Methods

Abstract

The present invention provides method, uses and agents for preventing or reducing cognitive decline in a patient following a planned inflammatory trigger. Such planned inflammatory trigger can be a surgical procedure or chemotherapy. The invention further provides methods, uses and agents for reducing cognitive decline in a patient with a cognitive disorder, wherein said patient has been exposed to an inflammatory trigger. Pharmaceutical compositions and kits are also provided.

1 . A method for preventing or reducing cognitive decline in a patient following a planned inflammatory trigger in said patient, the method comprising administering a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNFα) antagonist to said patient. 
     
     
         2 . The use of a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNFα) antagonist in the manufacture of a medicament for use in preventing or reducing cognitive decline in a patient following a planned inflammatory trigger in said patient. 
     
     
         3 . An agent for use in preventing or reducing cognitive decline in a patient following a planned inflammatory trigger in said patient, wherein the agent comprises a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNFα) antagonist. 
     
     
         4 . The method, use or agent of  claim 1 ,  2  or  3 , wherein the planned inflammatory trigger is surgery and the method, use or agent is for preventing or reducing post-operative cognitive dysfunction (POCD) in said patient. 
     
     
         5 . The method, use or agent of  claim 1 ,  2  or  3 , wherein the planned inflammatory trigger is chemotherapy. 
     
     
         6 . A method for reducing cognitive decline in a patient with a cognitive disorder, wherein said patient has been exposed to an inflammatory trigger, the method comprising administering a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNFα) antagonist to said patient after exposure of said patient to said inflammatory trigger. 
     
     
         7 . The use of a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNFα) antagonist in the manufacture of a medicament for use in reducing cognitive decline in a patient with a cognitive disorder, wherein said patient has been exposed to an inflammatory trigger. 
     
     
         8 . An agent for use in reducing cognitive decline in a patient with a cognitive disorder, wherein said patient has been exposed to an inflammatory trigger, and, wherein the agent comprises a therapeutically effective amount of a Tumour Necrosis Factor alpha (TNFα) antagonist. 
     
     
         9 . The method, use or agent of  claim 6 ,  7  or  8 , wherein the cognitive disorder is delirium, Alzheimer's Disease, multiple sclerosis, stroke, Parkinson's Disease, Huntington's Disease, dementia, frontotemporal dementia, vascular dementia, HIV dementia, Post-Traumatic Stress Disorder and/or Rheumatoid Arthritis. 
     
     
         10 . The method, use or agent of any one of  claims 6  to  9 , wherein the inflammatory trigger is infection, trauma, surgery, vaccination, arthritis, obesity, diabetes, stroke, cardiac arrest, burns, chemotherapy, blast injury, urinary tract infection (UTI), respiratory tract infection (RTI), HIV, poisoning, alcohol or other medication withdrawal, hypoxia, and/or head injury. 
     
     
         11 . The method, use or agent of  claim 4 , wherein the POCD is manifested as one or more of memory loss, memory impairment, concentration impairment, delirium, dementia and sickness behaviour. 
     
     
         12 . The method of  claim 1 ,  4 ,  5  or  6 , the method further comprising administering a therapeutically effective amount of an Interleukin 1 (IL-1) antagonist to said patient. 
     
     
         13 . The use or agent of  claim 2 ,  3 ,  4 ,  5 ,  7  or  8 , wherein the medicament or agent is for administration in combination with a therapeutically effective amount of an Interleukin 1 (IL-1) antagonist. 
     
     
         14 . The method, use or agent of  claim 12  or  13 , wherein the IL-1 antagonist is administered, or is for administration, before, after or simultaneously with the TNFα antagonist. 
     
     
         15 . The method, use or agent of  claim 12  or  13 , wherein the IL-1 antagonist is co-formulated with the TNFα antagonist. 
     
     
         16 . The method, use or agent of  claim 4  or  11 , wherein the TNFα antagonist is administered, or is for administration to the patient; before commencement of a surgical procedure; during a surgical procedure; or after completion of a surgical procedure, on said patient. 
     
     
         17 . The method, use or agent of  claim 16 , wherein the TNFα antagonist is administered, or is for administration, immediately before or up to 1 hour after completion of said surgical procedure. 
     
     
         18 . The method, use or agent of  claim 5 , wherein the TNFα antagonist is administered, or is for administration to the patient; before commencement of chemotherapy; during chemotherapy; or after completion of a round of treatment of chemotherapy on said patient. 
     
     
         19 . The method, use or agent of  claims 1  to  5 , wherein the patient has, or is at risk of developing, delirium, Alzheimer's Disease, multiple sclerosis, stroke, Parkinson's Disease, Huntington's Disease, dementia, frontotemporal dementia, vascular dementia, HIV dementia, Post-Traumatic Stress Disorder or Rheumatoid Arthritis. 
     
     
         20 . The method, use or agent of  claims 1  to  8 , wherein the patient is a human. 
     
     
         21 . The method, use or agent of  claim 20 , wherein the patient is less than 20 years of age, or over 50 years of age. 
     
     
         22 . The method, use or agent of  claims 1  to  21 , wherein the TNFα antagonist is a TNFα receptor antagonist. 
     
     
         23 . The method, use or agent of  claims 1  to  22 , wherein the TNFα antagonist is an antibody, an antibody fragment or fusion thereof. 
     
     
         24 . The method, use or agent of  claim 23 , wherein the TNFα antagonist is an anti-TNFα antibody. 
     
     
         25 . The method, use or agent of  claims 1  to  22 , wherein the TNFα antagonist is a small chemical entity. 
     
     
         26 . The method, use or agent of  claims 1  to  22 , wherein the TNFα antagonist is an siRNA molecule, an antisense oligonucleotide or a ribozyme. 
     
     
         27 . The method, use or agent of  claims 12  to  15 , wherein the IL-1 antagonist is an IL-1 receptor antagonist, an IL-1α antagonist, an IL-1β antagonist or a Toll-like receptor (TLR) antagonist. 
     
     
         28 . The method, use or agent of  claim 27 , wherein the IL-1 antagonist is an antibody, an antibody fragment or fusion thereof. 
     
     
         29 . The method, use or agent of  claim 27 , wherein the IL-1 antagonist is a small chemical entity. 
     
     
         30 . The method, use or agent of  claim 27 , therein the IL-1 antagonist is an siRNA molecule, an antisense oligonucleotide or a ribozyme. 
     
     
         31 . The method, use or agent of  claim 27 , wherein the IL-1 receptor antagonist is anakinra. 
     
     
         32 . The method, use or agent of  claim 12  or  13 , when dependent on  claim 4 , wherein the IL-1 antagonist is administered, or is for administration, to the patient; before commencement of a surgical procedure; during a surgical procedure; or after completion of a surgical procedure, on said patient. 
     
     
         33 . The method, use or agent of  claim 12  or  13 , when dependent on  claim 5 , wherein the IL-1 antagonist is administered, or is for administration to the patient; before commencement of chemotherapy; during chemotherapy; or after completion of a round of treatment of chemotherapy on said patient. 
     
     
         34 . The method, use or agent of  claim 4 ,  10 ,  11 ,  16 ,  17 ,  32  or  33 , wherein the surgical procedure is a cardiothoracic, an orthopaedic, a neurological, a vascular, a plastic & reconstructive, a gynaecological, an obstetric, a urological, a general, a head & neck, an ear, nose & throat (ENT), a paediatric, a dental, a maxillofacial, an ophthalmic, a pain management, a trauma, or a minor surgical procedure. 
     
     
         35 . The method, use or agent of  claim 34 , wherein the general surgical procedure is a colorectal, a hepatobiliary, or an upper gastro-intestinal surgical procedure. 
     
     
         36 . The method, use or agent of  claim 34 , wherein the minor surgical procedure is a catheterisation, a minor skin procedure, a minor orthopedic procedure, a nerve block, an endoscopy, a transoesophageal echocardiogram or another minor procedure. 
     
     
         37 . The method, use or agent of  claim 34 , wherein the surgical procedure is carried out under general anaesthesia, regional anaesthesia, local anaesthesia, sedation or a combination thereof. 
     
     
         38 . A kit of parts comprising an IL-1 antagonist and a TNFα antagonist for use in preventing or reducing cognitive decline in a patient following a planned inflammatory trigger. 
     
     
         39 . A kit of parts comprising an IL-1 antagonist and a TNFα antagonist for use in reducing cognitive decline in a patient with a cognitive disorder, wherein said patient has been exposed to an inflammatory trigger. 
     
     
         40 . A kit of parts comprising:
 an IL-1 antagoinist;   a TNFα antagonist; and   instructions for administration of said IL-1 antagoinist and TNFα antagonist to a patient before, during or after a planned inflammatory trigger.   
     
     
         41 . The kit of  claim 38  or  40 , wherein the planned inflammatory trigger is a surgical procedure or chemotherapy. 
     
     
         42 . A method for preventing or reducing cognitive decline in a patient following a planned inflammatory trigger in said patient, the method comprising administering a therapeutically effective amount of an Interleukin 1 (IL-1) antagonist to said patient. 
     
     
         43 . The method of  claim 42 , wherein the planned inflammatory trigger is surgery and the method is for preventing or reducing post-operative cognitive dysfunction (POCD). 
     
     
         44 . The method of  claim 42 , wherein the planned inflammatory trigger is chemotherapy. 
     
     
         45 . A method for reducing cognitive decline in a patient with a cognitive disorder, wherein said patient has been exposed to an inflammatory trigger, the method comprising administering a therapeutically effective amount of an Interleukin 1 (IL-1) antagonist to said patient after exposure of said patient to said inflammatory trigger. 
     
     
         46 . The method of  claim 45 , wherein the cognitive disorder is delirium, Alzheimer's Disease, multiple sclerosis, stroke, Parkinson's Disease, Huntington's Disease, dementia, frontotemporal dementia, vascular dementia, HIV dementia, Post-Traumatic Stress Disorder and/or Rheumatoid Arthritis. 
     
     
         47 . The method of  claim 45 , wherein the inflammatory trigger is infection, trauma, surgery, vaccination, arthritis, obesity, diabetes, stroke, cardiac arrest, burns, chemotherapy, blast injury, urinary tract infection (UTI), respiratory tract infection (RTI), HIV, poisoning, alcohol or other medication withdrawal, hypoxia, and/or head injury. 
     
     
         48 . The method of  claim 43 , wherein the POCD is manifested as one or more of memory loss, memory impairment, concentration impairment, delirium, dementia and sickness behaviour. 
     
     
         49 . The method of  claim 43 , wherein the patient has, or is at risk of developing, delirium, Alzheimer's Disease, multiple sclerosis, stroke, Parkinson's Disease, Huntington's Disease, dementia, frontotemporal dementia, vascular dementia, HIV dementia, Post-Traumatic Stress Disorder and/or Rheumatoid Arthritis. 
     
     
         50 . The method of  claim 42 , wherein the patient is a human. 
     
     
         51 . The method of  claim 50 , wherein the patient is less than 20 years of age or over 50 years of age. 
     
     
         52 . The method of  claim 42  to  45 , wherein the IL-1 antagonist is an IL-1 receptor antagonist, an IL-1α antagonist, an IL-1β antagonist or a Toll-like receptor (TLR) antagonist. 
     
     
         53 . The method of  claim 52 , wherein the IL-1 antagonist is an antibody, an antibody fragment or fusion thereof. 
     
     
         54 . The method of  claim 52 , wherein the IL-1 antagonist is a small chemical entity. 
     
     
         55 . The method of  claim 52 , therein the IL-1 antagonist is an siRNA molecule, an antisense oligonucleotide or a ribozyme. 
     
     
         56 . The method of  claim 52 , wherein the IL-1 receptor antagonist is anakinra. 
     
     
         57 . The method of  claim 43 , wherein the IL-1 antagonist is administered to the patient; before commencement of a surgical procedure; during a surgical procedure; or after completion of a surgical procedure, on said patient. 
     
     
         58 . The method of  claim 57 , wherein the surgical procedure is a cardiothoracic, an orthopaedic, a neurological, a vascular, a plastic & reconstructive, a gynaecological, an obstetric, a urological, a general, a head & neck, an ear, nose & throat (ENT), a paediatric, a dental, a maxillofacial, an ophthalmic, a pain management, a trauma, or a minor surgical procedure. 
     
     
         59 . The method of  claim 58 , wherein the general surgical procedure is a colorectal, a hepatobiliary, or an upper gastro-intestinal surgical procedure. 
     
     
         60 . The method of  claim 58 , wherein the minor surgical procedure is a catheterisation, a minor skin procedure, a minor orthopedic procedure, a nerve block, an endoscopy, a transoesophageal echocardiogram or another minor procedure. 
     
     
         61 . The method of  claim 58 , wherein the surgical procedure is carried out under general anaesthesia, regional anaesthesia, local anaesthesia, sedation or a combination thereof.