Monday, November 22, 2010

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,

Monday, November 8, 2010

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.

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

Thursday, November 4, 2010

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.

Thursday, October 7, 2010

Missing drugs

Idiopathic Pulmonary Fibrosis (IPF) is one of one of many diseases for which there is no Food and Drug Administration (FDA) approved drugs in USA. This does not mean, however, that there are no drugs of possible benefit for this disease. Based on the recommendation of Thoracic Society some pulmonary physicians prescribe glucocorticoids (e.g. prednisone) with or without immunosuppressants (e.g. azathioprine) . Only occasional benefit has been reported with this approach. Without FDA approval or recommendation of a professional society physicians are understandably reluctant to prescribe drugs that can conceivably be useful in the treatment of IPF, although they have right to prescribe drugs off-label. The reasons for this reluctancy include potential lawsuits and cost of malpractice insurance. There is also no readily available information source on the off-label use of drugs approved for other indications. Neither FDA, nor textbooks or databases provide such information and pharmaceutical companies are strictly prohibited to inform physicians about potential off-label indications for their drugs. One of the drugs used off-label in IPF is N-methyl-acetylcysteine (known also as NAC), a glutathione precursor and powerful antioxidant and hepatoprotective. In USA NAC is approved and commercially available (ACETADOTE) as an antidote for acetaminophen intoxication, but not other indications. Its usefulness in the therapy of IPF in combination with glucosteroids was suggested by a clinical trial (1), that led to still more ongoing trials. Since NAC's toxicity is very low and there is an urgent need for IPF therapeutics, NAC should be made available to all IPF patients. Fortunately, it is available also as a dietary supplement from Puritan's Pride, although this company cannot provide any information on its use in IPF. Even if additional clinical trial confirm effectiveness of NAC in IPF, it will probably never become a standard IPF therapeutic, since no pharmaceutical company will be capable of covering the cost of NAC development for this new indication without use patent coverage. NAC's availability for a very low cost as a dietary supplement will also further complicate its development as an IPF drug.

Wednesday, June 23, 2010

IPF SYMPTOMATOLOGY

Since Idiopathic Pulmonary Fibrosis (IPF) may not be a single disease, it is not surprising that disease symptoms may vary among patients. Also in the same patient the symptoms may differ with the stage of the disease. A chronic postnasal drip was my first symptom. I attributed subsequent attacks of non-productive cough to throat irritation caused by nasal discharge due to sinus infection. I consulted otorhinolaryngologist who found no evidence of any sinus disease. The persistent cough attacks in the mornings led my family physician to refer me to a radiologist for a chest X-ray and subsequently to a cardiologist because of slight right heart enlargement. Cardiologist found no evidence of heart failure and referred me to a pulmonologist who made a tentative diagnosis of IPF on the basis of X-ray, catscan and pulmonary function test.
At ca 3 years after the initial diagnosis I first experienced oxygen desaturation on exercise. Now, at 8 years after diagnosis, this is my major symptom. My arterial blood oxygen levels decrease from 95% at rest to as low as 83% after a few steps around the house. Desaturation is always associated with tachycardia, my heart increases from 70 or 80 beats/min to 110 or even 120 beats/min. Oxygen inhalation reduces desaturation effect but not necessarily cardiac acceleration. Postnasal drip is now replaced by frontal nasal discharge that is enhanced by oxygen inhalation. Another symptom at the late stage of the disease is a disturbance in temperature regulation. A burning feet sensation appears to be independent of either oxygen saturation levels or of actual skin temperature. If oxygen saturation is lowered below 90% an attack of dry cough is likely to follow, but occasionally I had cough attacks even at normal blood oxygen levels. Another symptom of the disease is weight loss; I started to loose weight at ca 6 years after diagnosis and lost ca 25 pounds within the last two years.
Hypersensitivity diseases are often associated with skin eruptions. I experienced eruptions in anal region that responded to local antihistaminics or steroids. These eruptions may indicate hypersensitivity to a dietary component, cytokine or a bacterial toxin. They may conceivably help in the elucidation of the etiology of my disease.

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

Wednesday, February 10, 2010

FDA meeting on pirfenidone
FDA Advisory Committee is meeeting on March 9 2010 to consider approval of pirfenidone for the treatment of pulmonary fibrosis. I am submitting the following opinion to FDA to be considered at this meeting:

My Experience with Idiopathic Pulmonary Fibrosis (IPF)

I am a retired MD pharmacologist and for the last 9 years an IPF patient.

As a patient I experienced an unusually slow progression of the disease: a gradual suffocation leading to a loss of my ability to run, climb stairs and now even walk without oxygen. Attacks of a severe unproductive cough have made the life particularly miserable. I am a patient at Yale pulmonary clinic but the best pulmonary physicians cannot cure me. I am not eligible for lung transplantation and my therapy consists only of oxygen, since there are no drugs capable of alleviating my suffering. In the clinic I am having annual pulmonary function tests to document a gradual decline in most parameters. There is also a support group of patients with IPF to share experiences. I am learning that some of the patients are in worse shape than I am. They are in wheelchairs and can no longer dress or take a shower without the help of a caregiver. I can see myself in a similar situation in the near future.

As a scientist I am deeply disturbed by our failure to recognize the medical need and to develop drugs for the treatment of IPF. Very little research is ongoing in this field at either academic institutions or the pharmaceutical industry. I spent a good portion of the last year researching IPF and the approaches to its therapy. My research culminated in an extensive review article published last December (Scriabine A and Rabin D.U.. New developments in the therapy of pulmonary fibrosis. In: Contemporary aspects of biomedical research: drug discovery. Enna S.J. and Williams, M. Eds. Academic Press 2009; 419-464). Targets for antifibrotic drugs have been proposed and models of fibrotic diseases are available, but only pirfenidone offers some hope for IPF patients in the near future. IPF is probably not a single disease, but a group of pulmonary diseases with similar pathology, but different etiology. If so, one drug is not likely to help every patient diagnosed with IPF and clinical trials will not demonstrate uniform efficacy in a heterogeneous population. Under these circumstances safety should be the major consideration for drug approval.

Alexander Scriabine, MD
ascriabine@comcast.net
435 Colonial Road
Guilford, CT 06437

Friday, January 15, 2010

Pulmonary Alveolar Proteinosis (PAP) vs Idiopathic Pulmonary Fibrosis (IPF) - Diagnostic Considerations
PAP is a rare clinical syndrome that is characterized by the accumulation of surfactant in the pulmonary airspaces (Greenhill SR and Kotton DN, 2009). Lung biopsies usually reveal presence of diastase-resistant intra-alveolar exudate with minimal interstitial fibrosis and "honeycombing". In some patients with PAP, however, interstitial fibrosis can be considerable and at least two PAP patients were initially thought to have IPF (Arbiser ZK et al., 2003). PAP is no longer idiopathic, since functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to cause the disease. The presence of autoantibodies against GM-CSF in serum is considered to be diagnostic for PAP (Kitamura T et al., 1999; Bonfield, TL et al., 2002). It is highly important to excude PAP as a possible diagnosis since the prognosis of PAP and IPF are different. The life expectancy of PAP patients is longer, 5-year mortality is 20% vs 80% for IPF patients. Also, patients with PAP favorably respond to pulmonary lavage and can possibly be treated with GM-CSF. It is unfortunate that GM-CSF antibodies test is not yet widely available in clinical laboratories.
Arbiser ZK et al. Ann Diagn Pathol 7:82-86, 2003
Bonfield TL et al. Clin Immunol 105:324-350, 2002.
Greenhill SR and Kotton. Chest 136:571-577, 2009
Kitamura T et al. J Exp Med 190:875-880, 1999.

Monday, January 4, 2010

IPF symptomatology

The first symptom of my disease, idiopathic pulmonary fibrosis (IPF), was cough. It appeared to be caused by a post-nasal drip. I assumed that my sinuses may have been infected and I contacted otolaryngologist who ordered scan of the sinuses and found nothing. The cough was initially non-productive, it lasted for ca 30 minutes every morning and subsided after breakfast. IPF was diagnosed at Yale pulmonary clinic on the basis of X-ray, pulmonary function tests and lung scan. It was explained to me that IPF is a terminal disease and that there are no FDA approved drugs for the treatment of IPF. The only therapy, recommended by the Thoracic society, consists of steroids (e.g. prednisolone) and/or immunosuppressants (e.g. azathioprine). This therapy has not been shown to prolong life expectancy, is ineffective in the majority of patients and is associated with substantial side effects. I chose not to be treated and used candies to reduce the severity of cough. I learned from the literature that antioxidants may have antifibrotic activity and treated myself with vitamin C (slow release), 1 g per day and N-acetyl cysteine ( 2 x 600 mg per day). The only other symptom I experienced early in the disease was what I called, "miniapnea", inability to breathe for a few seconds, followed by complete recovery. Thereafter, dyspnea during and after exertion became the major symptom.
Initially it was uphill walking that caused dyspnea, but gradually walking on the flat surface became difficult as well. Dyspnea was associated with oxygen desaturation, as measured with oximeter. Climbing steps to the 2nd floor at home reduced blood oxygen saturation very rapidly from 95% to 85 and eventually even to 78%. Breathing oxygen at 2 L/min for 5 to 10 minutes normalized oxygen levels. Desaturation below 90% was associated with dyspnea, dizziness, anxiety and occasional chest pain. The symptoms were proportional to the decrease in blood oxygen, they rapidly disappeared after oxygen inhalation. Thermoregulation appeared to be affected as well. Exposure of the skin to cold temperature led to oxygen desaturation and cough.
Another symptom was "burning feet" at night that was independent of actual skin or room temperature. The sensation was the same when the feet were hot or cold. Still another symptom was "running nose", nasal discharge of a very thin fluid, that was more pronounced during and after administration of oxygen.
Domestic tasks became difficult, I routinely desaturated in shower and switched to bath every second day. Initially, I could exercise on treadmill while inhaling oxygen, but later oxygen inhalation even at 3 L/min did not protect from desaturation during exercise. The disease appeared to progress in steps. The steps were initiated by common cold or other stress. Annual lung function tests indicated gradual decrease in vital capacity. I found it more and more difficult to maintain blood oxygen levels above 90%. According to the literature only 20% of patients are expecxted to survive 5 years after diagnosis. I am already in my 8th year. Does this mean that diagnosis may have been incorrect?