I was wrongly diagnosed with idiopathic pulmonary fibrosis (IPF) 9 years ago. According to the medical literature the average survival is only 2 to 3 years after diagnosis. After 5 years I started wondering, why am I still alive? It turns out, it was a wrong diagnosis. I have Deep Vein Thrombosis (DVT) in my left leg for at least 10 years after my fall and leg injury. My left ankle was swelling every night, but there was no pain or any other symptoms. Emboli were traveling to my lungs leading to lung damage that was wrongly diagnosed as IPF. Now I developed pulmonary embolism (PE), a thrombus in the main pulmonary arttery that can be seen on the scan. For the last 10 days I am injecting myself subcutaneously with low dose heparin and taking orally 5 mg warfarin. I am expected to stay on warfarin for at least 6 months. I am also taking prednisone 30 mg once a day orally, and will remain on prednisone probably for another month (total 3 months). In 6 to 12 months I may even recover completely.
The wrong diagnosis of IPF is apparently not uncommon. K.C. Meyer, M.D. (Director of Interstitial Lung Disease Clinic at the Univ. of Wisconsin UW) in his Update on Clinical Trials for IPF (on Internet) lists 12 alternative diagnoses made at UW in patients claimed to suffer from IPF. They are: lymphangitic carcinoma, hypersensitivity pneumonitis, polyomyositis, scleroderma, Langerhans cell histiocytosis, NSIP, DIP, RBILD, chronic aspiration, sarcoidois, congestive heart failure, drug toxicity. DVT and PE should be now added to this list!
The DVT and PE diagnosis in my case was made by Erica Herzog, M.D., PhD, Yale Pulmonary Clinic. She questioned the cause of my left leg swelling and ordered ultrasound that revealed DVT.
Keywords: Idiopathic pulmonary fibrosis; deep vein thrombosis, pulmonary embolism; warfarin, prednisone,
Showing posts with label IPF. Show all posts
Showing posts with label IPF. Show all posts
Monday, November 22, 2010
Saturday, November 6, 2010
Ambroxol
Ambroxol is an old drug, It has been developed and marketed in Germany by Boehringer-Ingelheim in 1970s as a mucolytic agent. It is currenly available as a drug in 18 countries, including Germany, India and Russia, but not USA or Canada. It can be purchased in large amounts from Chinese chemical manufacturing companies and in small amounts for experimental use from Western chemical supply houses (e.g. Tocries Biosciences). There is no known safety issue with ambroxol, although one case of rhabdomyolysis has been reported in a patient who was treated with ambroxol as well as other drugs. Apparently, Boehringer-Ingelheim did not apply for registration of ambroxol in USA when the drug was still under patent. After patent expiration its marketing for the same indication did not make any commercial sense.
Over the last 30 years ambroxol was studied extensively in various laboratories. Currently (2010) Medline lists 343 references to pharmacological or clinical studies with ambroxol. Malerba and Ragnoli reviewed 40 years of publications on pharmacological and clinical findings with ambroxol (1). In a more recent review article Gupta emphazised the need for well conducted clinical studies with ambroxol in severe obstructive airway disorders (2). Ambroxol was found to increase production of lung surfactant protein, to have antiinflammatory, antioxidant, local anesthetic, analgesic activities as well as to inhibit neuronal sodium channels and reduce murine influenza virus proliferation. Ambroxol was shown to reduce production of proinflammatory cytokines, including platelet derived growth factor (PDGF), TNFalpha, IL-1, IL-10 and IL-12(3-7). In some, paticularly severly ill, patients ambroxol reduced acute exacerbations of chronic pulmonary obstructive disease (e.g. COPD)(8). The pharmacological profile of ambroxol, in particularly, its ability to reduce release of cytokines, suggests its possible usefulness not only in obstructive diseases, but also in pulmonary fibrosis. Its clinical evaluation as a sole or adjunctive therapy of idiopathic pulmonary fibrosis (IPF) is indicated.
1. Malerba M., Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update Expert Opinion on the Drug Metabolism and Toxicology. 2008:4:1119-29.
2. Gupta R.R. Ambroxol - Resurgence of an old molecule as an antiinflammatory agent
in chronic obstructive airway disease. Lung India: 2010:22:, 46-9.
3. Betz, R. Glukokortikosteroide und Ambroxol hemmen die Sekretion entzuendungsfoerdernder Zytokine in tracheobronchialen Epithelzellen; Moegliche Rolle des Transkriptionsfaktors NF-kappaB. Pneumologie, 1997:51: 491-2.
4. Gibbs, B.F., Schmutzler W., Vollrath, I.B., Brosthardt P., Braam U., Wolff, H.H.,Zwadlo-Klarwasser, G. Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells. Inflammation Research, 1999:48:86-93.
5. Alhara M., Dobashi K, Aklyama M, Naruse I, Nakazawa T, Mori M. Effect of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages. Respiration. 2000: 67:662-71.
6.Utsugi M., Dobashi K., Kogo Y., Masubuchi K., Shimizu, Y., Endou K., Nakazawa T., and Mori M. Ambroxolinhibits platelet derived growth factor production in human monocytic cells.Eur J Pharmacol 2002: 436:47-51.
7. Gaida W., Klinder K., Arndt K., Weiser T., Ambroxol, a Nav 1,8-preferring Na(+)
channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacol 2005:49:1220-7
Over the last 30 years ambroxol was studied extensively in various laboratories. Currently (2010) Medline lists 343 references to pharmacological or clinical studies with ambroxol. Malerba and Ragnoli reviewed 40 years of publications on pharmacological and clinical findings with ambroxol (1). In a more recent review article Gupta emphazised the need for well conducted clinical studies with ambroxol in severe obstructive airway disorders (2). Ambroxol was found to increase production of lung surfactant protein, to have antiinflammatory, antioxidant, local anesthetic, analgesic activities as well as to inhibit neuronal sodium channels and reduce murine influenza virus proliferation. Ambroxol was shown to reduce production of proinflammatory cytokines, including platelet derived growth factor (PDGF), TNFalpha, IL-1, IL-10 and IL-12(3-7). In some, paticularly severly ill, patients ambroxol reduced acute exacerbations of chronic pulmonary obstructive disease (e.g. COPD)(8). The pharmacological profile of ambroxol, in particularly, its ability to reduce release of cytokines, suggests its possible usefulness not only in obstructive diseases, but also in pulmonary fibrosis. Its clinical evaluation as a sole or adjunctive therapy of idiopathic pulmonary fibrosis (IPF) is indicated.
1. Malerba M., Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update Expert Opinion on the Drug Metabolism and Toxicology. 2008:4:1119-29.
2. Gupta R.R. Ambroxol - Resurgence of an old molecule as an antiinflammatory agent
in chronic obstructive airway disease. Lung India: 2010:22:, 46-9.
3. Betz, R. Glukokortikosteroide und Ambroxol hemmen die Sekretion entzuendungsfoerdernder Zytokine in tracheobronchialen Epithelzellen; Moegliche Rolle des Transkriptionsfaktors NF-kappaB. Pneumologie, 1997:51: 491-2.
4. Gibbs, B.F., Schmutzler W., Vollrath, I.B., Brosthardt P., Braam U., Wolff, H.H.,Zwadlo-Klarwasser, G. Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells. Inflammation Research, 1999:48:86-93.
5. Alhara M., Dobashi K, Aklyama M, Naruse I, Nakazawa T, Mori M. Effect of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages. Respiration. 2000: 67:662-71.
6.Utsugi M., Dobashi K., Kogo Y., Masubuchi K., Shimizu, Y., Endou K., Nakazawa T., and Mori M. Ambroxolinhibits platelet derived growth factor production in human monocytic cells.Eur J Pharmacol 2002: 436:47-51.
7. Gaida W., Klinder K., Arndt K., Weiser T., Ambroxol, a Nav 1,8-preferring Na(+)
channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacol 2005:49:1220-7
Wednesday, May 26, 2010
Pirfenidone - comment to FDA
On 5.26.10 I forwarded the following comment to Food and Drug Administration:
The decision of the Food and Drug Administration (FDA) not to approve pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) was highly disappointing to all patinets suffering from this disease, their caregivers, as well as physicians who are treating IPF patients. The fact that that the Agency did not follow the advice of their Advisory Committee, which voted 9:3 for the approval of pirfenidone, is extremely disturbing. The Agency also did not listen to pleas of patients who have been waiting impatiently for any drug that could possibly offer some hope in alleviating their suffering or prolonging their life expectancy. The Agency found it impossible to deviate from the established guidelines, even though the safety of pirfenidone was not quetioned.
The request for another Phase III trial to confirm the efficacy of pirfenidone may sound reasonable, but in reality it makes the eventual marketing of pirfenidone unlikely, even if another trial confirms its efficacy. Al leaast 4 years and a few hundred millions of dollars will be needed for another trial and its evaluation. If the trial starts in 2011, FDA approval cannot be expected before 2015. The proposed use of pirfenidone in IPF is covered, however by a 1997 patent that will expire in 2014. No single pharmaceutical company can afford to pay for the development and marketing of a drug without patent protection and/or a few years of exclusivity.
No drug can be expected to produce absolutely conclusive results in patients with IPF. IPF is most probably not a single disease but a collection of fibrotic lung diseases with unknown causes, so that in respect to etiology the patient population will be heterogenous and pirfenidone cannot, therefore, be expected to help all IPF patients. The fact that pirfenidone helps some of the patients with IPF should provide an adequate basis for its approval, since the risk-benefit ratio favors the drug.
A possible solution for the FDA is to create a new category of drugs with only "conditional approval" which would not cary an approved disease indication, but would claim, like for "dietary supplements", only a possible supporting role in the maintenance of function of certain organs (lungs in the case of pirfenidone). These drugs could be conditionally appproved by FDA on the basis of their safety record and the medical profession could be responsible for their use in specific diseases. This "conditional approval" could be withdrawn after 5 years, if additional documentation is not provided. After completion of all required clinical trials a final approval would be considered. In any case, I hope that the FDA would be willing to reconsider or to modify their decision to request another Phase III trial for pirfenidone.
Sincerely, Alexander Scriabine, M.D., Guilford, CT, May 26. 2010
Pharmacologist and IPF patient
The decision of the Food and Drug Administration (FDA) not to approve pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) was highly disappointing to all patinets suffering from this disease, their caregivers, as well as physicians who are treating IPF patients. The fact that that the Agency did not follow the advice of their Advisory Committee, which voted 9:3 for the approval of pirfenidone, is extremely disturbing. The Agency also did not listen to pleas of patients who have been waiting impatiently for any drug that could possibly offer some hope in alleviating their suffering or prolonging their life expectancy. The Agency found it impossible to deviate from the established guidelines, even though the safety of pirfenidone was not quetioned.
The request for another Phase III trial to confirm the efficacy of pirfenidone may sound reasonable, but in reality it makes the eventual marketing of pirfenidone unlikely, even if another trial confirms its efficacy. Al leaast 4 years and a few hundred millions of dollars will be needed for another trial and its evaluation. If the trial starts in 2011, FDA approval cannot be expected before 2015. The proposed use of pirfenidone in IPF is covered, however by a 1997 patent that will expire in 2014. No single pharmaceutical company can afford to pay for the development and marketing of a drug without patent protection and/or a few years of exclusivity.
No drug can be expected to produce absolutely conclusive results in patients with IPF. IPF is most probably not a single disease but a collection of fibrotic lung diseases with unknown causes, so that in respect to etiology the patient population will be heterogenous and pirfenidone cannot, therefore, be expected to help all IPF patients. The fact that pirfenidone helps some of the patients with IPF should provide an adequate basis for its approval, since the risk-benefit ratio favors the drug.
A possible solution for the FDA is to create a new category of drugs with only "conditional approval" which would not cary an approved disease indication, but would claim, like for "dietary supplements", only a possible supporting role in the maintenance of function of certain organs (lungs in the case of pirfenidone). These drugs could be conditionally appproved by FDA on the basis of their safety record and the medical profession could be responsible for their use in specific diseases. This "conditional approval" could be withdrawn after 5 years, if additional documentation is not provided. After completion of all required clinical trials a final approval would be considered. In any case, I hope that the FDA would be willing to reconsider or to modify their decision to request another Phase III trial for pirfenidone.
Sincerely, Alexander Scriabine, M.D., Guilford, CT, May 26. 2010
Pharmacologist and IPF patient
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