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.

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 1 NH(CH 2 ) n NH(CH 2 ) m SR 2   (I)  
     or a pharmaceutically acceptable addition salt or hydrate thereof, wherein 
 R 1  is hydrogen, C 5 -C 7  aryl, C 2 -C 7  acyl, or C 1 -C 7  alkyl;  
 R 2  is hydrogen, PO 3 H 2  or R 3  wherein R 3  is R 1 NH(CH 2 ) n NH(CH 2 ) m S—;  
 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 2  to about 2,000 mg/m 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 1 NH(CH 2 ) n NH(CH 2 ) m SR 2    
     or a pharmaceutically acceptable addition salt or hydrate thereof, wherein 
 R 1  is hydrogen, C 5 -C 7  acyl, or C 2 -C 7  acyl, or C 1 -C 7  alkyl;  
 R 2  is PO 3 H 2  or R 3  wherein R 3  is R 1 NH(CH 2 ) n NH(CH 2 ) m S—;  
 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.