The present invention relates to compositions and methods for the protection and restoration of hearing. In particular, the present invention relates to methods and compositions for the prevention of chemical (e.g., cisplatin) induced deafness. The present invention thus provides methods of improving the outcome of subjects treated with cisplatin.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods for the protection and restoration of hearing. In particular, the present invention relates to methods and compositions for the prevention of chemical (e.g., cisplatin) induced deafness.

Accordingly, in some embodiments, the present invention provides a method for reducing chemotherapy induced ototoxicity, comprising: providing a subject; a chemotherapeutic agent that induces ototoxicity; and an ototoxicity preventing agent; and administering the ototoxicity preventing agent locally to an ear of the subject; administering the chemotherapeutic agent to the subject. In some preferred embodiments, the chemotherapeutic agent is active in the presence of the ototoxicity preventing agent. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the ototoxicity preventing agent is thiourea. In other embodiments, the ototoxicity preventing agent is dimethylthiourea. In some embodiments, the administering is via an osmotic pump implanted in the ear of the animal. In other embodiments, the administering is via manual injection into a cochleostomy. In still further embodiments, the administration is via diffusion from the middle ear. In some embodiments, the method further comprises the step of administering a nephrotoxicity preventing agent to the subject. In some embodiments, the nephrotoxicity agent is administered systemically. In some embodiments, the nephrotoxicity preventing agent includes, but it not limited to, sodium selenite and amifostine.

The present invention further provides a kit for use in preventing chemotherapy induced ototoxicity, comprising: a ototoxicity preventing agent; and instructions for using the kit for preventing chemotherapy induced ototoxicity. In some embodiments, the ototoxicity preventing agent is thiourea. In other embodiments, the ototoxicity preventing agent is dimethylthiourea. In some embodiments, the kit further comprises a local delivery system. In other embodiments, the kit further comprises an nephrotoxicity preventing agent. In some embodiments, the nephrotoxicity preventing agent includes, but it not limited to, sodium selenite and amifostine.

The present invention additionally provides a kit, comprising an ototoxicity preventing agent, wherein the ototoxicity preventing agent is formulated for local delivery; and a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the ototoxicity preventing agent is thiourea. In other embodiments, the ototoxicity preventing agent is dimethylthiourea. In some embodiments, the kit further comprises a local delivery system. In other embodiments, the kit further comprises an nephrotoxicity preventing agent. In some embodiments, the nephrotoxicity preventing agent includes, but it not limited to, sodium selenite and amifostine.

In yet other embodiments, the present invention provides a method for reducing chemotherapy induced ototoxicity, comprising: providing a subject; a chemotherapeutic agent that induces ototoxicity; and an ototoxicity preventing agent; and administering the ototoxicity preventing agent and the chemotherapeutic agent to the subject. In some preferred embodiments, the ototoxicity agent is administered prior to administering the chemotherapeutic agent. In some preferred embodiments, the ototoxicity preventing agent is administered locally to an ear of the subject. In some preferred embodiments, the chemotherapeutic agent is active in the presence of the ototoxicity preventing agent. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the ototoxicity preventing agent is thiourea. In other embodiments, the ototoxicity preventing agent is dimethylthiourea. In some embodiments, the administering is via an osmotic pump implanted in the ear of the animal. In other embodiments, the administering is via manual injection into a cochleostomy. In still further embodiments, the administration is via diffusion from the middle ear. In some embodiments, the method further comprises the step of administering a nephrotoxicity preventing agent to the subject. In some embodiments, the nephrotoxicity agent is administered systemically. In some embodiments, the nephrotoxicity preventing agent includes, but it not limited to, sodium selenite and amifostine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions and methods for the protection and restoration of hearing. In particular, the present invention relates to methods and compositions for the prevention of cisplatin-induced deafness.

Cisplatin is an anti-cancer agent that is used in the treatment of a variety of solid tumors. In adults, indications for cisplatin include the treatment of primary germ cell tumors, as well as metastatic tumors from the testis and ovary. In children, cisplatin-based chemotherapy is used for osteogenic sarcoma and Ewing's sarcoma. While an effective chemotherapeutic, cisplatin unfortunately has profound toxicity that severely limits its clinical application. In particular, cisplatin is known to cause kidney damage, peripheral neuropathy, and hearing loss.

Cisplatin-induced hearing loss typically affects the high-frequency range, although some patients develop a social hearing handicap as the hearing loss extends to lower frequencies during subsequent treatment courses (van der Hulst et al., Annals of Otology, Rhinology & Laryngology 97:133 [1988]). Risk factors for cisplatin-induced hearing loss include anemia and hypoproteinemia (Blakley et al., Archives of Otolaryngology--Head & Neck Surgery 120:541 [1994]). While not strictly stereo-typed across patients, cisplatin-induced hearing loss, the reported incidence of which varies from 9-90%, is typically cumulative and non-reversible (Blakley et al., Otolaryngology--Head & Neck Surgery 109:385 [1993]). Severe impairment can occur early in the course of treatment, without a clear correlation with cumulative dose (Myers et al., Otolaryngology--Head & Neck Surgery 104:122 [1991]). In animal models, anatomical changes observed with cisplatin include preferential loss of outer hair cells with preservation of inner hair cells; damage is greatest in the base of the cochlea, as expected given the high-frequency nature of the associated hearing loss (Nakai et al., Acta Oto-Laryngologica 93:227 [1982]).

Nephrotoxicity, which occurs in a dose-related fashion, has long been considered to be the primary limiting toxicity of cisplatin. The risk of nephrotoxicity can be minimized by dose reduction, use of alternative agents (e.g., carboplatin), and co-administration of amifostine or sodium selenite (Hensley et al., Journal of Clinical Oncology, 17:3333 [1999]; Camargo et al., Bio. Trace Elem. Res., 83:251 [2001]). In contrast, amifostine does not appear to be effective in ameliorating neuropathic and ototoxic effects of cisplatin (Hensley et al., Journal of Clinical Oncology, 17:3333 [1999]). With improved prevention of nephrotoxicity, ototoxicity is now considered to be the primary limiting factor on the use of cisplatin clinically.

Accordingly, the present invention provides methods and compositions for preventing cisplatin-induced ototoxicity. The methods of the present invention thus allow for cisplatin to be used much more effectively as a cancer-treating agent.

I. Protective Compounds

In some embodiments, small, neutral molecules are utilized as protective agents against cisplatin. In some preferred embodiments the molecules are strong nucleophiles. In some preferred embodiments, small, neutral and highly potent molecules that can reach inner ear targets when administered in the middle ear are utilized. For example, in some embodiments, thiourea is utilized.

In other embodiments, dimethyl-thiourea is utilized as a protective agent. The present invention is not limited to a particular agent. Any agent that is protective against the effects of cisplatin without interfering with cisplatin when administered locally may be utilized in the methods and compositions of the present invention. For example, a variety of thiourea-like compounds are contemplated. Compounds may be screened using any suitable assay including, but not limited to, the assay described in the illustrative example below.

In preferred embodiments, the protective agents of the present invention are formulated for local delivery. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences" (Mack Publishing Co, Easton Pa.). As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and interaction with other drugs being concurrently administered.

II. Administration of Treatments

When given systemically, thiourea eliminates the therapeutic efficacy of cisplatin (Burchenal et al., Cancer Treatment Reports, 63:1493 [1979]; Ishizawa et al., Japanese Journal of Pharmacology 31:883 [1981]). Consequently, it is preferred that this agent be used with cisplatin in a systemic manner as a rescue strategy. However, the small size of thiourea makes it amenable to the direct, local delivery methods of present invention, which allow delivery into the inner ear, thereby allowing the drug to prevent cisplatin-induced deafness while not interfering with the anti-tumor effects of cisplatin.

Accordingly, in preferred embodiments, protective compounds are administered directly to the ear. In preferred embodiments, systemic levels of the protective compound are low, so as not to interfere with the chemotherapeutic agent. Experiments conducted during the course of the development of the present invention (Illustrative Example below) demonstrated that administration of thiourea via a mini-osmotic pump prevented cisplatin-induced ototoxicity. Thus, in some embodiments, protective agents are administered via a mini-osmotic pump (Brown et al., Hear Res., 70:167 [1993]; Prieskorn and Miller, Hearing Res., 140:212 [2000]). In some embodiments, a cannula system is utilized to provide access, via a hand-drilled cochleostomy, to the inner ear, while allowing periodic pump changes in order to enable changes in the drug being infused over time, and/or to prolong the interval of drug delivery. In some embodiments, the cannula allows direct (manual) injection into the cochlea, as accessed through the round window or via a cochleostomy (Stover et al., Hear Res., 136:124 [1999]), as well as round window placement of the cannula tip for the purposes of middle ear drug delivery.

In other embodiments, treatments are injected into the cochlea through a cochleostomy created in the basal turn via manual injection (Brown et al., Hear Res., 70:167 [1993]; Prieskorn and Miller Hear Res., 140:212 [2000]). In still further embodiments, treatments are administered via indirect infusion. This method takes advantage of the semi-permeable nature of the round window membrane to deliver small molecules into the middle ear space, from which they pass into the inner ear. In yet other embodiments, the treatment is incorporated into a biopolymer matrix on a cochlear implant, resulting in gradual, chronic release of the substance from along the implant's length within the cochlea. The present invention is not limited to the local delivery methods described herein. Any suitable method that delivers therapeutics to the inner ear may be utilized.

III. Kits

In some embodiments, the present invention provides kits comprising the ototoxicity preventing agents of the present invention (e.g., thiourea). In some preferred embodiments, the ototoxicity preventing agent (e.g., thiourea) is supplied as a formulation suitable for local delivery. In some embodiments, the kits comprise instructions for the use and administration of the agents. In some embodiments, the kits comprise both the protective agent (e.g., thiourea) and the chemotherapeutic agent (e.g., cisplatin).
 

Claim 1 of 6 Claims

1. A method for reducing chemotherapy induced ototoxicity, comprising: a) providing i) a subject in need of chemotherapy, ii) a chemotherapeutic agent that induces ototoxicity, wherein said chemotherapeutic agent is cisplatin; and iii) an ototoxicity preventing agent wherein said agent is thiourea or dimethylthiourea; and b) administering a therapeutically effective amount of said ototoxicity preventing agent locally to an inner ear of said subject via a pump, wherein said administration of said ototoxicity preventing agent reduces ototoxicity in said subject when compared to ototoxicity present in said subject if said ototoxicity preventing agent was not administered; c) administering said chemotherapeutic agent to said subject.

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