Monday, September 28, 2009

Animal Models of Pulmonary Fibrosis

Reliable animal disease models greatly facilitate drug development, even when the precise trigger of a disease is unknown. Since this is the case with idiopathic pulmonary fibrosis (IPF), the availability of an animal model is particularly important for successful development of antifibrotic drugs. The standard models of pulmonary fibrosis are bleomycin-treated rodents. Extensive reviews of the bleomycin model and of its use in pulmonary research were recently published (Moeller et al., 2008). A single intratracheal administration of bleomycin produces pulmonary fibrosis in rodents, with a maximal effect at between 20 to 28 days after exposure to the drug. Thereafter fibrosis slowly resolves. The cause and the spontaneous resolution of fibrosis differentiate this model from IPF in humans, although it is similar with respect to the production of cytokines and free radicals. Moeller et al. listed published studies on the prevention or treatment of bleomycin-induced fibrosis in laboratory animals. They point out that to mimic clinical situations the potential antifibrotic drugs should be administered after, and not prior to, the development of bleomycin-induced fibrosis. Antioxidants, angiotensin converting enzyme inhibitors, angiotensin antagonists, immunosuppressants, macrolide antibiotics and many other agents are reported to reduce fibrosis in bleomycin-treated animals. Most of the drugs were never tested for antifibrotic activity in humans whereas others were ineffective in clinical trials. However, the fact that pirfenidone is effective in this model, and has yielded promising clinical results in a Phase III trial, suggests the potential utility of this model in drug discovery.
Other drugs or chemicals known to produce pulmonary fibrosis in humans are also
used in the search for potential antifibrotic drugs. For example, Cantor et al. (1984) produced amiodarone-induced fibrosis in hamsters, while Leeder et al. (1994) demonstrated a reduction of amiodarone-induced pulmonary toxicity by N-acetyl cysteine (NAC). Pulmonary fibrosis can be also produced in rats by paraquat and the angiotensin converting enzyme inhibitors captopril and enalapril reduce paraquat-induced pulmonary fibrosis in rats (Ghazi-Khansari et al., 2007). Parra et al. (2008) induced pulmonary fibrosis in mice by butyl-hydroxytoluene and found it to be histologically identical to fibrosis in humans with IPF. Ask et al. (2008) have induced pulmonary fibrosis in rats by adenoviral gene transfer of transforming growth factor beta (TGFβ) and assessed progression of the disease by non-invasive techniques.
Attempts have also been made to develop in vitro models of pulmonary fibrosis. As an example, cadmium chloride in combination with TGFβ produces fibrosis in rat lung slice cultures (Lin et al., 1998).
The adequate technology for the preclinical evaluation of potential antifibrotic drugs is available, although it is obvious that neither animal models nor in vitro techniques mimic the human condition in all respects.

Ask, K., Labiris, R., Farkas, L., Moeller, A., Froese, A., Farncombe, T., McClelland, G.B., Inman, M., Gauldie, J., and Martin, R.J. (2008). Comparison between conventional and “clinical” assessment of lung fibrosis. J Transl Med 6:16.

Cantor, J.O., Osman, M., Cerreta, J.M., Suarez, R., Mandi, I., and Turino, G.M. (1984). Amiodarone-induced pulmonary fibrosis in hamsters. Exp. Lung. Res. 6:1-10.

Ghazi-Khansari, M., Mohammadi-Karakani, A., Sotoudeh, M., Mokhtary, P., Pour-Esmaeil, E., Maghsoud, S. (2007). Antifibrotic effect of captopril and enalapril on paraquat-induced fibrosis in rats. J. Appl. Toxicol. 27:342-349.

Leeder, R.G., Brien, J.F., and Massey T.E. (1994). Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster. Can. J. Physiol. Pharmacol. 72:613-621.

Lin, C.J., Yang, P.C., Hsu, M.T., Yew, F.H., Liu, T.Y., Shun, C., Tyan, S.W., and Lee, T.C. (1998). Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming factor –beta1. Toxicology 127: 157-166.

Moeller, A., Ask, K., Warburton, D., Gauldie, J., and Kolb, M. (2008). The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol. 40:362-382.

Parra, E.R., Boufelli, G., Berthanha, F., Samorano, Lde.P., Aguiar, A.C. Jr., Costa, F.M., Capelozzi, V.L., Barbas-Filho, J.V. (2008). Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene. Int. J. Exp. Pathol. 89:350-357.

Alex Scriabine, MD
Guilford, CT

Monday, September 21, 2009

WHERE ARE DRUGS FOR TREATMENT OF IPF (IDIOPATHIC PULMONARY FIBROSIS)?_

During the last decade extensive research has been conducted on IPF and therapeutic approaches to treat this condition. New targets for drug development, as well as new leads, were identified. However, there are still no FDA-approved drugs for the treatment of this condition

There have been several barriers to the development of effective therapeutics for IPF. One is the fact that IPF is considered an orphan disease because of its prevalence, lessening the urgency for finding a cure. Moreover, the pharmaceutical industry underestimates the medical need and the potential profitability of antifibrotic drugs. Because the population in developed countries is rapidly aging, IPF is becoming a more common disorder. It is anticipated that companies will begin to look more favorably on drug development in this area as it is becoming apparent that fibrotic diseases as a group may share the same therapeutic targets. In this case, drugs developed for the treatment of pulmonary fibrosis may be useful in the therapy of renal, myocardial, hepatic and other fibrotic diseases as well, broadening the use of such agents.

The complexity of fibrogenesis and the multiplicity of profibrotic and antifibrotic factors, are other reasons for the failure to develop effective drugs. With the advancement of basic research in fibrosis many new targets for drug development have been discovered. However, these discoveries have yet to be translated through to drug discovery and clinical testing. In addition, the consolidation of the pharmaceutical industry has resulted in more focused research programs and less enthusiasm for undertaking higher risk projects that lack “proof of concept”.

There is also a justifiable skepticism about the relevance of the in vitro or animal research methodology that is currently used in drug discovery. The findings of cell culture experiments are not always applicable to the whole organism, and results obtained in mice or rats may not be relevant to humans. Although the bleomycin-induced fibrosis in rodents test tends to identify false positive leads, it might be most relevant in the “therapeutic” rather than the “preventive” protocol. Animal models are often more sensitive than patients in clinical trials, as experimental animals are homogenous in genetic background, sex, age, weight, general health and diet. Compounds which are safe and effective at reasonable doses in a “therapeutic” protocol of bleomycin-induced fibrosis should be considered for optimization and eventual clinical evaluation.

Lack of patentability, toxicity, ignorance of the molecular target or questionable “drugability” of potential antifibrotic drugs are common barriers to their development. In today’s highly competitive environment, few companies are willing to pay for the development of a generic agent like N-acetyl cysteine for the treatment of IPF without proprietary protection. Also, some of the drugs identified as antifibrotics belong to chemical classes known for their toxicity, extensive metabolism, or poor bioavailability and, therefore, are not considered good candidates for development.

It is conceivable that a blockade of only one profibrotic factor cannot stop or reverse fibrogenesis. A drug combination product designed to affect multiple fibrogenic pathways may be required for the effective therapy of IPF.
Another strategy is to search for drugs to enhance resolution of fibrosis. It has been shown that experimental hepatic fibrosis in rodents can be resolved by drugs. The reversibility of pulmonary fibrosis is a controversial subject. It has been suggested that in pulmonary fibrosis the loss of basement membrane, and consequently of normal lung architecture, establishes the point of no return.. Perhaps at earlier stages of the disease pulmonary fibrosis is reversible. Unfortunately, the mechanism of resolution of fibrosis is poorly understood and only a few approaches for the development of fibrolytic targets have been identified.
A better understanding of fibrogenesis and fibrolysis will greatly facilitate discovery and development of new antifibrotic drugs. Based on past experience, many more years are needed to advance the knowledge base of this field to a level adequate for successful design and development of drugs capable to selectively modifying fibrosis in humans. In the interim, available leads should be optimized on the basis of their activity in mice with bleomycin-induced fibrosis or a similar model. If the endpoint of a clinical trial is mortality, the same endpoint should be used in an animal model.
There is also an urgent need for better biomarkers for use in clinical trials. The duration of trials of drugs for treating IPF can be substantially reduced in time and cost if mortality is replaced by an endpoint based on a meaningful biomarker.

The histories of pirfenidone in pulmonary fibrosis reveal several important issues with drug development. The antifibrotic effectiveness of pirfenidone in animals has been known for 14 years and in humans for 10 years. However, resounding proof of its efficacy in human IPF is still not available. This illustrates the imperfect nature of the drug development process and a lack of focus on fibrotic diseases in the pharmaceutical industry.

Saturday, September 19, 2009

IPF

September 19, 2009
IPF or Idiopathic Pulmonary Fibrosis is a chronic interstitial pneumonia of unknown cause and poor prognosis. The life expectancy of IPF patients has been estimated as 2 to 3 years after diagnosis. IPF is characterized by clinical, radiologic and histologic criteria. The frequently used therapy of steroids (prednisolone) and immunosuppressants (azothioprine) has not been shown to be effective. No drugs for the therapy of IPF are approved in the USA. Bosentan, pirfenidone and N-acetyl cysteine are currently in clinical trials with preliminary results suggesting they may prolong the life expectancy of patients with IPF. New approaches to the treatment of IPF have been proposed. They include endothelial and cytokine antagonists, and antioxidants. Japanese health authorities approved pirfenidone (Shionogi) for the tretment of IPF earlier this year. Additional clinical studies are neeed for its approval by Food and Drug Administration in the USA. Pirfenidone is and old drug and its possible usefulness in the therapy of IPF has been known for over 15 years. Why does it take so long to make pirfenidone available to IPF patients in this country? My blogs will try to answer this question and explore other possible approaches to the therapy of IPF.
Alex Scriabine, MD pharmacologist and an IPF patient.