplan; Edward H.; (Skokie, IL) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Assignee: |
MedImmune Oncology, Inc.
Arizona University
|
Family ID: |
25533362 |
Appl. No.: |
11/501949 |
Filed: |
August 9, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10137686 |
May 3, 2002 |
7105575 |
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11501949 |
Aug 9, 2006 |
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09429290 |
Oct 28, 1999 |
6586476 |
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10137686 |
May 3, 2002 |
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08987550 |
Dec 9, 1997 |
5994409 |
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09429290 |
Oct 28, 1999 |
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Current U.S.
Class: |
514/114 ;
514/665 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
13/12 20180101; A61P 25/02 20180101; A61K 31/66 20130101; A61K
31/661 20130101; A61P 31/12 20180101; A61K 31/13 20130101; A61K
31/426 20130101; A61P 21/00 20180101; A61K 31/426 20130101; A61K
45/06 20130101; A61P 17/16 20180101; A61K 31/16 20130101; A61P
35/00 20180101; A61P 25/00 20180101; A61K 31/66 20130101; A61K
31/195 20130101; A61P 39/02 20180101; A61K 31/13 20130101; A61K
31/16 20130101; A61P 29/00 20180101; A61P 17/14 20180101; A61K
31/135 20130101; A61P 43/00 20180101; A61P 31/04 20180101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/195 20130101; A61K 2300/00 20130101; A61P 27/16
20180101; A61P 1/02 20180101; A61K 31/145 20130101; A61K 31/145
20130101; A61P 11/00 20180101; A61K 31/135 20130101; A61P 19/02
20180101; A61P 15/08 20180101 |
Class at
Publication: |
514/114 ;
514/665 |
International
Class: |
A61K 31/66 20060101
A61K031/66; A61K 31/13 20060101 A61K031/13 |
Claims
1. A method for treating toxicities associated with the
administration of a therapeutic agent to a mammal which comprises
administering a therapeutically effective amount of one or more
aminothiol compounds, or a pharmaceutically acceptable salt
thereof, to said mammal after the occurrence of one or more of said
toxicities.
2. The method of claim 1 wherein said aminothiol compound is a
compound of the formula:
R.sub.1NH(CH.sub.2).sub.nNH(CH.sub.2).sub.mSR.sub.2 (I) or a
pharmaceutically acceptable addition salt or hydrate thereof,
wherein R.sub.1 is hydrogen, C.sub.5-C.sub.7 aryl, C.sub.2-C.sub.7
acyl, or C.sub.1-C.sub.7 alkyl; R.sub.2 is hydrogen,
PO.sub.3H.sub.2 or R.sub.3 wherein R.sub.3 is
R.sub.1NH(CH.sub.2).sub.nNH(CH.sub.2).sub.mS--; n is an integer
from 1 to 10; and m is an integer from 1 to 10.
3. The method of claim 2 wherein said compound is selected from the
group consisting of WR-1065, WR-151326, WR-151327, WR-638, WR-3689,
WR-2822, WR-2529, WR-77913, WR-255591, WR-2823, WR-255709 and salts
and hydrates thereof; and mixtures thereof.
4. The method of claim 1 wherein said aminothiol is amifostine.
5. The method of claim 1 wherein said aminothiol is WR-33278.
6. The method of claim 1 wherein said aminothiol is an active
metabolite of WR-2721.
7. The method of claim 1 wherein said aminothiol is a prodrug of a
active metabolite of WR-2721.
8. The method of claim 1 wherein said toxicity is selected from the
group consisting of neurotoxicity, nephrotoxicity, ototoxicity,
cardiotoxicity, alopecia, mucositis, xerostomia, infertility,
pulmonary toxicity and renal failure.
9. The method of claim 1 wherein said aminothiol is administered
one or more days after the occurrence of said toxicity.
10. The method of claim 1 wherein two or more aminothiol compounds
are administered.
11. The method of claim 1 wherein said therapeutically effective
amount administered is from about 10 mg/m.sup.2 to about 2,000
mg/m.sup.2.
12. The method of claim 1 wherein said mammal is a human.
13. The method of claim 12 wherein said human is a cancer patient,
an AIDS patient, a diabetic, or hypertensive patient.
14. The method of claim 1 wherein said therapeutic agent is an
antiviral, an antibiotic, an antifungal, a contrast agent or a
antineoplastic agent.
15. The method of claim 14 wherein said antibiotic is an
aminoglycoside.
16. The method of claim 14 wherein said antiviral agent is
3'-azido-3'-deoxythymidine (AZT), d4T (stavadine), ddI
(didanosine), ddC (zalcitabine), 3TC (lamivudine), or a combination
thereof.
17. The method of claim 14 wherein said antibiotic is gentamicin,
tobramicin, kanamicin, amikacin, vaucamicin, or a combination
thereof.
18. The method of claim 14 wherein said antineoplastic agent is
cisplatin, carboplatin, paclitaxel, docetaxel, vinblastine,
vincristine, navelbine, gemcytobin, etoposide, doxorubicin,
daunorubicin or a combination thereof.
19. The method of claim 14 wherein said antifungal is amphotericin
B.
20-33. (canceled)
34. A method for treating a neuro-disorder in a human which
comprises administering a therapeutically effective amount of one
or more aminothiol compounds, or a pharmaceutically acceptable salt
thereof, to a human in need of such treatment after the occurrence
of said neuro-disorder, wherein said aminothiol compound is a
compound of the formula:
R.sub.1NH(CH.sub.2).sub.nNH(CH.sub.2).sub.mSR.sub.2 or a
pharmaceutically acceptable addition salt or hydrate thereof,
wherein R.sub.1 is hydrogen, C.sub.5-C.sub.7 acyl, or
C.sub.2-C.sub.7 acyl, or C.sub.1-C.sub.7 alkyl; R.sub.2 is
PO.sub.3H.sub.2 or R.sub.3 wherein R.sub.3 is
R.sub.1NH(CH.sub.2).sub.nNH(CH.sub.2).sub.mS--; n is an integer
from 1 to 10; and m is an integer from 1 to 10.
35. The method of claim 34, wherein said neuro-disorder is
chemically induced, drug induced, induced by aging, induced by
exposure to radiation, induced by diabetes or induced by an unknown
etiology.
36. The method of claim 35 wherein said neuro-disorder is induced
by diabetes.
37. The method of claim 34, wherein said neuro-disorder is a
neurotoxicity or nephrotoxicity associated with the administration
of radiation therapy of one or more therapeutic agent(s).
38. The method of claim 34 wherein said neuro-disorder is a
peripheral neuropathy, autonomic neuropathy, central neuropathy,
muscle weakness, arthralgia or myalgia.
39. (canceled)
40. The method of claim 37 wherein said therapeutic agent is an
antiviral, an antibiotic, an antifungal, an antineoplastic agent, a
contrast agent or a combination thereof.
41. The method of claim 34 wherein said neuro-disorder is a result
of the administration of cisplatin, carboplatin, pactitaxel,
docetaxel, vincristine, navelbine, gemcytobin, etoposide,
doxorubicin, daunorubicin or a combination thereof.
42. The method of claim 34 wherein said neuro-disorder is a result
of the administration of 3'-azido-3'-deoxythymidine (AZT), d4T
(stavadine), ddI (didanosine), ddC (zalcitabine), 3TC (lamivudine),
gentamicin, tobramicin, kanamicin, amikacin, vancamicin,
amphotericin B or a combination thereof.
43. The method of claim 1 wherein said aminothiol compound is
administered intravenously, subcutaneously, intramuscularly,
intradermally, topically or orally.
44. The method of claim 34 wherein said human is a cancer patient,
AIDS patient, diabetic, or hypertensive patient.
45. A method of treating the clinical symptoms and disorders
associated with Type I or Type II diabetes in a human which
comprises administering to a diabetic human a therapeutically
effective amount of one or more aminothiol compounds or a salt,
hydrate or metabolite thereof.
46. The method of claim 45 wherein said symptom or disorder is a
neurotoxicity.
47. The method of claim 34, wherein said aminothiol compound is
administered intravenously, subcutaneously, intramuscularly,
intradermally, topically or orally.
48. The method of claim 45, wherein said aminothiol compound is
administered intravenously, subcutaneously, intramuscularly,
intradermally, topically or orally.
Description
1. FIELD OF THE INVENTION
[0001] The present invention relates to new uses for
S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate, also
known as amifostine, its salts, hydrates, esters, metabolites,
functional derivatives, functional analogues, and related
aminothiol compounds, to treat and reverse certain toxicities,
including toxicities caused by drugs and/or radiation therapy, and
to treat certain disorders, particularly neuro- and
nephro-disorders.
2. BACKGROUND OF THE INVENTION
[0002] 2.1. Aminothiol Compounds
[0003] The compound S-2-(3-aminopropylamino)ethyl dihydrogen
phosphorothioate (which is also known as amifostine, ethiofos,
Ethyol.RTM., NSC 296961, and WR-2721 and which will hereinafter be
referred to as "amifostine") and other aminothiol compounds are
disclosed in U.S. Pat. No. 3,892,824 to Piper et al. These
compounds were originally developed as antiradiation agents
(radio-protectants), in particular to be used prior to exposure to
x-ray or nuclear radiation, to protect against the harmful effects
of such exposure which may be encountered during military
conflicts.
[0004] In addition to its utility as a military antiradiation
agent, amifostine has demonstrated excellent utility as a
non-military radioprotectant and chemoprotectant, i.e., as a
protectant administered prior to therapy to reduce the undesirable
adverse effects which arise during the use of chemotherapy and
radiation therapy in the treatment of cancer. Nygaard et al., eds.,
1983, Radioprotectors and Anticarcinogens, Academic Press, Inc.,
New York, pp. 73-85; Grdina et al., 1985, "Radioprotector WR-1065
Reduces Radiation-Induced Mutations of the HGPRT Locus in V79
Cells," Carcinogenesis (London) 6:929-931. In addition, these
compounds have been reported to afford protection against the
adverse effects of chemotherapeutic agents, for example, alkylating
agents such as cisplatin and carboplatin, when administered before
or concurrently with the chemotherapeutic agent. Jordan et al.,
1982, "Modulation of cis-platinum renal toxicity by the
Radioprotective agent WR-2721", Exp. Mol. Pathol. 36:297; Doz et
al., 1991, "Experimental Basis for Increasing the Therapeutic Index
of Carboplatin in Brain Tumor Therapy by Pretreatment With
WR-Compounds", Cancer Chemother. Pharmacol. 28:308. Similarly, it
has been reported that amifostine has been used experimentally
prior to therapy to protect HIV-infected patients (AIDS) from the
harmful side effects of 3'-azido-3'-deoxythymidine (AZT) therapy.
International Published Application WO 90/14007, published Nov. 29,
1990. Amifostine and its derivatives have been shown to exert these
reported protective effects without affecting the beneficial
properties of the administered therapeutic agents. This is, in the
case of chemotherapy, believed to be due to the selective uptake of
the protective thiol and other metabolites into normal tissue.
Yuhas, 1980, "Active versus Passive Absorption Kinetics as the
basis for Selective Protection of Normal Tissues by WR-2721",
Cancer Res. 40:1519-1524; Yuhas, 1979, "Differential Protection of
Normal and Malignant Tissues Against the Cytotoxic Effects of
Mechlorethamine" Cancer Treat. Rep. 63:971-976.
[0005] Amifostine and related aminothiol compounds have also been
shown to stimulate bone marrow growth. See U.S. patent application
Ser. No. 08/390,713; International Published Application WO
96/25045 published Aug. 22, 1996; List et al., "Amifostine
Stimulated Formation of Multipotent Progenitor and Generated
Macroscopic Colonies in Normal and Myelodysplastic Bone Marrow,"
Proc. Am. Soc. Clin. Oncol. 15:449 [1403] [Abstract]. Currently,
amifostine is in Phase II clinical trials as a bone marrow
stimulant in patients suffering from myelodysplastic syndrome. List
et al., 1996, "Amifostine Promotes Multilineage Hematopoiesis in
Patients with Myelodysplastic Syndrome (MDS): Results of a Phase
I/II Clinical Trial," Am. J. Hem. 1 (Abstract); List et al., 1996,
"Amifostine Promotes in vitro and in vivo Hematopoiesis in
Myelodysplastic Syndromes," Chem. Found Svmypos. (Abstract); List
et al., 1996, "Amifostine Promotes Multilineage Hematopoiesis in
Patients with Myelodysplastic Syndrome (MDS): Results of a Phase
I/II Clinical Trial," Abstract, 8th Annual Meeting, American
Society of Hematology, Orlando, Fla. Pre-exposure with aminothiol
compounds is capable of causing the bone marrow function to more
rapidly recover following chemotherapy. List et al., 1996,
"Amifostine Protects Primitive Hematopoietic Progenitors Against
Chemotherapy Cytotoxicity," Semin. Oncol. 23 (4) Supp. 8:58-63.
[0006] Presently, amifostine is indicated to reduce the cumulative
renal toxicity associated with repeated administration of cisplatin
in patients with advanced ovarian or non-small cell lung cancer.
Physicians' Desk Reference, 51st ed. 1997, p. 485-486. The
recommended starting dosage for adults in an FDA-approved
indication is 910 mg/m.sup.2 administered once daily as a 15-minute
intravenous (i.v.) infusion, starting 30 minutes prior to
chemotherapy. However, clinical trials have used doses as low as
100 mg.
[0007] U.S. Pat. Nos. 5,567,686 and 5,488,042, both to Grdina,
allege that the administration of an aminothiol compound before
irradiation of a mammal affords protection against genotoxic
mutagenesis. Although the U.S. Pat. No. 5,488,042 patent discloses
administering an aminothiol up to about three hours after
irradiation, both patents focus solely on prevention of mutations,
rather than the treatment or reversal of radiation- or
chemotherapy-induced damage. Further, the Grdina patents are silent
as to the use of any aminothiol compound in humans to treat
chemotherapy- or radiation-induced disorders and toxicities
including neuro-, nephro-, hematological or mucosal disorders.
[0008] Nagy et al., 1986, "Protection Against
cis-Diamminedichloroplatinum Cytotoxicity and Mutagenicity in V79
Cells by 2-[(Aminopropyl)amino]ethanthiol," Cancer Research
46:1132-1135, disclose that the free thiol metabolite of
amifostine, also known as WR-1065, protects against cytotoxicity in
V79-B310H Chinese hamster cells when administered before, during
and immediately after treatment of the cells with
cis-diamminedichloroplatinum (cis-DDP, "cisplatin"). Although some
protection against cell death was observed under all conditions,
Nagy et al. report that maximum protection was obtained when
WR-1065 was present in the cell growth medium for 30 minutes prior
to exposure of cells to cisplatin. In addition, Nagy et al. state
that little if any difference in the magnitude of protection
against cell killing was seen whether the WR-1065 was present
either during or immediately following cisplatin exposure.
[0009] Treskes et al., 1992, "Effects of the Modulating Agent
WR-2721 and its Main Metabolites on the Formation and Stability of
Cisplatin-DNA Adducts in Vitro in Comparison to the Effects of
Thiosulphate and Diethyldithiocarbonate," Biochemical Pharmacology
43(5):1013-1019 investigated the ability of amifostine and its main
metabolites, WR-1065 and WR-33278, to prevent formation of adducts
of cisplatin with the DNA of salmon sperm. They found that
amifostine, WR-1065 and WR-33278 caused a decrease in the
platination of salmon sperm in vitro when the compounds were
present concomitantly with cisplatin. It was also observed that
part of the already formed cisplatin-DNA adducts is disrupted
during post-incubation with subject compounds, but this decrease in
adduct levels was small compared to those obtained during
co-incubations. Treskes et al. speculated that conformational
changes in DNA induced by the WR-1065 metabolite of amifostine
observed by other researchers might provide a rational for applying
amifostine after cisplatin administration.
[0010] However, Treskes et al. later reported in 1993, "WR2721 as a
Modulator of Cisplatin- and Carboplatin-induced Side Effects in
Comparison with Other Chemoprotective Agents: A Molecular
Approach," Cancer Chemother. Pharmacol. 33:93-106, that neither
WR-1065 nor WR-2721 (amifostine) could protect cells from the
cytostatic effect of cisplatin when the compounds were incubated
with cells one hour after cisplatin exposure. Further, it was found
that amifostine given 30 minutes after cisplatin did not protect
mice at all from nephrotoxicity. Treskes et al. concluded that the
selective protection of multiple non-tumor tissue by WR-1065 from
cisplatin-induced toxicity is explained by a strong prevention, not
reversal, of cisplatin-induced cellular damage. Treskes et al.
further observed that these findings were in agreement with the
hypothesis that the prevention of damage is the main mechanism of
protection and that reversal of platinum-induced damage is not an
important mechanism of protection.
[0011] Nephrotoxicity, produced by drugs such as cisplatin, has
important consequences for the patient, with potential permanent
loss of 50% or more of normal renal function (Kemp, et al. J. Clin.
Oncology, 14:2101-2112, July, 1996). This can produce serious
disability, requiring the need for dialysis in severe cases, and
early mortality. It also has important consequences for the ability
of the patient to be safely treated with other forms of
life-sustaining chemotherapy and other medications such as
antibiotics that are themselves renally toxic or require adequate
renal function for elimination from the body.
[0012] Neurotoxicity may significantly decrease a patient's quality
of life because of loss or distortion of sensation in the fingers,
toes, hands and feet, as well as loss of fine muscle movements,
resulting in the inability to perform routine functions such as
buttoning of clothes. In more severe cases, patients suffer loss of
sufficient motor function so that they require walkers or
wheelchairs.
[0013] 2.2. Cisplatin- and Paclitaxel-Induced Toxicities
[0014] Cisplatin continues to be an agent of choice for the
treatment of advanced ovarian cancer, testicular cancer, bladder
cancer and head, neck and lung cancers. McGuire et al., 1996,
"Cyclophosphamide and cisplatin compared with Paclitaxel and
cisplatin in patients with stage III and stage IV ovarian cancer,"
N. Engl. J. Med. 334:1-6. However, the cytotoxic effects of
cisplatin on normal tissue, including the kidneys, can result in
long-term debilitating effects which may limit the ability to
deliver therapeutic doses against the cancer. Despite aggressive
hydration and administration of mannitol, cisplatin-induced
nephrotoxicity remains a significant cause of morbidity and
mortality. Finley et al., 1985, "Cisplatin nephrotoxicity: A
Summary of Preventative Interventions," Drug Intell. Clin. Pharm.
19:362-367; Kemp et al., 1996, "Amifostine Pretreatment of
Protection Against Cyclophosamide-induced and cisplatin-induced
toxicities: results of a randomized control trial in patients with
advanced ovarian cancer," J. Clin. Oncol. 14:2101-2112; Stewart et
al., "Association of Cisplatin Nephrotoxicity with patient
Characteristics and Cisplatin Administration Methods," Cancer
Chemother. Pharmacol. 40:293-308.
[0015] Even when protective agents are administered prior to or
during cisplatin treatment, toxicities may still be observed. The
cumulative cisplatin nephro-toxicity that occurs can be
treatment-limiting, precluding further administration of cisplatin
and the ability to administer effective doses of renally-excreted
second-line chemotherapy Kemp et al., 1996, J. Clin. Oncol.
14:2101-2112. In addition, drug therapy for other conditions can be
affected, either because the agents are renally excreted, or
because of their intrinsic potential to worsen renal function.
Nephrotoxicity is also associated with other platinum coordination
complexes such as carboplatin which are also used to treat
cancers.
[0016] The nephrotoxicity associated with cisplatin is cumulative,
i.e., incremental damage occurs with repeated courses of therapy.
Daugaard et al., 1989, "Cisplatin nephrotoxicity," Cancer
Chemother. Pharmacol. 21: 1; du Bois, et al., 1994, "Cisplatin and
carboplatin induced acute, cumulative and chronic nephrotoxicity,"
Proc. Annu. Meet. Am. Assoc. Cancer Res. 35: A1475. Loss of renal
function occurring secondary to cisplatin is typically permanent.
Macleod et al., 1988, "The effect of cisplatin on renal function in
patients with testicular tumors," Clin. Radiol. 39: 190-192; Aass
et al., 1990, "Renal function related to different treatment
modalities for malignant germ cell tumors," Br. J. Cancer
62:842-846; Meijer, et al., 1983, "Influence of combination
chemotherapy with cisdiammine chloroplatinum on renal function:
Long term effects," Oncology 40:170-173. Risk factors for
development of this toxic effect include age, a history of renal
irradiation, dehydration, and alcoholism. Anand et al., 1993,
"Newer insights into cisplatin nephrotoxicity," Ann. Pharmacother.
27:1519-1525.
[0017] Nephrotoxicity associated with administration of cisplatin
and other platinum coordination complexes is generally observed
during the second week after a dose and is manifested by elevations
in BUN and/or serum creatinine and/or a decrease in creatinine
clearance or serum magnesium. Renal toxicity becomes more prolonged
and severe with repeated courses of the drug. Nephrotoxicity may be
accentuated in patients with pre-existing risk factors such as
diabetes or hypertension as well as individuals who are receiving
other nephrotoxins such as aminoglycoside antibiotics or
antifungals such as amphoterecin. Options available to reduce
cumulative cisplatin renal toxicity are limited, and generally
involve reducing its dosage or frequency of administration, both of
which risk a potential reduction in antitumor effectiveness. Kemp
et al., 1996, J. Clin. Oncol. 14:2101-2112. Pretreatment or
simultaneous administration of amifostine is also an option, but
these treatments are not always effective.
[0018] In addition to nephrotoxicity, many other toxicities are
associated with the administration of platinum coordination
compounds. For example, ototoxicity has been observed in up to 31%
of patients treated with a single dose of cisplatin (50 mg/m.sup.2)
and is manifested by tinnitus and/or hearing loss in the high
frequency range (4000-8000 Hz). Decreased ability to hear normal
conversational tones may occur occasionally. Deafness after the
initial dose of cisplatin has been reported rarely. Hearing loss
can be unilateral or bilateral and tends to become more frequent
and severe with repeated doses. In addition, myelosuppression
occurs in 25-30% of patients treated with cisplatin. The nadirs in
circulating platelets and leukocytes occur between days 18 to 23
with most patients recovering by day 39. Leukopenia and
thrombocytopenia are observed at higher doses (>50
mg/m.sup.2).
[0019] Neurotoxicity, usually characterized by peripheral
neuropathies, is also associated with administration of platinum
coordination complexes. The neuropathies, in the form of loss or
distortion of sensation, or loss of fine motor function, usually
occur after prolonged therapy (4-7 months); however, neurologic
symptoms have been reported to occur after a single dose. Although
symptoms and signs of cisplatin-induced neuropathy usually develop
during treatment, symptoms of neuropathy may begin 3 to 8 weeks
after the last dose of the platinum coordination complex.
Generally, in the event of cisplatin-induced neuropathic symptoms,
cisplatin is discontinued until the symptoms subside or disappear.
The neuropathy, however, may progress even after treatment is
stopped. Some preliminary evidence suggests that neuropathy may be
irreversible in some patients. Lhermitte's sign, dorsal column
myelopathy, autonomic neuropathy, loss of taste and seizures have
also been reported. Muscle cramps, defined as localized, painful,
involuntary skeletal muscle contractions of sudden onset and short
duration, or loss of sufficient motor function so that a patient
requires a walker or wheel chair for movement, have been reported
and are usually associated in patients receiving a relatively high
cumulative dose of cisplatin and exhibiting advanced symptomatic
stages of peripheral neuropathy. Amifostine has demonstrated the
ability to reduce the incidence of neuropathies when administered
prior to cisplatin. In a prospective evaluation of patients treated
with cisplatin regimens.+-.amifostine at the Hospital of the
University of Pennsylvania Cancer Center, patients pretreated with
amifostine had a significantly lower incidence of cisplatin
neuropathies and the onset of neuropathies occurred at a
significantly higher cumulative dose of cisplatin [Mollman J E,
Glover D J, Hogan W M, Furman R E: Cisplatin neuropathy: Risk
factors, prognosis and protection by WR-2721. Cancer 61:2192-2195,
1988]. The ability of amifostine pretreatment to significantly
reduce the occurrence and severity of cisplatin neuropathy was
confirmed in a randomized controlled trial of cisplatin and
cyclophosphamide.+-.amifostine in women with advanced ovarian
cancer [Kemp G, Rose P, Lurain J et al.: Amifostine pretreatment
for protection against cyclophosphamide and cisplatin induced
toxicities: Results of a randomized control trial in patients with
advanced ovarian cancer. J. Clin. Oncol. 14:2101-2112, 1996].
[0020] Paclitaxel is indicated, after failure of first-line or
subsequent chemotherapy, for the treatment of metastatic carcinoma
of the ovary. Paclitaxel is also indicated for the treatment of
breast cancer after failure of combination therapy for metastatic
disease or relapse within six months of adjuvant therapy.
Paclitaxel is known to have the following adverse effects:
neutropenia, leukopenia, peripheral neuropathy, and
arthralgia/myalgias and other neurological manifestations. The
results of a clinical trial of amifostine and escalating doses of
paclitaxel, indicated that pretreatment with amifostine allowed
both higher single doses and cumulative doses of paclitaxel to be
administered without the occurrence of dose limiting neuropathies
and arthralgias/myalgias [DiPaolo R et al.: Amifostine and dose
intense paclitaxel in patients with advanced malignancies. Cancer
Therapeutics, Proc. Am. Soc. Clin. Oncology Vol. 16 (Abstract 826)
235a (1997)]. These may be accentuated when the drug is combined
with other neurotoxic agents such as cisplatin. Many patients
receiving paclitaxel also experience hypotension, asymptomatic
bradycardia, and occasional episodes of silent ventricular
tachycardia.
[0021] Hence, there is a need for a chemical agent for treating
symptoms of neurotoxicity and nephrotoxicity which result from the
administration of certain therapeutic agents, particularly,
chemotherapeutics, radiation therapy, or disease states such as
diabetes.
3. SUMMARY OF THE INVENTION
[0022] The present invention relates, in part, to methods for
treating toxicities associated with the administration to a mammal
of one or more therapeutic agents, which comprise administering a
therapeutically effective amount of one or more aminothiol
compounds, or pharmaceutically acceptable salts thereof, to the
mammal after the occurrence of one more of the toxicities. It has
been unexpectedly discovered that amifostine and its salts,
metabolites, analogues and derivatives can be used to treat or
reverse neuro- and nephro-disorders that occur in humans as a
result of a variety of insults, including, but not limited to,
treatment with therapeutic agents, cancer chemotherapy and/or
radiation therapy. The present invention also relates to methods
for treatment of neuro- and nephro-disorders resulting from a
variety of metabolic disorders, including, but not limited to
diabetes. The invention further encompasses methods for the
treatment of neuro- and nephro-disorders induced by an unknown
etiology.
[0023] Thus, in one embodiment, the present invention relates to a
method for treating toxicities associated with administration of a
chemotherapeutic agent wherein amifostine, or salts, metabolites,
functional derivatives, functional analogues, esters and pro-drugs
thereof, are administered subsequent to administration of the
chemotherapeutic agent, or alternatively, at the first indication
of toxicity caused by the chemotherapeutic agent(s). The present
invention further relates to methods for treating toxicities
associated with the administration of therapeutic agents by
administering amifostine, or salts, metabolites, functional
derivatives, functional analogues, esters and pro-drugs thereof
after clinical appearance of toxicities following therapeutic
treatment. In another embodiment, the invention relates to methods
of treating toxicities associated with the exposure of a mammal to
radiation therapy, which comprise administering to the mammal a
therapeutically effective amount of one or more aminothiol
compounds, or a pharmaceutically acceptable salt thereof, after the
occurrence of the toxicity.
[0024] In particular, the present invention provides a method for
treating neurotoxicity and nephrotoxicity associated with the
administration of a chemotherapeutic agent which comprises
administering a therapeutically effective amount of amifostine or a
salt, metabolite, ester, functional derivative, functional analogue
and pro-drugs thereof, subsequent to the administration of the
chemotherapeutic agent. In a preferred embodiment, a compound of
the invention is administered one or more days after the
administration of the chemotherapeutic agent, preferably, after the
disorder has appeared and been established. Toxicities which are
treatable according to the methods of the invention include, but
are not limited to, those associated with administration of
chemotherapeutic agents including but not limited to cisplatin,
carboplatin, paclitaxel, docetaxel, vincristine, navelbine,
gemcitabine, topotecan, irinotecan, doxorubicin, and other drugs
disclosed herein. Other disorders, toxicities and toxicity-causing
agents are described herein.
[0025] In still another embodiment, the present invention relates
to methods for treating neuro- or nephro-disorders which comprise
administering a therapeutically effective amount of one or more
aminothiol compounds, or pharmaceutically acceptable salts thereof,
to a patient in need of such treatment, after the occurrence of the
neuro- and nephro-disorders. The disorder may be chemically
induced, drug induced, induced by aging, induced by exposure to
radiation or induced by a variety of metabolic disorders,
including, but not limited to diabetes. In addition, the disorder
may be a neurotoxicity or nephrotoxicity associated with the
administration of radiation therapy of one or more therapeutic
agents. The methods of the present invention are also suitable for
the treatment of disorders induced by an unknown etiology.
Neuro-disorders which are treatable according to the methods of the
invention include, but are not limited to, peripheral neuropathy,
autonomic neuropathy, central neuropathy, muscle weakness,
arthralgia or myalgia. The present invention also relates to
methods of treating the clinical symptoms and disorders associated
with Type I or Type II diabetes in a human in which a
therapeutically effective amount of one or more aminothiol
compounds or a salt, hydrate or metabolite thereof, is administered
to a diabetic human.
4. BRIEF DESCRIPTION OF THE FIGURES
[0026] FIG. 1 is a graph showing serum creatinine levels (mg/dL) of
a 61-year-old patient suffering from renal failure induced by
cisplatin given in combination with paclitaxel. The graph shows a
starting serum creatinine level of about 1.0 mg/dL before
administration of cisplatin, a maximum level of about 5.5 mg/dL
after administration of cisplatin, and a drop in serum creatinine
level to about 2.8 mg/dL following treatment with amifostine.
5. DETAILED DESCRIPTION OF THE INVENTION
[0027] There are presently a number of chemotherapeutic agents that
can be used against various cancers, including solid tumors and
leukemias. Unfortunately, these chemotherapeutics frequently cause
adverse or undesirable side effects which limit the clinician's
ability to use the drug effectively. Most significantly,
chemotherapeutics can cause-tissue damage, organ damage and the
like, which is not only painful to the patient but can also be
irreversible or lethal depending upon the patient's tolerance and
condition.
[0028] The inventors have quite surprisingly and unexpectedly found
that the administration of amifostine, and related aminothiol
compounds disclosed herein, can be used to reverse or treat the
toxicities associated with the administration of various
chemotherapeutics, particularly platinum coordination complexes
such as cisplatin and paclitaxel. More specifically, upon clinical
evidence of neuro- or nephrotoxicity commonly associated with the
administration of cisplatin or paclitaxel, amifostine or related
compounds can be used to rescue the patient thereby improving the
overall treatment/therapy.
[0029] Based in part on this discovery, the present invention
encompasses a method of treating neuro- or nephro-disorders in a
human which comprises administering a therapeutically effective
amount of amifostine, or a pharmaceutically acceptable salt, ester,
analogue, metabolite, derivative or pro-drug thereof. The neuro-
and nephro-toxicities which are treatable according to the methods
of the present invention can arise from a variety of insults
including, but not limited to cancer chemotherapy, radiation
therapy, AIDS, chemotherapy, anti-fungal therapy, anti-bacterial
therapy, and I.V. Contrast Agents. These aminothiol compounds can
also be used to treat neuro- and nephro-disorders that are induced
by aging and metabolic disorders, including, but not limited to
diabetes. The methods of the present invention are also suitable
for the treatment of neuro- and nephro-disorders induced by an
unknown etiology. The methods of the invention are effective for
the treatment of patients with and without cancer, as well as
cancer patients undergoing or who have undergone chemotherapy. It
should be recognized that the present invention also encompasses a
method of treating various cancers by the combined use of a
chemotherapeutic agent and one or more of the aminothiol rescue
agents, such as amifostine, disclosed herein. Indeed, the use of
these rescue agents allows the continued use of the
chemotherapeutic agent which would have otherwise been discontinued
or postponed due to toxicity.
[0030] In another embodiment, the present invention provides a
method for treating toxicities associated with administration of a
therapeutic agent wherein amifostine, or a related compound is
administered subsequent to administration of the therapeutic agent.
The administration of amifostine, and the compounds disclosed
herein, after the occurrence of toxicities associated with
administration of the therapeutic agent ameliorates and reverses
the signs and symptoms of these toxicities. Thus, the present
invention encompasses methods for treating toxicities associated
with chemotherapy by administering amifostine, or salts,
metabolites, functional derivatives functional analogues, esters
and pro-drugs thereof after therapeutic treatment.
[0031] The present invention further provides a method for treating
toxicities associated with the administration of a chemotherapeutic
agent which comprises administering a therapeutically effective
amount of amifostine or a metabolite, functional derivative or
analogue thereof, or pharmaceutically acceptable salts thereof
after the occurrence of one or more of said toxicities.
[0032] In particular, the present invention provides a method for
treating neurotoxicity and nephrotoxicity associated with the
administration of cisplatin or paclitaxel agent which comprises
administering a therapeutically effective amount of amifostine or a
salt, metabolite, ester, functional derivative, functional analogue
and pro-drugs thereof, subsequent to the administration of the
chemotherapeutic agent. In a preferred embodiment, the compound is
administered after the disorder has appeared and been established,
typically one or more days after administration of the
chemotherapeutic agent.
[0033] The invention also encompasses the use of the aminothiols
for the specific treatment of peripheral neuropathy, central
neuropathy, autonomic neuropathy, muscle weakness, and
myalgaia.
[0034] 5.1. Aminothiols and Related Compounds that are Useful
within the Invention
[0035] As mentioned above, the compounds that can be used within
the present invention include amifostine (WR-2721), as well as
salts, hydrates, active metabolites, pro-drugs, and functional
derivatives or analogues. More specifically, the invention includes
all pro-drugs and metabolites of amifostine and pro-drugs of the
active metabolites. Thus, compounds known to the skilled artisan to
be suitable for administration to humans and known to be
metabolites or otherwise converted into active thiols including
metabolites such as WR-1065 and WR-33278 (disulfide) and the orally
bioavailable WR-151327 and its active thiols, including metabolites
such as WR-151326 and its corresponding disulfide, are encompassed
within the present invention.
[0036] Similarly, described herein are aminothiols that exhibit
activity similar to that of amifostine or its metabolites.
Preferably, these compounds are structurally related to amifostine.
Alternatively, these compounds are pro-drugs that are metabolized
in vivo to a biologically active agent. These compounds are also
encompassed by the present invention. Specific examples are
illustrated herein.
[0037] Aminothiol compounds which can be used in the present
invention are represented by the following formula (I):
R.sub.1NH(CH.sub.2).sub.nNH(CH.sub.2).sub.mSR.sub.2 (I) wherein
R.sub.1 is hydrogen, C.sub.5-C.sub.7 aryl, C.sub.2-C.sub.7 acyl, or
C.sub.1-C.sub.7 alkyl; R.sub.2 is hydrogen, PO.sub.3H.sub.2 or
R.sub.3, wherein R.sub.3 is
R.sub.1NH(CH.sub.2).sub.nNH(CH.sub.2).sub.mS--; n and m are each an
integer from 1 to 10; and preferably an integer from 2 to 6.
[0038] The methods of the present invention also encompasses the
use of pharmaceutically acceptable salts and hydrates of the
compounds of formula (I) above.
[0039] Preferred compounds useful in the methods of the invention
are the S-.omega.(.omega.-aminoalkylamino)alkyl dihydrogen
phosphorothioate analogues represented by the formula:
R--NH--(C.sub.nH.sub.2n)--NH--(C.sub.mH.sub.2m)--S--PO.sub.3H.sub.2
wherein R is hydrogen or an alkyl group containing 1 to 7 carbon
atoms and m and n independently have a value of from 1 to 10,
preferably 2 to 6.
[0040] The chemical structure of amifostine (WR-2721) can be
depicted as follows:
H.sub.2N--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.2--S--PO.sub.3H.-
sub.2.
[0041] One preferred metabolite of amifostine is a dephosphorylated
free thiol form known as WR-1065 (chemical nomenclature:
S-2-(3-aminopropylamino)ethanethiol), which can be depicted as
follows: H.sub.2N--(CH.sub.2).sub.3--NH(CH.sub.2).sub.2--SH.
[0042] Another preferred metabolite of amifostine is its disulfide,
known as WR-33278 (chemical nomenclature:
[0043]
[2-[(aminopropyl)amino]ethanthiol]-N,N'-dithioidi-2,1-ethanediyl)b-
is-1,3-propanediamine), which can be depicted as follows:
H.sub.2N--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.2--S--S--(CH.sub.2).sub.2--
-NH--(CH.sub.2).sub.3--NH.sub.2.
[0044] A preferred analogue of amifostine is the compound
designated as WR-15327 (chemical nomenclature:
1-propanethiol-3-[[3-(methylamino)propyl]amino]-dihydrogen
phosphothiorate), which can be depicted as follows:
CH.sub.3NH(CH.sub.2).sub.3NH(CH.sub.2).sub.3SPO.sub.3H.sub.2.
Another preferred analogue of amifostine is the compound designated
WR-151326, a dephosphorylated free thiol form of WR-151327 having
the chemical structure:
CH.sub.3NH(CH.sub.2).sub.3NH(CH.sub.2).sub.3SH.
[0045] Other specific compounds suitable for use in the present
invention include, but are not limited to: [0046]
S-1-(aminoethyl)phosphorothioic acid (WR-638); [0047]
S-[2-(3-methylaminopropyl)aminoethyl]phosphorothioate acid
(WR-3689); [0048] S-2-(4-aminobutylamino)ethyl phosphorothioic acid
(WR-2822); [0049] 3-[(2-mercaptoethyl)amino]propionamide
p-toluene-sulfonate (WR-2529); [0050] S-1-(2-hydroxy-3-amino)propyl
phosphorothioic acid (WR-77913); [0051]
2-[3-(methylamino)propylamino]ethanethiol (WR-255591); [0052]
S-2-(5-aminopentylamino)ethyl phosphorothioic acid (WR-2823);
[0053] 1-[3-(3-aminopropyl)thiazolidin-2-Y1]-D-gluco-1,2,3,4,5
pentane-pentol dihydrochloride (WR-255709).
[0054] Additional aminothiols suitable for use in the present
invention include, but are not limited to,
S-2-(3-ethylaminopropylamino)ethyl dihydrogen phosphorothioate,
S-2-(3-aminopropylamino)-2-methylpropyl dihydrogen
phosphorothioate, S-2-(2-aminoethylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(4-aminobutylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(5-aminopentylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(6-aminohexylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(2-methylaminoethylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(3-methylaminopropylamino)-2-ethyl dihydrogen
phosphorothioate, and S-3-(3-methylaminopropylamino)-3-propyl
dihydrogen phosphorothioate (WR-151327) and pharmaceutically
acceptable salts thereof. Preferably, the aminothiol is amifostine,
WR-1065, WR-33278, WR-151327 or WR-151326; most preferably it is
amifostine.
[0055] Amifostine, and many of its salts, analogues and derivatives
thereof suitable for use in the methods of the invention are
commercially available, or can easily be prepared using standard
techniques. The aminothiol compounds useful in the methods of the
invention may be prepared by methods known in the art (see, e.g.,
Cortese, 1943, Organic Synthesis pp. 91-93, Coll. Vol. II, Blatt,
Ed., John Wiley & Sons, Inc., New York, N.Y.; Akerfeldt, 1960,
Acta Chem. Scand. 14:1980; Piper et al., 1966, Chem. Ind.
(London):2010). Certain aminothiol compounds, as well as methods of
synthesizing such compounds, are described in detail in U.S. Pat.
No. 3,892,824 to Piper et al., U.S. Pat. Nos. 5,424,472 and
5,591,731, both to Kennedy et al., and WO 96/25045, each of which
is incorporated herein by reference in its entirety.
[0056] The aminothiol compounds useful in the methods of the
invention may be in the form of free acids, free bases, or
pharmaceutically acceptable addition salts thereof. Such salts can
be readily prepared by treating an aminothiol compound with an
appropriate acid and/or base. Such acids include, by way of example
and not limitation, inorganic acids such as hydrohalic acids
(hydrochloric, hydrobromic, hydrofluoric, etc.), sulfuric acid,
nitric acid, phosphoric acid, etc. and organic acids such as acetic
acid, propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic
acid, 2-oxopropanoic acid, propandioic acid, butandioic acid, etc.
Conversely, the salt can be converted into the free base form by
treatment with alkali.
[0057] The aminothiol compounds useful in the methods of the
invention, as well as the pharmaceutically acceptable addition
salts thereof, may be in a hydrated, solvated or anhydrous form.
Methods of preparing such forms will be apparent to those of skill
in the art of organic chemistry.
[0058] 5.2. Definitions
[0059] As used herein the term "aminothiol" means a compound
represented by formula (I) set forth in Section 5.1 above, or any
other compound disclosed therein.
[0060] The term "rescue agent" as used herein is intended to mean a
compound capable of ameliorating, treating, reversing, reducing or
arresting the signs and symptoms and pathology associated with the
administration of chemotherapeutic agents radiation and pathology
of associated diseases.
[0061] As used herein the term "disorder" means an illness, a
sickness or a disease manifested by an interruption, cessation,
derangement or abnormality of body functions, systems or
organs.
[0062] As used herein, the term "toxicity" means a disorder
characterized by a recognized etiologic agent or agents, an
identifiable group of signs and symptoms, including adverse
effects, unwanted effects, undesired effects, or abnormal signs or
symptoms or consistent anatomical alterations.
[0063] The preferred subjects of the present invention are mammals,
including humans. The subjects include cancer patients that are
undergoing or have undergone chemotherapy, radiation treatment or
both; AIDS patients and diabetics.
[0064] The term "treating" as used herein is intended to mean the
administering to a subject the rescue agent of the present
invention, preferably amifostine or a functional analogue or
derivative thereof, for purposes which may include amelioration of
symptoms of, or reversal of toxicities associated with
chemotherapy.
[0065] As used herein the term "reversing" means that the progress
of the disease, disorder or toxicity is inhibited and its symptoms
are reversed or improved.
[0066] 5.3. Toxicities/Disorders to be Treated
[0067] The methods of the present invention comprise administration
of a pharmaceutical composition which contains an effective amount
of an aminothiol of the invention in an acceptable carrier to a
subject during or preferably after the subject has received
therapy. The aminothiol is preferably amifostine, alone or in
combination with one or more other drugs useful in the treatment of
toxicities associated with therapy. Also included within the scope
of the invention is the administration of compositions comprising a
mixture of two or more of the aminothiol compounds of the present
invention described above.
[0068] The methods of the present invention are suitable for
treating toxicities associated with a wide variety of therapeutic
agents. In addition, the methods of the invention are suitable for
treatment of a variety of neuro- and nephro-disorders resulting
from a variety of insults.
[0069] 5.3.1 Chemically- and Radiation-Induced Toxicities
[0070] In one embodiment, the methods of the invention are used to
treat toxicities associated with administration of chemotherapeutic
agents which include, but are not limited to, cisplatin,
carboplatin, paclitaxel, vinblastine, vincristine and methotrexate.
In another embodiment, the methods of the invention are used to
treat toxicities associated with radiation therapy (x-ray, nuclear
and particularly gamma radiation).
[0071] The methods of the invention may be used to treat toxicities
associated with the administration of the following
chemotherapeutic agents: taxanes such as paclitaxel and docetaxel;
alkylating agents, which include: nitrogen mustards such as
mechlorethamine, cyclophosphamide, ifosamide, melphalan
(phenalphenine mustard) and chlorambucil; ethylenimines and
methylmelamines such as altretamine, diaziquone (AZQ) and thiotepa;
alkyl sulfonates such as busulfan; nitrosoureas such as carmustine
(BCNU), lomustine (CCNU), semustine (methyl-CCNU) and streptozocin
(streptozotocin); and triazenes such as dacarbazine (DTIC;
dimethyltriazenoimidazolecarboxamide); antimetabolites, which
include folic acid analogs such as methotrexate, trimetrexate and
other dihydrofolates; pyrimidine analogs such as fluorouracil
(5-fluorouracil; 5-FU), floxuridine (fluorodeoxyuridine; FUdR) and
cytarabine (cytosine arabinoside); purine analogs and related
inhibitors such as mercaptopurine (6-mercaptopurine; 6-MP),
thioguanine (6-thioguanine; TG) and pentostatin
(2'-deoxycoformycin); natural products, which include vinca
alkaloids such as vinblastine, vincristine, navelbine and
vincristine; epipodophylotoxins such as etoposide and teniposide;
antibiotics such as dactinomycin (actinomycin D), daunorubincin
(daunomycin; rubidomycin); doxorubicin, bleomycin, plicamycin
(mithramycin) and mitomycin (mitomycin C); enzymes such as
L-asparaginase; and biological response modifiers such as
interferon-alfa and other interferons; platinum coordination
complexes such as cisplatin (cis-DDP) and carboplatin;
anthracenediones such as mitoxantrone; substituted ureas such as
hydroxyurea; methylhydrazide derivatives such as procarbazine
(N-methylhydrazine, MIH), and adrenocortical suppressants such as
mitotane (o,p'-DDD) and aminoglutethimide; hormones and antagonists
which include adrenocorticosteroids such as prednisone; progestins
such as hydroxyprogesterone caproate, medroxy progesterone acetate
and megestrol acetate; estrogens such as diethylstilbestrol and
ethinyl estradiol; antiestrogens such as tamoxifen; androgens such
as testosterone propionate and fluoxymetsterone; antiandrogens such
as flutamide; and gonadotropin-releasing hormone analogs such as
leuprolide; camptothecins such as irinotecan, topotecan;
gemciatdins such as gemcitabine; estramustine phosphate, VM-26
(vumon) and all-trans retinoic acid (ATRA). These agents are
normally used in the treatment of head and neck, ovarian, breast,
colon, lung, prostate, testicular and cervical cancers, as well as
certain lymphomas, leukemias, and cancers of the CNS.
[0072] The toxicities associated with the administration of these
agents or radiation therapy include, but are not limited to
nephrotoxicity, neurotoxicity, ototoxicity, myelosuppression,
cardiotoxicity, alopecia, infertility and local inflammation from
extravasation into the skin, xerostomia and mucositis.
[0073] The methods of the present invention are also suitable for
treating comparable toxicities associated with anti-virals such as
ddI (didanosine), ddC (zalcitabine), d4T (stavadine), 3TC
(lamivudine), AZT (zidovudine, 3'azido-3'-deoxythymidine) and the
like, anti-bacterials such as aminoglycosides, and anti-fungals,
such as amphotericin B.
[0074] 5.3.2 Nephro-Disorders to be Treated
[0075] The following nephro-disorders, which are also referred to
herein as renal diseases, may be treated according to the methods
of the present invention: Various types of glomerulonephritis,
including diffuse forms of glomerulonephritis such as acute
poststreptococcal, acute nonstreptococcal, rapidly progressive,
chronic progressive, and end-stage chronic; focal forms of
glomerulonephritis, such as those with systematic bacterial
infection, of probable immunologic origin, i.e., IgA focal
glomerulonephritis, and hereditary forms; nephrotic syndromes such
as minimal change disease, lipoid nephrosis, or nil disease, focal
segmental glomerular sclerosis, congenital nephrotic syndrome,
membranoproliferative glomerulonephritis, idiopathic membranous
nephropathy (membranous glomerulonephritis), systemic lupus
erythematosus, systemic infection or hypersensitivity reactions,
circulatory disturbances and renal vein thrombosis, amyloidosis,
and toxemia of pregnancy; renal diseases of vascular origin such as
hypertensive vascular disease, benign nephrosclerosis, malignant
nephrosclerosis, diabetic nephropathy, renal infarction,
polyarteritis nodosa and Wegener's granulomatosis; thrombotic renal
diseases such as disseminated intravascular coagulation, bilateral
renal cortical necrosis, hemolytic uremic syndrome, and thrombotic
thrombocytopenic purpura; scleroderma; radiation nephritis; tubular
diseases such as acute tubular necrosis, including toxic
nephropathy and ischemic tubular necrosis, osmotic nephrosis,
hypokalemic nephropathy, chronic interstitial and tubular diseases
such as interstitial nephritis, pyelonephritis, tuberculous
pyelonephritis, urinary tract obstructive disease, renal papillary
necrosis, analgesic abuse nephropathy, multiple myeloma
nephropathy, gout nephropathy, hypercalemic nephropathy and renal
calcinosis, and renal lithiasis; congenital malformations and
anomalies such as agenesis and hypoplasia, fusion, ectopia, and
reduplication, dysplasia and polycystic dysplasia, congenital
obstructive microcystic disease, simple cysts, infantile polycystic
disease, adult polycystic disease, and medullary cystic disease;
renal neoplasms such as benign tumors, which include adrenocortical
nodules, hamartomas, mesenchymal tumors, and cortical tubular
adenomas; and malignant tumors, such as adenocarcinoma, Wilms'
tumor, leukemic infiltration, and transitional cell carcinoma.
[0076] 5.3.3 Metabolic Disorders to be Treated
[0077] The present invention provides methods for the treatment of
a wide variety of metabolic disorders. One such metabolic disorder
is diabetes. The methods of the present invention are also suitable
for the treatment of disorders relating to basal metabolism, i.e.,
heat production of an individual at the lowest level of cell
chemistry in the waking state, or the minimal amount of cell
activity associated with the continuous organic functions of
respiration, circulation and secretion; carbohydrate metabolism,
i.e., the changes that carbohydrates undergo in the tissues,
including oxidation, breakdown, and synthesis; electrolyte
metabolism, i.e., the changes which the various essential minerals,
sodium, potassium, calcium magnesium, etc. undergo in the fluids
and tissues of the body; fat metabolism, i.e., the chemical
changes, oxidation, decomposition, and synthesis, that fats undergo
in the tissues; protein metabolism, i.e., the chemical changes,
decompositions, and synthesis that protein undergoes in the
tissues; and respiratory metabolism, i.e., the exchange of
respiratory gases in the lungs and the oxidation of foodstuffs in
the tissues with the production of carbon dioxide and water.
[0078] 5.3.4 Disorders Associated with Diabetes
[0079] Diabetes patients often suffer from numerous debilitating
disorders. One such disorder, peripheral neuropathy, is
particularly likely to occur in the older diabetic patient, with
approximately 30% to 50% of the patients showing minor reflex
changes and evanescent pains in the extremities. The basic
pathologic change in the peripheral nerves is a segmental
demyelination. The autonomic nervous system may also be involved in
diabetic patients, with resultant development of severe diarrhea
and abdominal pain. Greatly elevated levels of sorbitol and
fructose have been demonstrated in peripheral nerves of animals
with experimentally induced diabetes. The accumulation of sorbitol
and fructose is apparently attributable to a partial shunting of
the metabolism of glucose through the aldose reductase pathway. It
is unknown whether this abnormal metabolism of glucose with the
formation of sorbitol is responsible for the decreased nerve
conduction and segmental demyelination in diabetic subjects. In
experimental diabetes, degenerative changes have been found in
autonomic nerve fibers of the intestinal tract of rats and were
associated with the development of megacolon in these animals.
Control of the diabetes by islet transplantation resulted in either
prevent or disappearance of the degenerative lesions in the
autonomic nerves.
[0080] Kidney disease is common in diabetes and renal failure is
one of the major causes of death. The dominant form of diabetic
nephropathy is microvascular disease affecting the renal
glomerulus. Early in diabetes, the kidney increases in size and the
associated glomerular hypertrophy leads to an increased glomerular
filtration rate with hyperfiltration and microalbuminuria in up to
50% of patients with new onset insulin dependent diabetes mellitus.
Later in the disease, diffuse thickening of the glomerular basement
membrane is noted along with increased mesangial volume and
progressive impairment of renal function which in turn leads to
further expansion of the mesangium and eventual glomerular
occlusion.
[0081] Clinically, in some cases mild proteinuria can remain
constant for many years, while in other cases it progresses to
reduction in glomerular filtration and renal function with all the
classical features of nephrotic syndrome. Once azotemia (increased
serum creatinine and BUN) develops, progression to renal failure
and uremia is inevitable within a few months to two to three years.
Once renal failure develops, the only alternatives are dialysis or
transplantation.
[0082] The treatment of the above disorders is included within the
scope of the present invention.
[0083] 5.4 Effective Dosages
[0084] Pharmaceutical compositions suitable for use with the
present invention include compositions wherein the active
ingredient is contained in a therapeutically effective amount,
i.e., an amount effective to achieve its intended purpose. Of
course, the actual amount of active ingredient will depend on,
among other things, the particular disorder being treated.
Determination of an effective amount is well within the
capabilities of those skilled in the art.
[0085] For any compound described herein the therapeutically
effective amount can be initially estimated from cell culture
assays. For example, a dose can be formulated in animal models to
achieve a circulating concentration range of compound, and/or an
active metabolite thereof, that includes an effective concentration
as determined in cell culture. Such information can be used to more
accurately determine useful doses in humans. See, e.g., Washburn et
al., 1976, "Prediction of the Effective Radioprotective Dose of
WR-2721 in Humans Through an Interspecies Tissue Distribution
Study" Radiat. Res. 66:100-5.
[0086] Therapeutically effective amounts for use in humans can also
be estimated from animal models. For example, a dose for humans can
be formulated to achieve a circulating concentration found to be
effective in animals.
[0087] A therapeutically effective dose can also be estimated from
current clinical experience and data, including human
pharmacokinetic data. While not intending to be bound by any
particular theory, it is believed that efficacy is related to a
subject's total exposure to an applied dose of administered drug,
and/or an active metabolite thereof, as determined by measuring the
area under the blood concentration-time curve (AUC). Thus, a dose
administered according to the methods of the invention that has an
AUC of administered compound (and/or an active metabolite thereof)
within about 50% of the AUC of a dose known to be effective for the
indication being treated is expected to be effective. A dose that
has an AUC of administered compound (and/or an active metabolite
thereof) within about 70%, 80% or even 90% or more of the AUC of a
known effective dose is preferred. Adjusting the dose to achieve
maximal efficacy in humans based on the methods described above,
particularly on the blood concentration and duration of
administered compound and/or its active metabolites is well within
the capabilities of the ordinarily skilled artisan.
[0088] Usual patient doses for administration of amifostine and/or
its active metabolite WR-1065 usually range from about 50 mg/day to
6000 mg/day, commonly from about 100 mg/day to 4000 mg/day, and
typically from about 200 mg/day to 3500 mg/day. Stated in terms of
patient body weight, usual dosages range from about 0.6 to 100
mg/kg/day, commonly from about 1.1 to 66 mg/kg/day, and typically
from about 2.2 to 58 mg/kg/day. Stated in terms of patient body
surface areas, usual dosages range from about 23 to 4000
mg/m.sup.2/day, commonly from about 45 to 2666 mg/m.sup.2/day, and
typically from about 90 to 2333 mg/m.sup.2/day.
[0089] For other modes of administration, dosage amount and
interval can be adjusted individually to provide effective plasma
and/or tissue levels of the administered compound, and/or an active
metabolite thereof, according to the pharmacokinetic profiles
described herein, as previously described.
[0090] The actual amount of composition administered will, of
course, be dependent on the subject being treated, the subject's
weight, the severity of the affliction, the mode of administration
and the judgement of the prescribing physician.
[0091] Dosages are in the range of between about 10-1000 mg/m.sup.2
administered parenterally. Preferred doses for intravenous
administration are between about 100-750 mg per m.sup.2 of body
surface area, more preferably between about 200-750 mg/m.sup.2.
Preferred doses for oral administration are between about 20-2000
mg per m.sup.2 of body surface area, more preferably between about
500-1500 mg/m.sup.2 body surface area.
[0092] 5.5 Formulations and Dosage Administration
[0093] The aminothiol compounds described herein, or
pharmaceutically acceptable addition salts or hydrates thereof, can
be delivered to a patient according to the invention using a wide
variety of routes or modes of administration. Suitable routes of
administration include but are not limited to, inhalation, or
parenteral routes, including intravenous (infusion or bolus
injection), intramuscular, intraperitoneal, intrathecal,
subcutaneous, intranasal, transmucosal, buccal, sublingual,
vaginal, rectal, intestinal, local intradermal or transdermal
routes. Alternatively, or concurrently, administration may be by
the oral route. Intravenous administration is particularly
desirable.
[0094] The aminothiol compounds described herein, or
pharmaceutically acceptable salts and/or hydrates thereof, or
mixtures thereof, may be administered alone, or in combination with
other aminothiol compounds of the invention, and/or in combination
with one or more therapeutic agents, including cancer
chemotherapeutic agents, intended to also treat the toxicity or
disorder suffered by the subject being treated. Examples of such
additional drugs include but are not limited to vitamins, in
particular the B complex.
[0095] Medicaments are considered to be provided "in combination"
with one another if they are provided to the subject concurrently,
sequentially or if the time between the administration of each
medicament is such as to permit an overlap of biological
activity.
[0096] The aminothiol compounds of the present invention may be
administered by any means that achieve their intended purpose.
Amounts and regimens for the administration of the aminothiol
rescue agents can be determined readily by those with ordinary
skill in the clinical art of treating neuro- and nephro-disorders,
toxicities or cancer.
[0097] It is understood that the dosage of the aminothiol compound
will be dependent upon the age, sex, health, and weight of the
recipient, kind of concurrent treatment, if any, frequency of
treatment, and the nature of the effect desired. An effective
amount of the active compound of the present invention is any
amount which would serve to treat or reverse symptoms of the neuro-
or nephro-disorder or the neurotoxicity or nephrotoxicity caused by
administration of a chemotherapeutic agent in vivo. The ranges of
effective doses provided herein are not intended to limit the
invention and represent preferred dose ranges. However, the most
preferred dosage will be tailored to the individual subject, as is
understood and determinable by one of ordinary skill in the art
without undue experimentation.
[0098] For any mode of administration, the actual amount of
compound delivered, as well as the dosing schedule necessary to
achieve the advantageous effects described herein, will also
depend, in part, on such factors as the bioavailability of the
compound (and/or an active metabolite thereof), the disorder being
treated, the desired therapeutic dose, and other factors that will
be apparent to those of skill in the art. The actual amount
delivered and dosing schedule can be readily determined by those of
skill without undue experimentation by monitoring the blood plasma
levels of administered compound and/or an active metabolite
thereof, and adjusting the dosage or dosing schedule as necessary
to achieve the desired therapeutic effect. Additionally the dosage
or dosing schedule can be adjusted as necessary to achieve the
desired therapeutic effect by monitoring the signs and symptoms of
the disorder.
[0099] The active compound(s) may be administered alone or in the
form of a pharmaceutical composition, wherein the active
compound(s) is in admixture with one or more pharmaceutically
acceptable carriers, excipients or diluents. Pharmaceutical
compositions for use in accordance with the present invention may
be formulated in conventional manner using one or more
physiologically acceptable carriers comprising excipients and
auxiliaries which facilitate processing of the active compounds
into preparations which can be used pharmaceutically. Proper
formulation is dependent upon the route of administration
chosen.
[0100] The present methods also include providing a liquid based
dosage form of the active compound suitable for administration to a
subject in need thereof. The liquid base may be any liquid capable
of transporting the active ingredient into the body without
disrupting the activity of the compound or harming the patient. A
preferred base is an isotonic solution, which may also contain
conventional additives such as sugars. These solutions are useful
for both oral and intravenous administration.
[0101] For injection, the agents of the invention may be formulated
in aqueous solutions, preferably in physiologically compatible
buffers such as Hanks's solution, Ringer's solution, or
physiological saline. For transmucosal administration, penetrants
appropriate to the barrier to be permeated are used in the
formulation. Such penetrants are generally known in the art.
[0102] Suitable injectable solutions include intravenous
subcutaneous and intramuscular injectable solutions. The active
compound may also be administered in the form of an infusion
solution or as a nasal inhalation or spray.
[0103] For intravenous administration, the active compound is
preferably administered by drip infusion in an aqueous solution.
The active ingredient may be administered in single or divided
doses.
[0104] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example, water-soluble salts. In addition, suspensions of the
active compounds as appropriate oily injection suspensions may be
administered. Suitable lipophilic solvents or vehicles include
fatty oils, for example, sesame oil, or synthetic fatty acid
esters, for example, ethyl oleate or triglycerides. Aqueous
injection suspensions that may contain substances which increase
the viscosity of the suspension include, for example, sodium
carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the
suspension may also contain stabilizers.
[0105] For oral administration, the active ingredient, preferably
amifostine or a functional derivative or analogue thereof such as
WR-151327, may be a preparation in any dosage form capable of oral
administration. Such dosage forms include tablets, hard or soft
gelatin capsules, caplets, dragees, pills, tablets including coated
tablets, and solutions including elixirs, suspensions, gels,
slurries or syrups, and the like. Pharmaceutical preparations for
oral use can be obtained solid excipient, optionally grinding a
resulting mixture, and processing the mixture of granules, after
adding suitable auxiliaries, if desired, to obtain tablets or
dragee cores.
[0106] The active compound of the present invention may be
administered rectally in the form of suppositories or enemas.
[0107] In general, the preparation in which the active compound of
the present invention is administered contains from about 0.1 to
about 100 percent, preferably from about 25-85 percent, of active
compound(s), together with a carrier or excipient. Suitable
pharmaceutically acceptable carriers comprise excipients and
auxiliaries which facilitate processing of the active compounds
into preparations which can be used pharmaceutically. Suitable
excipients are, in particular, fillers such as sugars, such as
lactose, sucrose, mannitol, or sorbitol; cellulose preparations
and/or calcium phosphates, such as tricalcium phosphate or calcium
hydrogen phosphate; as well as binders such as starch paste made
using, for example, maize starch, wheat starch, rice starch, potato
starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethylcellulose, sodium carboxymethyl cellulose,
and/or polyvinylpyrrolidone. If desired, disintegrating agents may
also be added, such as the above-mentioned starches as well as
carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof, such as sodium alginate.
[0108] Auxiliaries which can be used in the compositions according
to the present invention include flow-regulating agents and
lubricants such as silica, talc, stearic acid or salts thereof,
and/or polyethylene glycol.
[0109] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0110] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0111] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0112] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g. gelatin for use in an inhaler or insufflator may
be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0113] The compounds may be formulated for parenteral
administration by injection, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multi-dose containers, with an
added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0114] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds may be
prepared as appropriate oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or
agents which increase the solubility of the compounds to allow for
the preparation of highly concentrated solutions.
[0115] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, before use.
[0116] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0117] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation,
subcutaneous or intramuscular injection. Thus, for example, the
compounds may be formulated with suitable polymeric or hydrophobic
materials (for example as an emulsion in an acceptable oil) or ion
exchange resins, or as sparingly soluble derivatives, for example,
as a sparingly soluble salt.
[0118] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients. Examples of such
carriers or excipients include but are not limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0119] It will be understood that the aminothiol rescue agents of
the invention may be administered in accordance with the methods of
the invention at any time during or after administration of the
chemotherapeutic agent, preferably after administration. For
example, the rescue agent may be administered one hour after, or
more preferably, four or more hours after administration of the
chemotherapeutic agent. Most preferably, the rescue agent is
administered days, or even weeks after chemotherapy. The rescue
agent may be administered after toxicities associated with
administration of chemotherapy are observed. Preferably, the rescue
agent is administered after chemotherapeutically-induced toxicities
are observed or demonstrated.
[0120] Indications of toxicity in a patient who has received
chemotherapy are well known to those of ordinary skill in the art
of treating cancer patients. For example, indications or "markers"
of neurotoxicity caused by chemotherapy include, but are not
limited to clinical signs and symptoms, nerve conduction studies,
and vibrometer measurements. Markers of nephrotoxicity caused by
chemotherapy include, but are not limited to increased levels of
serum creatinine above 1.5 mg/Dl, BUN greater than 20, abnormal
electrolytes, for example decrease in serum, magnesium, bicarbonate
or elevations in serum potassium. Preferably, the aminothiol
compounds of the invention are administered after one or more of
such toxicity markers are observed following chemotherapeutic
treatment.
[0121] It will be understood that the aminothiol compounds of the
invention may be administered according to the methods of the
invention after any one or more cycles of administration of a
chemotherapeutic drug. For example, the rescue agent may be
administered after one cycle of administration of a
chemotherapeutic agent, but prior to the next cycle of
administration of chemotherapeutic agent.
[0122] Having now generally described the invention, the same will
be more readily understood through reference to the following
examples which are provided by way of illustration, and are not
intended to be limiting of the present invention, unless
specified.
6. WORKING EXAMPLES
6.1. Example 1
Case Study
[0123] A 61-year-old patient with new onset cisplatin-induced renal
failure that was identified 6 days post-cisplatin therapy was
treated with amifostine 400 mg intravenously for 3 days, with
partial recovery of her renal function and improvement in her
overall clinical status.
[0124] The patient was referred by her primary care physician for a
gynecologic evaluation for complaints of increasing pain in her
lower abdomen with costovertebral angle tenderness over a 10-month
period. Ovarian cysts were identified and monitored by ultrasound
on several occasions during that time. The patient had a history of
recurrent urinary tract infections, and she had a stent placed for
approximately two weeks prior to the gynecologic consult. A CAT
scan at that time revealed ureteral stenosis and slight
hydronephrosis of her right kidney. Other relevant past medical
history included congenital absence of her left kidney, double
uteri, and a total abdominal hysterectomy and left
salpingo-oophorectomy approximately 30 years previously.
[0125] The patient underwent an exploratory laparotomy to determine
if the etiology of her increasing pain was secondary to the cystic
ovary, urinary tract infections, or ureteral stenosis and
hydronephrosis. The patient was found to have grade III papillary
adenocarcinoma arising from a serious type adenofibroma, with
metastasis to the omentum. A right oophorectomy and partial
omentectomy were performed, with lysis of adhesions. Repeat surgery
was performed approximately one month later for lymph node biopsy
for staging of the cancer and to remove additional omentum.
Intraperitoneal and intravenous (iv) catheters were placed at this
time for future chemotherapy.
[0126] The patient was evaluated for chemotherapy and was placed on
a treatment regiment consisting of paclitaxel 135 mg/m.sup.2 (223
mg) administered iv on day 1, followed by cisplatin 100 mg/m.sup.2
(165 mg) intraperitoneally on day 2. However, after receiving days
1 and 2 of chemotherapy, the patient presented to the emergency
room on day 3 with nausea, vomiting, and abdominal cramping. She
was admitted for hydration and treatment of nausea. For the next 5
days, she continued to complain of nausea and vomiting, despite
treatment with intensive antiemetic regimens, including
granisetron, dexamethasone, and promethazine. Other treatment at
that time included ketorolac for pain, lorazepam for anxiety, and
large volumes of iv fluids. By hospital day 5, the patient's serum
creatinine had risen to 4.9 mg/Dl and the BUN to 39 mg/Dl.
Electrolyte abnormalities at that time were: sodium--128 mMol/L,
potassium--1.9 Mmol/L, chloride--94 Mmol/L, and CO.sub.2--22
Mmol/L. Also, the serum calcium was 4.5 mMol/L. The patient was
transferred to telemetry for observation and normalization of her
electrolytes.
[0127] A renal consultation determined the patient's acute renal
failure to be secondary to cisplatin therapy and complicated by
volume depletion. She continued to be rehydrated, and further
chemotherapy was withheld. Because of persistent, unresponsive
renal failure, amifostine 400 mg per day was administered
intravenously on post-cisplatin days 7, 8, and 9 in an effort to
reduce the drug-induced nephrotoxicity. The patient tolerated
therapy well, with only mild nausea. Her renal function improved
over the next 3 days on amifostine, with her creatinine decreasing
from a peak concentration of 6.0 mg/dL before amifostine to 4.6
mg/dL on day 3 of amifostine therapy. At that time, her
electrolytes had normalized, her abdominal cramping significantly
lessened, and she was able to tolerate oral fluids. By hospital day
12, the patient's creatinine had decreased to 2.8 mg/dL and she was
discharged on hospital day 13. The patient's response to amifostine
therapy, as demonstrated by improvement in serum creatinine, is
shown in FIG. 1.
[0128] Two days later the patient was readmitted with dystonia
caused by increased promethazine usage for intractable nausea and
vomiting. The patient was hydrated and monitored over the next 5
days, and electrolyte abnormalities were corrected. Amifostine 400
mg iv was administered once again on hospital day 2, with
ondansetron 24 mg administered as needed for nausea. The patient
tolerated the treatment well. Her renal function stabilized during
this hospitalization, with creatinine/BUN ranging between 2.8/17
mg/dL and 3.2/13 mg/dL. She was discharged on hospital day 5.
[0129] A follow-up clinic visit was scheduled for 3 days
post-discharge, at which point the patient chose not to pursue
further chemotherapy. Amifostine 400 mg iv was administered 5 days
later to assess whether further improvement in her renal function
could be achieved. Granisetron 1 mg was given orally as
premedication. The patient's creatinine at that time was 2.5 mg/dL.
Two weeks later, it was decided to administer a final 2-week course
of amifostine 400 mg, with reassessment at the end of therapy.
Amifostine was administered every 2 to 3 days for a total of 5
doses over the 2 weeks. Lorazepam 1 mg iv and ondansetron 24 mg iv
were administered as premedication. Approximately 6 months later,
the patient's serum creatinine was 2.0 mg/dL.
[0130] In this Example, the patient received amifostine on days 7
through 9 post-cisplatin therapy, after renal failure had already
developed. Amifostine partially reversed the toxic renal effects of
cisplatin, with the patient's serum creatinine decreasing over the
3-day course of treatment from 6.0 mg/dL to 4.6 mg/dL, and to 2.8
mg/dL by discharge from the hospital on day 13. Concurrent with her
improving renal function, the patient's overall clinical status
improved during this time, with normalization of electrolyte
imbalances and defervescence of abdominal cramping, nausea, and
vomiting.
6.2. Example 2
Case Study
[0131] The patient, a 75-year-old white male, who is a survivor of
the concentration camps of World War II, was diagnosed with bladder
cancer that had metastized to the lungs. He received 3 cycles
carboplatinum, vinblastine and methotrexate. While in the
concentration camp, the patient suffered damage to his lower legs
which caused him constant pain. This pain was made worse by
chemotherapy. The tumors were shrinking in his lungs, but he
developed severe neurotoxicities of his right arm and refused
further treatment. These neurotoxicities seemed to worsen after
chemotherapy was stopped. He was given demerol for acute relief and
required 2-100 mcg/hr. Duragesic Patches in order to make his pain
"bearable." The patient was tried on many other agents and
combination of agents including steroids and non-steroidals. Soon
the Duragesic patches were no longer making his pain bearable, and
he was very depressed, and complaining of sleepiness.
[0132] After premedication with antiemetics, the patient was given
500 mg of amifostine in 50 cc 0.9 saline over 10 minutes. Two days
later, the patient reported that he had no pain for the first time
in months, even the pain in his legs was getting better. He was
able to walk without his cane. The patient received subsequent
Ethyol infusions and has remained without arm pain. The pain in his
legs has improved and he is managing with only one Duragesic
Patch.
6.3. Example 3
Case Study
[0133] A 72-year-old white female was diagnosed with lung cancer
and received 3 cycles of amifostine, paclitaxel, and carboplatin in
which the amifostine was administered prior to chemotherapy. By the
fourth cycle she was confined to a wheel chair with foot drop and
unable to feed herself or brush her teeth because of her
neurotoxicities. Chemotherapy had to be stopped even though her
tumor was responding to treatment. Several medications were tried
along with physical therapy to reduce her problems of neuropathy.
When she did not respond to several months of this treatment,
Ethyol single agent therapy was initiated.
[0134] The patient was premedicated with Zofran (ondanestron) 32
mg, Decadron 20 mg in 50 cc normal saline IVPB over 15 minutes and
then given amifostine 970 mg in 50 cc normal saline over 10
minutes. She tolerated this treatment without problems. Two days
later, the patient reported improvement in strength in her upper
arms and legs. She was able to hold a tooth brush and silverware
again. The patient continued to receive weekly infusions of
amifostine. By the third treatment, she was walking again with the
aid of a walker. However, the day after the fourth treatment with
amifostine, the patient experienced erythema and blistering all
over her body, which eventually led to total skin peeling. The
amifostine treatments were terminated. One month later, the
patient's skin was back to normal and her neuropathy remained
stable.
6.4 Example 4
Case Study
[0135] A 55-year-old male with myelodysplastic bone marrow syndrome
(MDS) suffered with neurotoxicities for eight years which developed
as a result of CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone) chemotherapy given for Non-Hodgkins Lymphoma. This
patient initiated treatment for MDS with Ethyol, 840 mg, Monday,
Wednesday and Friday of each week. After receiving five weeks of
such amifostine therapy for MDS, the patient stated (unsolicited)
that his neurotoxicities were better since receiving amifostine.
The patient continues on Ethyol for MDS and is doing well.
[0136] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
[0137] Various publications are cited herein, the disclosures of
which are incorporated by reference in their entireties.
* * * * *