Methods of improving microvascular integrity
Inventors
Nicolls, Mark R. • Kossen, Karl • Cohen, Alan
Assignees
LEGACY PHARMA INC. SEZC • US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-9682071-B2
Publication Date
2017-06-20
Expiration Date
2034-03-13
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Abstract
The disclosure relates to methods of preserving or improving microvascular integrity in a patient in need thereof comprising administering pirfenidone therapy to the patient.
Core Innovation
The invention relates to methods of preserving or improving microvascular integrity in a patient by administering pirfenidone therapy. It is based on the discovery that pirfenidone preserves microvasculature integrity, demonstrated in a murine trachea allograft model where pirfenidone treatment prevented microvasculature impairment and maintained tissue oxygenation levels through at least day 12 post-transplantation, whereas untreated allografts exhibited loss of perfusion by day 10.
The problem being solved is the impairment and loss of microvascular integrity following injury such as ischemic insult or acute transplant rejection. Microvascular injury is characterized by leakage and loss of perfusion, which compromises tissue oxygenation and organ function. The microvasculature plays a critical role in long-term survival of solid organ transplants and other conditions, yet no therapies have previously addressed preserving microvascular integrity before the onset of fibrosis or overt symptoms.
The invention provides methods for administering pirfenidone or its analogs to patients with acute organ or tissue injury prior to diagnosis, onset, or signs of fibrosis to preserve or improve microvascular integrity, thereby reducing severity and sequelae of the injury. It also provides methods of treating microvascular disorders not associated with fibrosis by administering pirfenidone or analogs in amounts effective to treat such conditions. The disclosure includes use of various pirfenidone analogs, dosing regimens, routes of administration, co-therapies, and kits containing pirfenidone with instructions for preserving or improving microvascular integrity or treating microvascular disorders.
Claims Coverage
The patent includes three independent claims focused on a method of preserving or improving microvascular integrity or treating a microvascular disorder in bronchiolitis obliterans patients using pirfenidone administration.
Method for preserving or improving microvascular integrity or treating microvascular disorder in bronchiolitis obliterans patients
Administering pirfenidone to a patient suffering from bronchiolitis obliterans, wherein pirfenidone is administered prior to diagnosis, onset, or showing signs or symptoms of fibrosis.
Administration regimen with food for microvascular integrity improvement
Administering pirfenidone three times per day with food to patients suffering from bronchiolitis obliterans for preserving or improving microvascular integrity or treating a microvascular disorder.
Effective dosage regimen for microvascular integrity preservation or treatment
Administering about 2400 or 2403 mg/day of pirfenidone, given three times per day with food, to preserve or improve microvascular integrity or to treat a microvascular disorder in patients suffering from bronchiolitis obliterans.
The claims principally cover methods of using pirfenidone to preserve or improve microvascular integrity or treat microvascular disorders, specifically for bronchiolitis obliterans patients, emphasizing early administration before fibrosis onset, specific dosing schedules with food, and effective daily dosages around 2400 mg.
Stated Advantages
Pirfenidone treatment preserves microvascular integrity and maintains tissue oxygenation following acute injury or transplant rejection.
Pirfenidone significantly protects microvasculature from impairment and reduces fibrosis progression.
The preservation of microvascular integrity reduces the severity, symptoms, or sequelae of acute organ or tissue injury.
Pirfenidone or analog administration expands therapeutic uses beyond anti-fibrotic effects to treat microvascular disorders.
Documented Applications
Treatment or preservation of microvascular integrity in patients suffering from acute organ or tissue injury prior to fibrosis diagnosis or onset.
Treatment of microvascular disorders not associated with fibrosis, including diseases such as bronchiolitis obliterans, lung transplantation/chronic rejection, scleroderma, focal segmental glomerulosclerosis, Pneumotosis intestinalis, Susac's syndrome, atherosclerotic disease of renal, cardiac, brain or peripheral vasculature, and others explicitly listed.
Use in diverse diseases with microvascular impairment including dementia (non-Alzheimer's), small vessel disease unrelated to diabetes, microangiopathy, ischemia-reperfusion injury, and haemolytic uraemic syndrome.
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