Stimualtion of angiotensin II type 2 receptors as a new approach to the therapy of pulmonary and renal fibrosis
I read today a review article by H.M. Siragy in J Clin Hypertension, 11: Suppl.1, S26-29, 2009 on angiotensin II subtype 2 receptor (AT2R): potential therapy. Apparently, stimulation of these receptors has many potential benefits including prevention of myocardial infarction, atherosclerosis, renal and pulmonary fibrosis, inflammatory injury and neurological deficits. The first synthetic small molecule agonists of this receptor were discovered by Wu et al. in the Department of Medicinal Chemistry, Uppsala University in Sweden (J Med Chem 49:7160-8, 2006). Pharmacological evaluation of their leading compound (C21) was reported by scientists from the Institute of Pharmacology at Charite, Berlin (Circulation 118:2523-32, 2008) and in abstracts of ESC/ISH meeting, Berlin, 2008. The renal antifibrotic effect of AT2R stimulation was demonstrated by Okada H et al. (Am J Nephrol 24:322-9, 2004). Sakai N et al ( J Hypertension 26:780-90, 2008) found that inhibition of AT2R signaling increased expression of type 1 collagen in isolated human fibrocytes. The publication of Siragy's article was supported by Daiichi Sankyo, Inc, a company apparently interested in promoting AT2R agonists (and possibly C21) for the treatment or prevention of cardiovascular diseases. C21 and/or a similar compound should be studied in experimental fibrosis and eventually developed as a novel antifibrotic drug.

December 12, 2009

Oxygen therapy of IPF
The only IPF therapy my pulmonologist, Dr. Richard Matthay of Yale, recommends is oxygen. I am currently using it during exercise and whenever my oxygen blood saturation gets below 90%. With the delivery rate of 2L/min I can bring oxygen saturation from 85 to 95% in ca 3 to 5 minutes. When I seat queitly in my chair oxygen saturation remains above 90%, but climbing stairs to second floor immediately reduces it to 80-82%. Oxygen therapy has not been shown to prolong life, but it restores normal breathing very rapidly, it also prevents or even abolishes a cough attack. I am concerned that excess oxygen will enhance formation of reactive oxygen species (ROS), e.g. hydrogen peroxide, hydroxy radicals etc. ROS are known to enhance fibrotic process and can be expected, therefore, to shorten life expectancy.
I am treating myself with antioxidants: N-acetyl cysteine (NAC), 2 X 600 mg, vitamin C, 1 g per day and resveratrol, 60 mg per day. Hopefully, these antioxidants will prevent excessive formation of ROS.

Living with IPF

IPF (idiopathic pulmonary fibrosis) is a terminal pulmonary disease with a life expectancy of 2 to 5 years after diagnosis. The lungs become fibrotic, "rubber-like", unable to function and maintain adequate oxygen levels in the blood. IPF affects more men than women and the incidence of the disease is increasing with age. The most likely patient is a 60 to 80 years old male. The cause of the disease in unknown, therefore, the name "idiopathic". There are no drugs approved for the therapy of IPF. Professional societies suggest steroids (e.g. prednisolone) and immunosuppressants (e.g. azathioprine). This therapy has not been shown to prolong life and is associated with severe side effects. Therefore, some pulmonologists recommend only oxygen as the sole therapy. The first symptom of the disease is dry cough, particularly in the morning. Gradually the patients develop shortness of breath, particularly in climbing hills or steps. The patients "desaturate" , this means that their blood oxygen saturation (as measured with finger oximeter) is easily diminishing, particularly with bending or any exercise. Normal oxygen saturation is 95 to 100%. while in patients with IPF it can easily decrease to 85 or even 75% after climbing a few steps. Oxygen saturation below 90% is associated with dizziness and further decline of oxygen levels can lead to loss of consiousness. The eventual death is usually multi-organ failure due to chronic oxygen deficiency. Pneumonia or any respiratory infection is likely to be deadly for patients with IPF. Only lung transplant offers a chance for IPF patients to avoid premature death. Many elderly patients are not eligible for lung transplant and, those who are, have to wait years for the availble lungs. It is not easy to live with IPF. Cough attacks and inability to perform daily tasks are particularly disturbing. Exercise under oxygen protection and psychological counseling can make the life of an IPF patient a liitle easier. Cough attacks do not respond to usual over-the counter antitussive drugs, but can occasionally respond to hydrocodone/homatropine mixture. Antioxidants have been shown to prevent experimental fibrosis in animals and are often used as a supportive therapy in patients with IPF. All IPF patients wait impatiently for development and release of new drugs, but curative therapy is not yet on the horizon. Alexander Scriabine, MD and also a patient with IPF