IPF- is your diagnosis correct?

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,

VARGATEF

Vargatef (BIBF-1120)is a multikinase inhibitor under development by Boehringer-Ingelheim primarily as an antiangiogenic and antineoplastic (ovarian and non-small cell lung cancer) agent. It inhibits kinase receptors that mediate the effects of vascular endothelial growth factor (VEGF), platelet derived (PDGFalpha), fibroblasts growth factor (FGF) and Src family of kinases (Lck, Lyn, and FLT-3). Cell proliferation is inhibited by vargatef at 10-80 nmol/L. Currently 18 clinical trials with Vargatef in cancer and 3 in idiopathic pulmonary fibrosis (IPF) are listed on Clinicaltrials.gov. One Phase I safety study and one Phase II study with Vagatef in patients with IPF have been completed, but the results of the phase II trial have not been posted by the sponsor. Another trial is being planned in Japan.

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

TRANILAST IN PULMONARY FIBROSIS

Tranilast (RIZABEN) is an old antiallergic drug, it is sold in Japan by KISSEY Pharmaceutical company for the treatment of allergies and also hypertrophic scar formation. Nuon Pharmaceuticals (San Mateo,CA) is developing it for new indications, including gout, rheumatoid arthritis and MS. Considerable amount of information on its pharmacology is available. Tranilast has been found to inhibit collagen synthesis in fibroblasts, decrease production of IL-6 and IL-8, inhibit VEGF-induced proliferation and migration of vascular endothelial cells, and to bind to aryl hydrocarbon receptors. These and other findings suggest that tranilast could be useful in the treatment of pulmonary fibrosis. Unfortunately, no clinical studies
in this indication are available or even planned.