Article: "New Anti-Inflammatory Molecule Safe" from Medpage Today.
I tried to do some research to find the original article that this article by Michael Smith from Medpage Today was referencing based on the citation at the end, but it turns out that it is actually an oral presentation by P. Wiesel and associates at the American College of Allergy, Asthma, and Immunology Conference in July 2009. This article describes a new and innovative drug, FX125L, that is considered an oral anti-inflammatory and is targeted for the treatment of mainly asthma and COPD. They claim that at even relatively high doses, the medication is safe. Based on the article, a very recent study was performed with 66 volunteers regarding the drug and doses ranging from 0.3 to 3,000 mg. I don't know about you, but that is a VERY large range of dosing. According to the abstract of the presentation, there were no serious side effects, but some effects were adverse with the most common side effect being headache (4 on FX125L and 2 on placebo), dizziness (1 on FX125L and 1 on placebo), and nausea (1 on FX125L and 1 on placebo).
According to the 6th edition of Immunology - A Short Course by Coico, et.al, asthma involves cytokine-induced recruitment of inflammatory cells (mainly eosinophils) that can cause tissue injury due to toxic substances released by these cells that can include oxygen radicals, nitric oxide, and cytokines. Cytokines released by TH2 cells and mast cells (IL-4, IL-13, and TNFalpha) upregulate expression of leukocyte and endothelial adhesion molecules such as ICAM-1 and E-selectin. Because of these adhesion molecules, there in an increase in eosinophil-endothelial cell adhesion that causes migration and prolonged survival within lung tissue.
So, what is FX125L? It seems to be a broad-spectrum chemokine receptor inhibitor. FX125L acts similar to a corticosteroid, but the article claims that it doesn't have as adverse effects as corticosteroids. According to theasthmacenter.org, corticosteroids (like Advair and Pulmicort) in asthma suppress the inflammatory reaction that causes swelling and narrowing of the bronchi. It is normally used when asthma can't be controlled with bronchodilaters like albuterol. The most significant side effects with corticosteroids is usually caused by a high daily oral dose over a period of months to years.
The exact molecular action of FX125L was hard to find. The only thing I could find was that it blocked migration of inflammatory cells. This would obviously prevent the inflammation from occuring if the cells associated with inflammation are unable to chemotax to the site. Also, according to the presentation abstract, FX125L inhibits neutrophil recruitment to the lung. Neutrophils are the first line of defense against fungal and bacterial infections, but when recruited to the lung, can release chemokines and cytokines that enhance inflammation such as IL-6, IL-8, IL-1beta, andTNFalpha.
The term "broad-spectrum" usually refers to being effective over a wide range. It would be interesting to know exactly how this is accomplished. If FX125L targets a specific receptor, how can it be broad-spectrum? I think about antibiotics and how there are broad-spectrum ones that are used to treat a number of strains of bacteria that cause infections so it can be prescribed for many infections. How does FX125L target chemokine receptors in general and manage to target a particular one? Maybe it targets a specific receptor that is associated with inflammation in general or in most to all cases. This is one of many questions that I hope will be explained soon as the research progresses.
"ACAAI: New Anti-Inflammatory Molecule Safe" Medpage Today. Ed. Michael Smith. 9 Nov. 2009. Web. 16 Nov. 2009..
Presentation - Wiesel P, et al "First clinical experience with FX125L, an anti-inflammatory oral small molecule with an entirely novel mechanism of action" Ann Allergy Asthma Immunol 2009; 103(5)(suppl 2): Abstract 5
Corticosteroids - http://www.theasthmacenter.org/manual/part2-12.html
Neutrophils - http://www.springerlink.com/content/j71781x837m85n12/fulltext.pdf
I tried to do some research to find the original article that this article by Michael Smith from Medpage Today was referencing based on the citation at the end, but it turns out that it is actually an oral presentation by P. Wiesel and associates at the American College of Allergy, Asthma, and Immunology Conference in July 2009. This article describes a new and innovative drug, FX125L, that is considered an oral anti-inflammatory and is targeted for the treatment of mainly asthma and COPD. They claim that at even relatively high doses, the medication is safe. Based on the article, a very recent study was performed with 66 volunteers regarding the drug and doses ranging from 0.3 to 3,000 mg. I don't know about you, but that is a VERY large range of dosing. According to the abstract of the presentation, there were no serious side effects, but some effects were adverse with the most common side effect being headache (4 on FX125L and 2 on placebo), dizziness (1 on FX125L and 1 on placebo), and nausea (1 on FX125L and 1 on placebo).
According to the 6th edition of Immunology - A Short Course by Coico, et.al, asthma involves cytokine-induced recruitment of inflammatory cells (mainly eosinophils) that can cause tissue injury due to toxic substances released by these cells that can include oxygen radicals, nitric oxide, and cytokines. Cytokines released by TH2 cells and mast cells (IL-4, IL-13, and TNFalpha) upregulate expression of leukocyte and endothelial adhesion molecules such as ICAM-1 and E-selectin. Because of these adhesion molecules, there in an increase in eosinophil-endothelial cell adhesion that causes migration and prolonged survival within lung tissue.
So, what is FX125L? It seems to be a broad-spectrum chemokine receptor inhibitor. FX125L acts similar to a corticosteroid, but the article claims that it doesn't have as adverse effects as corticosteroids. According to theasthmacenter.org, corticosteroids (like Advair and Pulmicort) in asthma suppress the inflammatory reaction that causes swelling and narrowing of the bronchi. It is normally used when asthma can't be controlled with bronchodilaters like albuterol. The most significant side effects with corticosteroids is usually caused by a high daily oral dose over a period of months to years.
The exact molecular action of FX125L was hard to find. The only thing I could find was that it blocked migration of inflammatory cells. This would obviously prevent the inflammation from occuring if the cells associated with inflammation are unable to chemotax to the site. Also, according to the presentation abstract, FX125L inhibits neutrophil recruitment to the lung. Neutrophils are the first line of defense against fungal and bacterial infections, but when recruited to the lung, can release chemokines and cytokines that enhance inflammation such as IL-6, IL-8, IL-1beta, andTNFalpha.
The term "broad-spectrum" usually refers to being effective over a wide range. It would be interesting to know exactly how this is accomplished. If FX125L targets a specific receptor, how can it be broad-spectrum? I think about antibiotics and how there are broad-spectrum ones that are used to treat a number of strains of bacteria that cause infections so it can be prescribed for many infections. How does FX125L target chemokine receptors in general and manage to target a particular one? Maybe it targets a specific receptor that is associated with inflammation in general or in most to all cases. This is one of many questions that I hope will be explained soon as the research progresses.
"ACAAI: New Anti-Inflammatory Molecule Safe" Medpage Today. Ed. Michael Smith. 9 Nov. 2009. Web. 16 Nov. 2009.
Presentation - Wiesel P, et al "First clinical experience with FX125L, an anti-inflammatory oral small molecule with an entirely novel mechanism of action" Ann Allergy Asthma Immunol 2009; 103(5)(suppl 2): Abstract 5
Corticosteroids - http://www.theasthmacenter.org/manual/part2-12.html
Neutrophils - http://www.springerlink.com/content/j71781x837m85n12/fulltext.pdf
I would agree that I was also a bit skeptical when I read this article and was disappointed in the limited amount of information that was available in regard to this drug. I highly doubt that this drug could be administered in a dose as high as 3000 mg without some effects of in vivo cytotoxicity.
ReplyDeleteI work in a lab on a project that is looking at a specific receptor whose activation may be responsible for the manifestation of lung airway epithelium inflammation seen in asthma. The receptor is a G-protein Coupled Receptor, PAR-2, and we have found it to be activated by a fungus that is very commonly responsible for many people’s asthma that live in dry, arid environments. The fungus Alternaria has serine protease activity as do many other allergens that cleave and activate the receptor. Our group has also developed several small peptides and peptidomimetics that can activate PAR-2 and compete with allergens like Alternaria for binding to the receptor and therefore not allow the allergen to bind and cause an inflammatory response. These compounds have predictive limited in vivo toxicity and are not corticosteroids. I believe that these would provide a treatment for a person’s asthma without having to worry about the side effects of taking a potential high dose of steroids for a long duration. Studies are currently being performed to look at how these compounds respond in different doses to the Alternaria and other PAR-2 agonists to find effective doses.
In response to the question, “How does FX125L target chemokine receptors in general and manage to target a particular one?” My guess would be that FX125L is a small molecule that has the correct shape and high affinity for that one specific chemokine receptor just as some of our compounds can and do specifically target PAR-2 as opposed to other receptors present on lung airway epithelium.