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Methods and compositions for ameliorating the undesirable effects of chemotherapy

a technology of undesirable effects and compositions, applied in the direction of drug compositions, dipeptide ingredients, medical preparations, etc., can solve the problems of affecting the health of patients, ototoxicity, seizures, etc., and achieve the effects of reducing the risk of recurrence, reducing and improving the effect of recurren

Inactive Publication Date: 2006-04-27
SOUND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] In another aspect, the present invention provides methods of ameliorating at least one adverse effect of chemotherapy, the methods each comprising the step of administering to a subject undergoing chemotherapy an amount of a chemoprotectant composition that is effective to ameliorate at least one adverse effect of the chemotherapy. The chemoprotectant composition comprises one or more (such as at least two) of the chemoprotectants disclosed herein.

Problems solved by technology

Unfortunately, most, if not all, chemotherapeutic agents cause undesirable effects that adversely affect the health of the patient.
Unfortunately, cisplatin causes numerous adverse effects, such as seizures, peripheral neuropathies, ototoxicity, hearing loss, deafness, vertigo, dizziness, blurred vision, nausea, vomiting, anorexia, diarrhea, constipation, myelosuppression, thrombocytopenia, anemia, neutropenia, and nephrotoxicity.

Method used

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  • Methods and compositions for ameliorating the undesirable effects of chemotherapy
  • Methods and compositions for ameliorating the undesirable effects of chemotherapy
  • Methods and compositions for ameliorating the undesirable effects of chemotherapy

Examples

Experimental program
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Effect test

example 1

[0057] This example shows that N-acetylcysteine, Ebselen and allopurinol, alone, or in combination, do not inhibit the ability of cisplatin to kill cultured NuTu-19 ovarian cancer tumor cells as measured using the MTS cell viability assay.

[0058] NuTu-19 cells were plated at a density of 3,000 cells per well in 96 well culture dishes, and incubated at 37° C., in the presence of 5% carbon dioxide, for 24 hours. N-acetylcysteine, Ebselen or allopurinol were incubated for one hour, or for four hours, with the NuTu-19 cells, then cisplatin was added to the cultures which were further incubated at 37° C., in the presence of 5% carbon dioxide, for 24 hours. The NuTu-19 cells were then rinsed with media and incubated in the presence of cisplatin for an additional 24 hours.

[0059] The NuTu-19 cells were then rinsed twice with phosphate buffered saline (PBS), then MTS assays were performed to measure the number of living cells. MTS is an abbreviation for (3-(4,5-dimethylthiazol-2-yl)-5-(3-ca...

example 2

[0066] This Example shows that Ebselen protects inner ear hair cells from damage by cisplatin in vitro.

[0067] Three cochlea per treatment, obtained from P3-4 mouse pups, were cultured in 0.4 micrometer MilliCell-CM inserts with NeuroBasal A medium plus B27 supplement. After 24 hours in culture Ebselen was added to the medium, incubated for ten minutes, and then cisplatin was added to the medium at a final concentration of 43 μM. A first control treatment included 43 μM cisplatin. A second control treatment included 47 μM Ebselen without the addition of cisplatin. All cultures were incubated for 24 hours at 37° C. in 5% carbon dioxide.

[0068] The explants were then harvested, fixed, and stained with calbindin (which detects hair cells) and DAPI (4′,6-Diamindino-2-phenylindole; for detection of nuclear DNA). FIG. 7 shows the number of inner ear hair cells in mice cochlea that were cultured, in vitro, in the presence of 43 μM cisplatin (10), or 43 μM cisplatin plus 47 μM Ebselen (12),...

example 3

[0070] This Example shows that Ebselen, and the combination of Ebselen and allopurinol, protect rat inner ear hair cells from damage by cisplatin in vivo.

[0071] Auditory Evoked Brainstem Response (ABR) was used to assess hearing in rats before and after exposure to cisplatin and chemoprotectants. Ebselen or DMSO (control vehicle) were introduced intraperitoneally into rats one hour before intraperitoneal administration of cisplatin at a dosage of 16 mg / kg body weight. Seventy two hours after delivery of cisplatin, ABR data were collected, animals were sacrificed, cochleae were collected, dissected, stained with FITC-phalloidin (to detect F-Actin in hair cells), and DAPI (to detect nuclear DNA).

[0072]FIG. 8 shows the permanent threshold shift (PTS) in hearing, at 8 kHz, 16 kHz, 24 kHz and 32 kHz, of rats treated with cisplatin (at a dosage of 16 mg / kg body weight) in the presence of Ebselen (at a dosage of 16 mg / kg body weight) (22), or in the presence of saline and DMSO (control) ...

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Abstract

In one aspect, the present invention provides chemoprotectant compositions that each comprise at least two of the chemoprotectants disclosed herein. The chemoprotectant compositions of the invention are useful, for example, for ameliorating at least one adverse effect of chemotherapy. In another aspect, the present invention provides methods of ameliorating at least one adverse effect of chemotherapy, the methods each comprising the step of administering to a subject undergoing chemotherapy an amount of a chemoprotectant composition that is effective to ameliorate at least one adverse effect of the chemotherapy.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 334,140, filed Nov. 29, 2001.FIELD OF THE INVENTION [0002] The present invention relates to methods and compositions for ameliorating the undesirable effects of chemotherapy, such as chemotherapy that utilizes cisplatin. BACKGROUND OF THE INVENTION [0003] One approach to the treatment of cancer is chemotherapy in which one or more chemical substances that are toxic, or otherwise deleterious, to the cancerous cells are administered to an individual suffering from cancer. Unfortunately, most, if not all, chemotherapeutic agents cause undesirable effects that adversely affect the health of the patient. [0004] By way of example, the chemotherapeutic agent cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex, with platinum as the central atom surrounded by two chloride atoms and two ammonia molecules in the cis position. Cisplatin produces interstrand and ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/05A61K31/7076A61K31/519A61K31/41A61K31/198C07D277/20A61K31/145A61K31/197A61K31/426A61K31/7056A61K31/724A61K33/243A61K38/00A61K38/04A61K45/06A61P35/00A61P39/00C07D277/56C07D293/12C07D487/04C07H19/167C08B37/16
CPCA61K31/197A61K31/198A61K31/519A61K31/7076A61K33/24A61K38/04A61K45/06A61K2300/00A61P35/00A61P39/00A61P43/00A61K33/243A61K31/195A61K38/05
Inventor KIL, JONATHANLYNCH, ERIC D.
Owner SOUND PHARMA
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