Patent Application: US-74918900-A

Abstract:
specific cytokine antagonists , including tnf antagonists and / or interleukin - 1 antagonists , are used as novel therapeutic agents for the treatment of hearing loss , including presbycusis and other forms of sensorineural hearing loss . the present invention provides a method for inhibiting the action of tnf and / or il - 1 antagonists for treating hearing loss in a human by administering a tnf antagonist and / or an il - 1 antagonist for reducing the inflammation affecting the auditory apparatus of said human , or for modulating the immune response affecting the auditory apparatus of said human , by administering a therapeutically effective dosage level to said human of a tnf antagonist and / or an il - 1 antagonist . administration may be systemic , through the subcutaneous , intramuscular , oral , or intravenous routes ; or by delivering an anatomically localized application in the region of the head . the tnf antagonist is selected from the group consisting of etanercept , infliximab , d2e7 , cdp 571 , or thalidomide ; and the il - 1 antagonist is either il - 1 ra or il - 1r type ii receptor . antiviral agents may be added for treating certain patients .

Description:
presbycusis , or age - related hearing loss , affects one - third of the u . s . population over age 75 , and presents a significant hardship to these people , many of whom are faced with the burden of other age - related illnesses . at this time , it is difficult to determine the degree to which any individual patient will respond to treatment with the cytokine antagonists discussed herein . the advantages of using etanercept are its rapid onset of action , general lack of side effects , ease of administration , and relatively low cost per dose . for adult patients the dose will uniformly be 25 mg , administered subcutaneously in the same manner as with rheumatoid arthritis patients , i . e . into the abdominal area or the thigh . some patients may have a better response from subcutaneous injection directly overlying the mastoid process . for these patients it is recommended that the side of the head be rotated with each dose , i . e . one dose on the right side of the head , and the next dose on the left side , etc . some patients will respond to a lower dose , in the range of 5 mg to 15 mg , when etanercept is administered directly to the mastoid area . for all patients dosing is continued twice per week with the same dose . etanercept administration is discontinued if the patient develops an infection at any site , and is not started in any patient that has an infection . d2e7 is a fully human anti - tnf antibody . d2e7 is administered in exactly the same way as etanercept , with the same precautions . the only difference is the dose interval and the dosage . d2e7 for presbycusis will usually be administered at a starting dose of 20 mg subcutaneously given once every two weeks . the effective dose and interval may vary , according to individual response , from as little as 10 mg administered once per month to as much as 20 mg given weekly . as with etanercept , some patients may have a better response from subcutaneous injection directly overlying the mastoid process . cdp - 571 is a tnf antagonist in clinical development . it is a monoclonal antibody , and for purposes of this patent , it functions in a manner similar to infliximab . the intravenous route of administration is currently the preferred method for infliximab . infliximab carries with it the advantage of reimbursement by additional third parties , and the advantage of a longer interval between doses than either etanercept or d2e7 . the dosage regimen for infliximab recommended for initial use is the same as that recommended by the manufacturer for the treatment of arthritis , i . e . 3 mg / kg given as an intravenous infusion followed with additional 3 mg / kg doses at 2 and 6 weeks after the first infusion , then every 8 weeks thereafter . because infliximab is a chimeric monoclonal antibody , with a mouse component , human anti - chimeric antibodies ( haca ) may develop . methotrexate has been shown to reduce the development of haca . for this reason , methotrexate may need to be administered with infliximab . thalidomide is also beneficial for certain patients . the recommended starting dose is 50 mg orally taken once per day . patients not responding can have their dose escalated monthly by a 50 mg increment , up to a maximum of 200 mg per day . a new aqueous formulation of thalidomide may allow the use of subcutaneous dosing . in this case , patients could be given a lower dosage , especially if injected subcutaneously in the area overlying the mastoid . certain patients may respond to the use of interleukin - 1 antagonists , used instead of a tnf antagonist . the two medications in this class to be used here are il - 1 ra ( anakira , a mgen ) and il - 1 r type ii ( immunex ). the recommended dosage and dose interval are similar to the parameters recommended for their use for rheumatoid arthritis . some patients will receive additional therapeutic benefit from the use of a tnf antagonist administered with an interleukin - 1 antagonist . the use of these medications in this manner has been demonstrated to be synergistic when used to treat an arthritis model in animals . the combination produces a more potent anti - inflammatory effect than when either agent is administered alone . patients with other forms of sensorineural hearing loss , and patients with central hearing loss are treated in the same manner as those with presbycusis discussed above . the only difference will be the dosages , which in children will need to be adjusted appropriately for the patient &# 39 ; s lean body mass . certain patients with selected forms of sensorineural and / or central hearing loss , including certain patients with presbycusis , will benefit from the addition of an antiviral agent in addition to a cytokine antagonist . this is because certain forms of hearing loss are due to focal infection of a locus of the auditory pathway by a neurotropic virus . known neurotropic viruses include those in the herpes family , especially herpes simplex 1 and 2 , human herpes virus 6 , and varicella - zoster . these viruses can involve the neural components of the auditory pathway , such as the eighth cranial nerve , and thereby produce either sudden sensorineural hearing loss ( in the case of acute infection ) or chronic , progressive hearing loss ( in the case of low - grade , chronic viral involvement ). certain patients will therefore require acute therapy , and others will require chronic therapy with antiviral agents , such as famciclovir , acyclovir , or valacyclovir . antiviral therapy in combination with cytokine antagonists is the subject of a previous patent application by the inventor . idiopathic sudden sensorineural hearing loss is a known clinical entity . the only treatment with reported success is the use of corticosteroids . some of these cases are thought to have viral causation . the use of a cytokine antagonist in combination with an antiviral medication may prove beneficial for these patients . no studies of this combination for this clinical condition have been published . the recommended regimen would be etanercept 25 mg subcutaneously twice a week in combination with valacyclovir 1 gram po bid for one month , with tapering as needed . for children , there are additional considerations . sensorineural hearing loss is an important cause of disability in children . many of the causes are genetic , and these can lead to profound deafness . those disorders with a known component of inflammation should give the best response to the antagonists disclosed herein . etanercept has proven to be both safe and effective for chronic use for arthritis in children . the aforementioned caveats with regard to infection apply to children as well as to adults . d2e7 is also a therapy for use in children . for certain neurotropic viral infections of children , the combination of cytokine antagonists with antiviral medications will reduce or , even in some cases , prevent the development of hearing loss . a 73 year old caucasian woman patient presented with a history of slowly increasing hearing loss in both ears . the patient had noticed decreasing hearing beginning approximately 20 years earlier , in her 50 &# 39 ; s . her father had experienced hearing loss beginning about the same age . one year prior the patient had noticed that she was having great difficulty hearing conversation when at family meetings . her grandchildren were urging her to get hearing aids about that time . six months prior to her visit she obtained digital hearing aids , and used them daily . the patient had a recent history of sciatica ; a history of spinal stenosis ; and a previous diagnosis of sensorineural hearing loss . a subcutaneous injection of etanercept was administered at a dose of 25 mg . one hour later the patient noticed that sounds were significantly louder . improved hearing continued for the duration of treatment with etanercept . one day after receiving the second dose of etanercept 25 mg , which was administered four days after the first dose , the patient needed to remove her digital hearing aids because her hearing was so improved that sounds were too loud while the hearing aids were in place . this had not been necessary during the entire time of use of these hearing aids , prior to her treatment with etanercept . for treating the above diseases with the above - mentioned tnf antagonists , these tnf antagonists may be administered by the following routes : the above tnf antagonists may be administered subcutaneously in the human and the dosage level is in the range of 5 mg to 50 mg for acute or chronic regimens . the above tnf antagonists may be administered intranasally in the human and the dosage level is in the range of 0 . 1 mg to 10 mg for acute or chronic regimens . the above tnf antagonists may be administered intramuscularly in the human and the dosage level is in the range of 25 mg to 100 mg . the above tnf antagonists may be administered intravenously in the human and the dosage level is in the range of 2 . 5 mg / kg to 20 mg / kg . the above tnf antagonists may be administered transepidermally in the human and the dosage level is in the range of 10 mg to 100 mg . the above tnf antagonists may be administered by inhaling by the human and the dosage level is in the range of 0 . 2 mg to 40 mg . the above tnf antagonists may be administered orally by the human and the dosage level is in the range of 10 mg to 300 mg . etanercept is administered intramuscularly in a human wherein the dosage level is in the range of 25 mg to 100 mg . infliximab is administered intravenously in a human wherein the dosage level is in the range of 2 . 5 mg / kg to 20 mg / kg . etanercept is administered subcutaneously in a human wherein the dosage level is in the range of 5 mg to 50 mg . the thalidomide group is administered orally to a human wherein the dosage level is in the range of 10 mg to 300 mg . the above tnf antagonists may be administered at a dosage interval of from once a day to once every six months . etanercept is usually administered twice a week ; with a range from twice a week to once per week . d2e7 is usually administered twice a month , with a range from once a week to once per month . il - 1 ra is usually administered three times a week , with a range from once per day to once per week . the usual subcutaneous dose of etanercept is 25 mg twice per week . the usual subcutaneous dose of d2e7 is 20 mg , with a range from 5 mg to 40 mg . il - 1 ra and il - 1 r type ii dosages are similar and are approximately 0 . 02 to 3 . 0 mg / kg when given daily by subcutaneous bolus injection . the usual dosage and route of administration for famciclovir is 500 mg given orally either bid or tid . the usual dosage and route of administration for valaciclovir is 500 mg to 1 gram given orally bid . the usual dosage and route of administration for acyclovir is 400 mg to 800 mg given orally every 5 hours . for idiopathic sudden sensorineural hearing loss it may also be administered intravenously . accordingly , an advantage of the present invention is to provide a tnf antagonist , and / or an interleukin - 1 antagonist , for treating hearing loss in a human , wherein the use of these antagonists results in the amelioration of hearing loss in a human . another advantage of the present invention is that it provides a tnf antagonist for the treatment of presbycusis in a human such that the use of this antagonist results in improved hearing . another advantage of the present invention is that it provides a tnf antagonist for the treatment of sensorineural hearing loss in a human such that the use of this antagonist results in improved hearing . another advantage of the present invention is that it provides a tnf antagonist for the treatment of sensorineural hearing loss in a human such that the use of this antagonist results in improved hearing without the use of a hearing aid , in a manner that is both safe and effective . another advantage of the present invention is that it provides a tnf antagonist and / or interleukin - 1 antagonist for the treatment of hearing loss in a human such that the use of this antagonist results in improved hearing without the need for surgery . another advantage of the present invention is that it provides a tnf antagonist and an interleukin - 1 antagonist for the treatment of sensorineural hearing loss in a human such that the use of these antagonists together results in improved hearing , to an extent greater than the use of either one of these agents alone . another advantage of the present invention is that it provides a tnf antagonist and an anti - viral medication for the treatment of sensorineural hearing loss in a human such that the use of these medications together results in improved hearing , to an extent greater than the use of either one of these agents alone . another advantage of the present invention is that it provides novel and improved routes of administration for the selected tnf antagonist and / or interleukin - 1 antagonist for the treatment of sensorineural hearing loss in a human such that the use of this antagonist in this manner results in improved hearing with a method that is both safe , effective , and economical . a latitude of modification , change , and substitution is intended in the foregoing disclosure , and in some instances , some features of the invention will be employed without a corresponding use of other features . accordingly , it is appropriate that the appended claims be construed broadly and in a manner consistent with the spirit and scope of the invention herein . adams et al . 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