Rintatolimod

Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of chronic fatigue syndrome (CFS). There is low-strength evidence it can diminish CFS symptoms. Rintatolimod, sold under the tradename Ampligen, is a medication intended for treatment of chronic fatigue syndrome (CFS). There is low-strength evidence it can diminish CFS symptoms. It is an immunomodulatory double stranded RNA drug synthesized in the 1970s and manufactured by Hemispherx Biopharma. Although Ampligen was cleared for use in Canada in 1997, and obtained orphan drug status for treatment of CFS in the European Union in 2000, it is so far without FDA approval, and therefore classed as experimental in the United States. In 2007, Hemispherx filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) to market and sell rintatolimod for the treatment of CFS, but this was rejected in December 2009, because the FDA concluded that the two RCTs 'did not provide credible evidence of efficacy' and 'because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies.' The FDA requested Hemispherx conduct at least one additional controlled trial to demonstrate efficacy in treating CFS. In August 2012, Hemispherx submitted further analyses of the original clinical trial data, but did not submit additional trials for review. Four months later, a committee of the FDA voted 8-5 against approval for rintatolimod, again citing insufficient data. For people with chronic fatigue syndrome, there is low quality evidence that rintatolimod can improve the quality of life. Rintatolimod is designed to boost cellular defenses against viruses and tumors, and could be synergistic with other anti-virals used for avian influenza. An independent review of rintatolimod trials in chronic fatigue syndrome was published in the December 2006 issue of the Journal of Clinical Virology. It concluded that Ampligen has been 'generally well tolerated', with a 'low incidence of clinical toxicity', particularly when compared with the toxicity of the diseases it is used to treat. 'No serious safety issues have resulted from the administration of ~75,000 doses IV (most commonly 400 mg) twice weekly for up to one year periods or greater. Animal toxicity studies support this observation in humans, with primates demonstrating the greatest margin of safety.' A mild flushing reaction has occurred in about 15% of patients, and more rarely reported side effects include chills, fever, malaise, leukopenia, neutropenia and leukocytosis. Some of these side effects may be attributed to a temporary Herxheimer reaction in response to pathogen die off. According to Hemispherx and patient testimonials, side-effects, when they occur, usually subside within three to four months or less. One mode of action of this drug is to protect and stimulate the innate immune system, also called the nonspecific immune system, and the first line of defense. According to a study published in the Journal of Immunology and reflected in a press release by Hemispherx, Rintatolimod protects and stimulates the innate immune system by binding to Toll-like receptors 3 (TLR-3), and activating the TLR-3 receptors for broad-spectrum immune response. TLR-3 receptors are located on cell surfaces. They are part of a family of 'pattern recognition' receptors that detect pathogens immediately, even those the body has not yet encountered, long before adaptive immunity can intervene against foreign invaders. These receptors are critical to the first line of immunological defense against a broad range of pathogens, including otherwise lethal viruses and various forms of cancer. When, for example, double-stranded RNA molecules from an RNA viral infection bind to TLR-3 receptors, the virus in this way inactivates the innate immune system, rendering it unable to signal the rest of the body's defenses. When rintatolimod binds to TLR-3 receptors, the virus cannot do so, and the body is able to marshal its defenses and launch an assault on the virus. The mechanism of rintatolimod in relation to CFS is not certain, but is thought to include the RNase L enzyme. Rintatolimod is a dsRNA, and when TLR-3 senses a dsRNA, it is thought to relay a message to cells to produce interferons (IFNs). IFNs are a group of signaling molecules released by cells in response to the presence of pathogenic viruses or bacteria. These signaling molecules activate (among other things) the protective defenses of the immune system that eradicate pathogens. One such defense mechanism thought to be activated by rintatolimod is the production of the enzyme RNase L. This enzyme degrades pathogenic RNA, both viral and cellular. Degradation of RNA prevents viral and cell replication, and destruction of all RNA within a virus or cell is the last step before apoptosis or death. Accumulation of an inactive form of RNase L may be associated with CFS. Rintatolimod development evolved from a 1960s synthesis by Merck & Co., a double-stranded RNA compound of inosinic and cytidylic acid residues (poly I:poly C or poly I:C). Poly I:C inhibited tumor growth by inducing interferon production, but was too toxic to use. In the mid-1970s, William A. Carter, a post-doctoral researcher at Johns Hopkins University, modified the dsRNA molecule by adding uridylic acid molecules at specific intervals along the RNA chain. The new compound, called Ampligen (for AMPLIfied GENetic activity) stimulated interferon production like poly I:C, but with much lower toxicity. It is also known as 'poly I:poly C12U'.