The US National Institute of Health is launching a clinical trial (Phase III) for using Methotrexate as an anti-inflammatory for cardiovascular issues.

Methotrexate has been used against cancer, some autoimmune disorders,  even abortion!

Methotrexate, as of 1947…


This is a very potent drug, what is the NIH ‘s drive for this clinical trial [1]?   Finding out if attacking the cardiovascular inflammation will help heart disease.

Quoting NIH News:

“…[The] Cardiovascular Inflammation Reduction Trial (CIRT) will determine whether treatment with a drug specifically targeting inflammation reduces rates of cardiovascular events among adults who have had a heart attack within the past five years and who also have type 2 diabetes or metabolic syndrome.”

However, when consulting the Pubmed library, we found out that many entries on Methotrexate were devoted to its toxicity. Indeed, the NIH itself issued the following warning [2]:

“…Methotrexate may cause very serious side effects. Some side effects of methotrexate may cause death. You should only take methotrexate to treat life-threatening cancer, or certain other conditions that are very severe and that cannot be treated with other medications. Talk to your doctor about the risks of taking methotrexate for your condition…”

A Portuguese study[3] singles out that Methotrexate  is a Folate antagonist. Folate is a vitamin of the B group. Further, “…Methotrexate inhibits the synthesis of DNA, RNA, thymidylates, and proteins… inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells…”[wikipedia]. So Methotrexate is an immunosuppressant. Since the immune system is involved in inflammation, it has an anti-inflammatory effect.  For example immunosuppressant drugs have been used to combat inflammatory bowel disease [4]

To be sure, inflammation has been shown to be a main component of cardiovascular disease, as we discussed in a previous post [5]. The link between inflammation and heart disease is not much of a question anymore, as is shown in an article of Cardiobrief [6].

Methotrexate has been shown to be anti inflammatory in a study on mice [7]. But so did another drug called Dexamethasone. One of the striking concluding remarks of the Arthritis Research Journal was that “inflammatory diseases of some organs but not of other organs respond to methotrexate therapy.”

There is a position paper on the effect anti-inflammatory drugs  on Heart Disease by the European Journal of Heart Failure [8].  Unfortunately, the same article asserts that previous anti inflammatory clinical trials of this sort did not have much success. That article stresses that  we are really in its early stages of research, and defines the questions to be answered and the requirements for clinical trials.


  • How different are the inflammation processes of the various causes of heart disease
    • Ischemic (reduced blood supply to heart muscle)
    • Viral heart failure
    • Diabetes, hypertensive…
  • How to choose the patient population on which to base a specific clinical trial
The European paper [8] concludes essentially that the inflammation processes (“pathways”) are very different for the various forms of heart disease, and that any success will depend on associating the right pathway to the right heart disease type.
The NIH clinical trial will involve patients with “type 2 diabetes or metabolic syndrome that have had a heart attack” and  ” …In addition to measuring the number of strokes, heart attacks, and heart-related deaths among participants, CIRT will determine if low-dose methotrexate reduces death from all causes and certain heart- and blood vessel-related conditions and events…”
 Is that a tight enough clinical trial definition? Maybe

Why choose Methotrexate as an anti-inflammatory immuno-suppressant drug? A clue might be found in a study on the positive effect on Congestive Heart Failure (CHF) of some disease-modifying anti-rheumatic drugs [9].

This a good goal,  except that the trial of methotrexate involves substantial risks, including death!


  1.  The Clinical Trial is not funded directly by large pharmaceutical companies, but by an NIH grant [1]. This makes sense since Methotrexate is an old drug, and most manufacturers are in China or India. [12]. Is there another reason for the choice of that drug, i.e., there is no current private pharma conflict?
  2. The NIH Clinical trial is in Phase III, which presumes some success for phases I, and II, see the Wikipedia entry on Clinical Trials

What else could be attempted against cardiovascular inflammation?  The question is what treatment is appropriate to slow down or halt the inflammatory process. We discussed precisely that in [5], putting the accent on nutraceuticals such as vitamin K, rather than powerful pharmacologics.

The problem is that nutraceuticals have to  survive the digestive process and they are also not very targeted, so they are good for  prevention,  or the early stages of a disease. For advanced disease cases, the  more energetic (and therefore dangerous) approach of pharmaceuticals could be required.

Unless, research finds a more direct path to deliver the active element of the nutraceutical. Take the study in Biochemical Pharmacology [10], which proposes to use nanotechnology to vector the goods to the diseased target. We published, [11], on the use of nanoparticles for drug delivery. These nanoparticles can be based on bacteria’s liposome, they can be polymer molecules, the field is wide open.

Here lies the dilemma.

But the delivery of nutrients by nanoparticles to various organs is still in its infancy compared to the brute force of a drug like Methotrexate. But the NIH clinical trial seems more designed to demonstrate that a powerful anti-inflammatory can be effective against heart disease. If successful, it could open the doors of private for profit research to come up with (hopefully) a safer drug.

Talk to your Doctor


  1. NIHNews ; “NIH Starts Trial for Anti-Inflammatory Treatments to Prevent Cardiovascular Deaths” ; Aug 2012
  2. PubmedHealth ; “Methotrexate” ; 2009
  3. Acta Reumatologica Portuguesa ; “The network of methotrexate toxicity” ; Jan 2009
  4. ; AJG ; “Efficacy of Immunosuppressive Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis ” ; April 2011
  5. medinewsdigest ; “”IN DEPTH: Is There A Role For Nutraceuticals In Heart Disease?” July 19, 2012
  6. cardiobrief ; “Studies Provide Strongest Evidence To Date For Causative Role of Inflammation in Heart Disease” ; March 2012
  7. arthritis research therapy; “Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis” ; 2006
  8. European Journal of Heart Failure ; “Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology” ; Feb 2009
  9. Oxford Journals ; Rheumatology ; “Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis” ; Feb 2005
  10. biochemical pharmacology ; “Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer.” ; Dec 2010
  11. medinewsdigest ; “New Drug Delivery: Nanoparticles Remotely Activated To Release Protein Producing DNA To Fight Disease” ; July 2012

3 Comments for this entry

  • ruggierifp says:

    un’altro farmaco che accellera le malattie infiammatorie E/O MALATTIE MULTIPLE, TIPO TUMORI, SM, SLA ECCC…, sopprimendo il sistema immunitario !!!, per presunte_fantasiose malattie immunitarie !!!!! …. ” Tuttavia, quando si consulta la biblioteca Pubmed, abbiamo scoperto che molte voci su Metotrexato sono state dedicate alla sua tossicità. Infatti, la stessa NIH isuues il seguente avviso [2]:” …..

  • Yves Eljas says:

    Immuno suppressant drugs do not usually bring inflammation since inflammation requires an active and strong immune system…

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