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[[File:Ampligen.jpg|right|200px]] '''Rintatolimod''' (tradename '''Ampligen'''Ā®) is a mismatched, double-stranded [[RNA]] molecule with immunomodulatory and [[antiviral]] properties. The drug acts as a [[toll-like receptor 3|TLR3]] agonist which stimulates the production of [[interferon]]s and [[TNF-alpha|tumor necrosis factor]]s. It is manufactured by AIM ImmunoTech, formerly known as [[Hemispherx Biopharma]].<ref>{{Cite web | url = https://aimimmuno.com/products/ | title = Products | last = AIM ImmunoTech | first = | website = AIM ImmunoTech Inc.|language=en-US | access-date = 2019-11-20}}</ref> It has been shown to raise [[natural killer cell]] (NK) function.<ref name=":3" /> Numerous studies have found evidence of reduced NK function in patients with [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS).<ref>{{Cite journal | last = Barker | first = Edward | author-link = | last2 = Fujimura | first2 = Sue F. | author-link2 = | last3 = Fadem | first3 = Mitchell B. | author-link3 = | last4 = Landay | first4 = Alan L. | author-link4 = | last5 = Levy | first5 = Jay A. | author-link5 = Jay Levy | date = 1994-01-01 | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | url =http://academic.oup.com/cid/article/18/Supplement_1/S136/316964/Immunologic-Abnormalities-Associated-with-Chronic | journal = Clinical Infectious Diseases|language=en | volume = 18 | issue = Supplement_1| pages=S136āS141|doi=10.1093/clinids/18.Supplement_1.S136|issn=1537-6591|pmc=|pmid=|access-date=|quote=|via=}}</ref><ref>{{Cite journal | last = Whiteside | first = Theresa L | author-link = | last2 = Friberg | first2 = Diana | author-link2 = | date = Sep 1998 | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome | url =https://linkinghub.elsevier.com/retrieve/pii/S0002934398001557 | journal = The American Journal of Medicine|language=en | volume = 105 | issue = 3 | pages = 27Sā34S|doi=10.1016/S0002-9343(98)00155-7|pmc=|pmid=|access-date=|quote=|via=}}</ref><ref>{{Cite journal | last = Brenu | first = Ekua Weba | author-link = Ekua Brenu | last2 = Huth | first2 = Teilah K. | author-link2 = Teilah Huth | last3 = Hardcastle | first3 = Sharni L. | author-link3 = Sharni Hardcastle | last4 = Fuller | first4 = Kirsty | author-link4 = | last5 = Kaur | first5 = Manprit | author-link5 = | last6 = Johnston | first6 = Samantha | author-link6 = Samantha Johnston | last7 = Ramos | first7 = Sandra B. | author-link7 = Sandra Ramos | last8 = Staines | first8 = Don R. | author-link8 = Donald Staines | last9 = Marshall-Gradisnik | first9 = Sonya M. | author-link9 = Sonya Marshall-Gradisnik | date = Apr 2014 | title = Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis |url =https://academic.oup.com/intimm/article-lookup/doi/10.1093/intimm/dxt068 | journal = International Immunology|language=en | volume = 26 | issue = 4 | pages = 233ā242|doi=10.1093/intimm/dxt068|issn=1460-2377|pmc=|pmid=|access-date=|quote=|via=}}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | author-link = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | author-link2 = | last3 = Klimas | first3 = Nancy | author-link3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome|journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002| page=129ā139|doi= 10.1016/S1529-1049(01)00047-2|url= http://www.sciencedirect.com/science/article/pii/S1529104901000472}}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | author-link1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | author-link2 = | last3 = Staines | first3 = Donald R | author-link3 = Donald Staines | last4 = Ashton | first4 = Kevin J | author-link4 = | last5 = Hardcastle | first5 = Sharni L | author-link5 = Sharni Hardcastle | last6 = Keane | first6 = James | author-link6 = | last7 =Tajouri | first7 = Lotti | author-link7 = | last8 = Peterson | first8 = Daniel | author-link8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | author-link9 = Sandra Ramos | last10= Marshall-Gradisnik | first10 = Sonya M | author-link10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal =Journal of Translational Medicine | year = 2012 | volume = 10 | page = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref> As of 2016, it has been approved for [[Severe and very severe ME|severe ME/CFS]] in [[Argentina]].<ref>{{Cite news |url =http://www.globenewswire.com/news-release/2016/08/23/866212/0/en/Hemispherx-Biopharma-Announces-Major-Breakthrough-Approval-for-Commercial-Sale-of-Rintatolimod-U-S-Tradename-Ampligen-to-Treat-Severe-Cases-of-Myalgic-Encephalomyelitis-Chronic-Fat.html | title = Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: AmpligenĀ®) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic | last = Hemispherx Biopharma, Inc. | date = Aug 23, 2016|work=GlobeNewswire News Room | access-date = 2018-08-13|archive-url=|archive-date=|language=en-US}}</ref><ref>{{Cite news |url =http://cdn2.hubspot.net/hubfs/150154/docs/Hemispherx-Executive-Informational-Overview-11-27-16.pdf | title=Hemispherx Biopharma, Inc. Executive Informational Overview | last = | first = | date = Nov 27, 2016|work=Crystal Research Associates|access-date=|archive-url=|archive-date=|format=PDF}}</ref> That same year it was approved for an Early Access Program in EU and Turkey.<ref>{{Cite web | url = https://www.bizjournals.com/philadelphia/news/2016/07/25/hemispherx-ships-ampligen-for-european-chronic.html | title = Hemispherx ships Ampligen for European chronic fatigue syndrome program | last = George | first = John | date = Jul 25, 2016 | website = bizjournals.com|archive-url=|archive-date= | access-date = 2018-08-13}}</ref> The [[United States|US]] [[U.S. Food and Drug Administration|Food and Drug Administration]] (FDA) have not approved Ampligen for wide use in ME/CFS.<ref name="experimental" /> On January 2, 2018, the FDA approved the compassionate care (expanded access) program AMP-511 which "will allow treatment of up to 100 [[ME/CFS]] patients at any one time at approved clinical infusion therapy sites."<ref name="AMP-511">{{Cite web | url = https://finance.yahoo.com/news/hemispherx-biopharma-inc-announces-advancement-133000883.html | title = Hemispherx Biopharma Inc. Announces Advancement in Expanded Access Program for Ampligen in the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | last = | first = | author-link = | date = Jan 2, 2019 | website = finance.yahoo.com| publisher = GlobeNewswire|language=en-US|archive-url=|archive-date= | access-date = 2019-02-10}}</ref> ==History== AmpligenĀ® was based on a double-stranded RNA ([[Double-stranded RNA viruses|dsRNA]]) compound developed by the pharmaceutical company, Merck, in the 1960s, as a potential cancer drug. Though effective in the petri dish, the original compound proved to be too toxic for human use.<ref name=":2">{{Cite web | url = http://pomerantzlawfirm.com/assets/complaints/hemispherx.pdf | title=FRATER VS HEMISPHERX BIOPHARMA, Case 2:12-cv-07152-WY | last = | first = | author-link = | date = 2013-05-20 | website = Pomerantz Law Firm|archive-url=|archive-date= | access-date = 2019-09-26}}</ref><ref>{{Cite web | url = https://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/immune/antivirals-and-immunemodulators/ampligen-rintatolimod/ampligen-i-effectiveness | title = Ampligen I: Effectiveness | website = Phoenix Rising|language=en-US | access-date = 2019-09-26}}</ref> [[William Carter | William A. Carter]], MD, a researcher at Johns Hopkins University, was able to modify the compound in the 1970s to reduce its toxicity (see section below on "Mechanism of action"). The new compound was named AmpligenĀ®, short for āAMPLIfied GENetic activity.ā In the 1980s, while a researcher at Hahnemann University in Philadelphia, Dr. Carter obtained the license for the compound from Johns Hopkins University. He and several other researchers at Hahnemann University affiliated with a small company, Hemispherx, now called AIM ImmunoTech, to manufacture it.<ref name=":2" /> In the late 1980s, AIM ImmunoTech partnered with Dupont to start clinical trials for AmpligenĀ®. After a couple years, Dupont severed its business relationship with AIM ImmunoTech.<ref>{{Cite web | url = https://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/immune/antivirals-and-immunemodulators/ampligen-rintatolimod/ampligen-part-ii-twisted-history | title = Twisted History: Ampligen and CFS | website = Phoenix Rising|language=en-US | access-date = 2019-09-26}}</ref> Through the years, Dr. Carter's confidence in AmpligenĀ®'s ability to stimulate the body's immune system lead to him offering the drug as a treatment for a variety of diseases including cancer, AIDS, [[chronic fatigue syndrome]], [[hepatitis C]], [[Gulf War Illness]], [[Influenza A virus subtype H1N1|swine flu]], and [[Ebola virus disease|ebola]].<ref>{{Cite web | url = http://www.bio-medicine.org/medicine-technology/Hemispherx-Presents-Evidence-of-Ampligen-Synergies-with-Existing-0AAntivirals-at-International-Avian-Influenza-Conference-453-1/ | title = Hemispherx Presents Evidence of Ampligen Synergies with Existing,Antivirals at International Avian Influenza Conference ( PARIS--(BUSINESS WIRE)--Jun 4 2007 - H...) | website = bio-medicine.org | access-date = 2019-09-26}}</ref><ref>{{Cite web | url = https://www.marketwatch.com/story/tiny-biotech-says-it-may-have-an-answer-for-ebola-2015-02-02 | title = Tiny biotech says it may have an answer for Ebola | last = Britt | first = Russ | website = MarketWatch|language=en-US | access-date = 2020-02-04}}</ref> AIM ImmunoTech stated: "...we believe that AmpligenĀ® may have broad-spectrum anti-viral and anti-cancer properties."<ref>{{Cite web | url = https://aimimmuno.com/ | title = Home | last = ImmunoTech | first = A. I.M. | website=AIM ImmunoTech Inc.|language=en-US | access-date = 2019-09-26}}</ref> This over-confidence resulted in a class action suit by stockholders in 2013.<ref name=":2" /> Testing for efficacy in [[ME/CFS]] started in 1990 and continues to the present (see section below on "Drug approval status"). Testing for other conditions has been sporadic. In 2016, the University of Pittsburgh was sponsoring Phase I/II studies using AmpligenĀ® as an adjunct treatment in ovarian, peritoneal, and colorectal cancer.<ref>{{Cite web | url = https://aimimmuno.com/pipeline/ | title = Pipeline | last = ImmunoTech | first = A. I.M. | website=AIM ImmunoTech Inc.|language=en-US | access-date = 2020-02-04}}</ref><ref>{{Cite web | url = https://aimimmuno.com/1568-2/ | title = Hemispherx Issues 2019 Second Quarter Report Citing Strong Steady Progress in Cancer Clinical Trials | last = ImmunoTech | first = A. I.M. | date = 2019-08-15 | website = AIM ImmunoTech Inc.|language=en-US | access-date = 2019-11-20}}</ref> Hahnemann University and AIM ImmunoTech are collaborating on Phase II studies for AmpligenĀ® as a single agent for renal cell carcinoma and melanoma. Georgia Regents University is in the preclinical stage of testing AmpligenĀ® as part of a combination therapy for colorectal cancer and melanoma.<ref name="Crystal, 2016" /> In late fall 2015, Dr. [[Francis Collins]] announced that the [[National Institutes of Health]] (NIH) was considering the possibility of sponsoring a clinical trial for AmpligenĀ®, as well as [[Rituximab]] and other treatments.<ref>{{Cite web | url = https://www.meaction.net/2015/12/21/nih-considering-ampligen-and-rituximab-trials/ | title = NIH considering Ampligen and Rituximab trials | date = 2015-12-21 | website = #MEAction|language=en-US | access-date = 2019-09-26}}</ref> By the end of 2016, the [[National Institutes of Health|NIH]] has not announced any further plans for a clinical trial for either drug. At the 12th International [[IACFS/ME]] Research and Clinical Conference in October 2016, representatives from AIM ImmunoTech announced "that a retrospective analysis of the AMP-516 Phase III trial of AmpligenĀ® in patients with [[CFS/ME|chronic fatigue syndrome/myalgic encephalomyelitis]] (CFS/ME), segmented primarily by disease duration, showed that 51% of AmpligenĀ® treated patients in a cohort with a disease duration of two to eight years vs. 18% of placebo patients demonstrated at least 25% improvement in placebo-adjusted exercise tolerance whereas the patient subset with less than two years or greater than eight years of disease duration failed to show a clinically-significant response."<ref>{{Cite web | url = http://www.globenewswire.com/news-release/2016/10/31/884673/0/en/Hemispherx-Biopharma-Announces-Identification-of-High-Responder-Patient-Subgroup-from-Ampligen-Phase-III-Trial-in-Patients-with-CFS-ME.html | title = Hemispherx Biopharma Announces Identification of High Responder Patient Subgroup from AmpligenĀ® Phase III Trial in Patients with CFS/ME | last = Inc | first = Hemispherx Biopharma | date = 2016-10-31 | website = GlobeNewswire News Room | access-date = 2019-09-26}}</ref> ==Marketing history== ''{{main article| page_name = Marketing History of Ampligen}}'' ==Mechanism of action== [[File:Ampligen chemical structure.png|right|frame|'''Poly I:C12U''' Source: Hemispherx Biopharma, Inc]] The chemical formation of AmpligenĀ® begins with the known immunostimulant called Polyinosinic:polycytidylic acid (usually abbreviated Poly I:C). Poly I:C is a mismatched double-stranded RNA (dsRNA) with one strand being a polymer of [[inosinic acid]] and the other strand a polymer of [[cytidylic acid]].<ref name="HemBio,2012" /> Poly I:C is structurally similar to the type of dsRNA present in some [[virus]]es. When introduced into the body it stimulants the [[immune system]] because the body thinks a virus is present. AmpligenĀ® is formed when uridine (one of the five standard nucleosides which form the building blocks of RNA) is introduced into this Poly I:C strand, altering the strand to Poly I:C12U.<ref name="HemBio,2012" /> As a result, one strand of the dsRNA is a homopolymer, poly rI and annealed to this strand is a heteropolymer, polyC12U.<ref name="HemBio,2012" /> This alteration increases the compound's instability and shortens the half life to less than 40 minutes after IV administration. Plasma RNase (an enzyme naturally present in blood) degrades the AmpligenĀ® compound into separate ribonucleotides which are completely natural degradation products the body can easily handle, thus lessening its toxicity.<ref name="HemBio,2012" /> AmpligenĀ® is a [[TLR3]] agonist.<ref name="HemBio,2012" /> It stimulates the production of [[toll-like receptor]] 3 (TLR3), which is a naturally occurring protein. we TLR3 recognizes the [[dsRNA]] present in some viruses, such as [[retrovirus]]es, and stimulates a series of biochemical reactions that result is an increase in the production of [[interferon]]. Interferon, an important player in the body's immune system, protects against viral infections and activates immune cells, such as [[Natural killer cell|NKC]]. ==Evidence== ===Coxsackie B=== In a mouse model, AmpligenĀ® was found to be protective of [[Coxsackie B3]]-induced [[myocarditis]].<ref name="Padalko,2004" /> ===HHV6=== *1994, A study done by the Department of Biochemistry, Temple University School of Medicine, Philadelphia, using IV therapy of AmpligenĀ® "resulted in a significant decrease in [[Human herpesvirus 6]] activity (P < .01) and in downregulation of the 2-5A synthetase/[http://me-pedia.org/wiki/Ribonuclease_L RNase L] pathway in temporal association with clinical and neuropsychological improvement."<ref name="Suhadolnik,1994" /> ===Efficacy in ME/CFS=== *1995, Long Term Improvements in Patients with Chronic Fatigue Syndrome Treated with AmpligenĀ®<ref name="Strayer,1995" /> *2001, Chronic Fatigue Syndrome, Ampligen, and Quality of Life: A Phenomenological Perspective<ref>{{Cite journal | last = Snell | first = Christopher R. | author-link = Christopher Snell | last2 = Stevens | first2 = Staci R. | author-link2 = Staci Stevens | last3 = Vanness | first3 = J. Mark | author-link3 = Mark VanNess | date = Jan 2001 | title = Chronic Fatigue Syndrome, Ampligen, and Quality of Life: A Phenomenological Perspective | url =http://www.tandfonline.com/doi/full/10.1300/J092v08n03_11 | journal = Journal of Chronic Fatigue Syndrome|language=en | volume = 8 | issue = 3-4 | pages = 117ā121|doi=10.1300/J092v08n03_11|issn=1057-3321|pmc=|pmid=|access-date=|quote=|via=}}</ref> * 2004, A study done at the Rega Institute for Medical Research, Belgium on [[coxsackie B3]] virus-induced myocarditis in C3H/HeNHsd mice show AmpligenĀ® markedly reduced the virus titers in the normalized heart electrocardiographic parameters<ref name="Padalko,2004" /> *2012, A double-blind, placebo-controlled, randomized, clinical trial of the [[TLR3|TLR-3]] agonist rintatolimod in severe cases of chronic fatigue syndrome<ref name="Strayer, 2012" /> *2012, Hemispherx Biopharma (now AIM ImmunoTech) presented several studies on efficacy at a [[U.S. Food and Drug Administration|US Food and Drug Administration]] (FDA) meeting:<ref name="HemBio,2012" /> ::The increase of baseline in mean exercise tolerance tests (ETT) improved 95.7% in the group on AmpligenĀ® and 28.2% in the placebo group. (p value= 0.047; slide 81)<ref name=":1">{{Cite journal | last = Strayer | first = David R. | last2 = Carter | first2 = William A. | last3 = Stouch | first3 = Bruce C. | last4 = Stevens | first4 = Staci R. | last5 = Bateman | first5 = Lucinda | last6 = Cimoch | first6 = Paul J. | last7 = Lapp | first7 = Charles W. | last8 = Peterson | first8 = Daniel L. | last9 = Chronic Fatigue Syndrome AMP-516 Study Group| date = 2012 | title = A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/22431963 | journal = PloS One | volume = 7 | issue = 3| pages = e31334|doi=10.1371/journal.pone.0031334|issn=1932-6203|pmc=3303772|pmid=22431963}}</ref> ::A greater percentage of AmpligenĀ® patients (68.0%) decreased their use of concomitant medications used in an attempt to palliate symptoms of CFS compared to the placebo group (54.6%). (slide 59)<ref name=":1" /> ::No Evidence for induction of autoantibodies with AmpligenĀ® by assessment of Anti-dsDNA and Rheumatoid Factor in 64 randomly selected patients in controlled study AMP-516 at week 32; In the placebo group, 0% developed Anti-dsDNAand one patient (3.7%) developed Rheumatoid Factor autoantibodies. (slide 54) *2015, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod<ref name="Strayer, 2015" /> :See [[Ampligen Exercise Tolerance - graph 1]] | last4 *2015, [[David Strayer]], et al., published "Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity," in the ''Journal of Clinical & Cellular Immunology.'' The study reviewed previous studies that concluded that the more decreased the Natural Killer cell cytotoxicity was in patients, the greater the CFS severity. The study, also, reported that ''in vitro'' exposure of peripheral blood mononuclear cells from CFS patients (fulfilling both the [[Centers for Disease Control and Prevention|CDC]] 1988 and 1994 case definitions) to AmpligenĀ® increased Natural Killer cell cytotoxicity 100-178%.<ref name=":3">{{Cite journal | last = Scott | first = Victoria | author-link = | last2 = Strayer | first2 = David | author-link2 = David Strayer | date = 2015 | title = Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity | url = http://www.omicsonline.org/open-access/low-nk-cell-activity-in-chronic-fatigue-syndrome-cfs-and-relationship-to-symptom-severity-2155-9899-1000348.php?aid=59415 | journal = Journal of Clinical & Cellular Immunology|language=en | volume = 06 | issue = 04| pages=|doi=10.4172/2155-9899.1000348|issn=2155-9899|pmc=|pmid=|access-date=|quote=|via=}}</ref> *2016, [[William Mitchell|William M. Mitchell]] published a review in the journal, ''Expert Review of Clinical Pharmacology'' that stated: "Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe." Mitchell is the Chairman of the Board for AIM ImmunoTech and a Professor of Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine, Nashville, Tennessee.<ref name=":4">{{Cite journal | last = Mitchell | first = William M | author-link = William Mitchell | date = 2016-06-02 | title = Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) | url = http://www.tandfonline.com/doi/full/10.1586/17512433.2016.1172960 | journal = Expert Review of Clinical Pharmacology|language=en | volume = 9 | issue = 6 | pages = 755ā770|doi=10.1586/17512433.2016.1172960|issn=1751-2433|pmc=4917909|pmid=27045557|access-date=|quote=|via=}}</ref> ==Drug approval status== ===United States=== [[File:FDA Review chart for Ampligen approval.png|center|frame|Source: Hemispherx Biopharma, Inc, Dec 2012]] AmpligenĀ® has been passed through five different [[U.S. Food and Drug Administration|FDA]] review divisions since 1990. Hemispherx Biopharma, Inc, now AIM ImmunoTech, wrote in a presentation to the FDA on Dec 20, 2012: "Most products have [the] same review Division during their entire development. Guidance from five (5) different Divisions [has provided] diverged/conflicting advice on major points, such as: interpreting primary endpoints (method of analysis), its collection and analysis, and different thresholds for determining toxicity and safety. In contrast, AIM ImmunoTech has had the same medical monitor for more than 20 years (Dr. David Strayer)."<ref name="HemBio,2012" /> [[File:History of Hemispherxās application for Ampligen.png|center|frame|Source: FDA website]] ::::::::::History of AIM ImmunoTechās application to the FDA for Ampligen<ref>{{Cite web | url = https://web.archive.org/web/20130208065906/https://www.fda.gov/Drugs/NewsEvents/ucm337759.htm | title = Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS): Questions and Answers | last = | first = | first2 = | date = 5 February 2013 | website = FDA|publication-date=5 February 2013|archive-url=https://web.archive.org/web/20130208065906/https://www.fda.gov/Drugs/NewsEvents/ucm337759.htm|archive-date=8 February 2013|url-status=dead|access-date=February 5, 2013}}</ref> ====Expanded access ==== The AMP-511 [[expanded access]] program allows a limited number of patients access to Ampligen. ===Europe=== In 2016 AmpligenĀ® started being made available on a limited basis in Europe.<ref>{{Cite news |url =https://www.bizjournals.com/philadelphia/news/2016/07/25/hemispherx-ships-ampligen-for-european-chronic.html | title = Hemispherx ships Ampligen for European chronic fatigue syndrome program | last = George | first = John | date = 2016-07-25|work=Philadelphia Business Journal | access-date = 2019-09-26|archive-url=|archive-date=|quote=}}</ref> === South America === [[Argentina]] (Argentine Republic) has approved the use of AmpligenĀ® for [[Severe ME/CFS: A Guide to Living|severe ME/CFS]] on August 23, 2016. <ref>[http://www.globenewswire.com/news-release/2016/08/23/866212/0/en/Hemispherx-Biopharma-Announces-Major-Breakthrough-Approval-for-Commercial-Sale-of-Rintatolimod-U-S-Tradename-Ampligen-to-Treat-Severe-Cases-of-Myalgic-Encephalomyelitis-Chronic-Fat.html Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: AmpligenĀ®) to Treat Severe Cases of] [[Myalgic encephalomyelitis|Myalgic Encephalomyelitis]]/[[Chronic fatigue syndrome|Chronic Fatigue Syndrome]] (ME/CFS) in the Argentine Republic - NasDaq GlobeNewswire</ref> Approval is limited to ME/CFS patients who are severely disabled and who have been diagnosed for more than one year.<ref name="Crystal, 2016" /> ==Notable studies== *1994, Ampligen inhibits human herpesvirus-6 in vitro.<ref name="Ablashi, 1994" /> *1994, A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome<ref name="Strayer,1994" /> *2004, The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis<ref>{{Cite journal | last = Padalko | first = E. | last2 = Nuyens | first2 = D. | last3 = De Palma | first3 = A. | last4 = Verbeken | first4 = E. | last5 = Aerts | first5 = J.L. | last6 = De Clercq | first6 = E. | last7 = Carmeliet | first7 = P. | last8 = Neyts | first8 = J. | date = 2004-01-01 | title = The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis | url =http://aac.asm.org/cgi/doi/10.1128/AAC.48.1.267-274.2004 | journal = Antimicrobial Agents and Chemotherapy|language=en | volume = 48 | issue = 1 | pages = 267ā274|doi=10.1128/AAC.48.1.267-274.2004|issn=0066-4804|pmc=310159|pmid=14693549}}</ref> - [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC310159/ (Full Text)] *1995, Long Term Improvements in Patients with Chronic Fatigue Syndrome Treated with Ampligen<ref name="Strayer,1995" /> *2012, A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome.<ref name="Strayer, 2012" /> *2015, [http://annals.org/article.aspx?articleid=2322801 Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop] *2016, [https://www.ncbi.nlm.nih.gov/pubmed/27045557 Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me)]<ref name=":4" /> *2020, Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<ref name="Strayer2020">{{Cite journal | title = Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | date = 2020-10-29 | url = https://dx.plos.org/10.1371/journal.pone.0240403 | journal = PLOS ONE | volume = 15 | issue = 10| pages = e0240403 | last = Strayer | first = David R. | author-link = David Strayer | last2 = Young | first2 = Diane | author-link2 = | last3 = Mitchell | first3 = William M. | author-link3 = William Mitchell|language=en|doi=10.1371/journal.pone.0240403|pmc=PMC7595369|pmid=33119613|access-date=|issn=1932-6203|quote=|via=}}</ref> - [https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403 (Full text)] ==Clinics== The two clinics that are approved to deliver Ampligen infusions are [[Sierra Internal Medicine]] in Incline Village, Nevada, and [[Hunter-Hopkins Center]], North Carolina. Patient numbers are limited. Some patients have moved near to a clinic to minimise travel for the frequent infusions.<ref name="Ampligen-Town">{{Cite news | date = Sep 3, 2019| first = Mike | last = Mariani | url = https://www.newyorker.com/culture/personal-history/a-town-for-people-with-chronic-fatigue | title = A Town for People with Chronic Fatigue Syndrome|publisher =New Yorker | access-date = 2022-04-12}} </ref> {{See also|Compassionate use}} ==Experiences of patients on AmpligenĀ®== *April, 1998 [http://wwcoco.com/cfids/karenampligen.html Testimony from Karen Lang] *October, 1998, [http://www.cfids-me.org/aacfs/ampligen.html Abstracts of Papers Presented at The Bi-Annual Research Conference of the American Association for Chronic Fatigue Syndrome (AACFS) - Four Patients of the AmpligenĀ® 511 Cinical trial: Karen Lang, Linda Barossi, Steve Edwardsm and Stuart Craig Woolman] *1999, [http://www.cfids-me.org/cfscc/amptestimony.html Testimony before the Chronic Fatigue Syndrome Coordinating Committee (CFSCC) of the U.S. Department of Health and Human Services by patient,] [[Mary Schweitzer|Mary M. Schweitzer]], Ph.D. *2012, [[Jeannette Burmeister]]'s comments to The Advisory Committee Reviewing AmpligenĀ® - [https://thoughtsaboutme.com/2012/12/05/you-can-make-a-difference-ampligen-approval-within-reach-with-your-help/ (Full text)] *2012, [http://www.cfscentral.com/2012/09/what-have-your-experiences-been-on.html Tell the] [[FDA]]: What Have Your Experiences Been on AmpligenĀ®? *2012-2013, [http://ampligen-treatment.blogspot.com/ The New AmpligenĀ® Diaries by Kelvin Lord] *2012, [http://www.healthrising.org/testimonials-2/anita-patton-what-ampligen-means-to-me/ Anita Patton - What AmpligenĀ® Means To Me] *2013, [[Robert Miller]]'s comments to HHS regarding being in a second clinical trial for AmpligenĀ® - [http://www.hhs.gov/advcomcfs/meetings/presentations/miller_061312.pdf (PDF file)] *2013, [https://www.youtube.com/watch?v=yuUBysDdDbU Terry, an AmpligenĀ® Patient] *2016, [https://slightlyalive.blogspot.co.uk/2016/08/my-22-years-with-myalgic_8.html My 22 years with Myalgic Encephalomyelitis] ([[Mary Schweitzer]]) == Talks, interviewsand news articles== *2019, [https://www.newyorker.com/culture/personal-history/a-town-for-people-with-chronic-fatigue A Town for People with Chronic Fatigue Syndrome] - New Yorker - written by an Ampligen patient *2016, [https://www.youtube.com/watch?v=RVwAHIjNkb4&feature=youtu.be Small Cap Nation - ME/CFS (Updated)] ([[Thomas Equels]], [[Hemispherx Biopharma|AIM ImmunoTech]]) ==Learn more== *[https://en.wikipedia.org/wiki/Rintatolimod Wikipedia - Rintatolimod] *1990, [http://europe.newsweek.com/chronic-fatigue-syndrome-205712?rm=eu Chronic Fatigue Syndrome] *1994, The Aids Drug No One Can Have Mindy Kitei (see also [[Mindy Kitei]]) *2004, [https://www.ncbi.nlm.nih.gov/pubmed/15357629 Mismatched double-stranded RNA: polyI:polyC12U] *2012, [http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/immune/antivirals-and-immunemodulators/ampligen-rintatolimod/ampligen-i-effectiveness AmpligenĀ® I: Effectiveness] *2012, Slide presentation to [[FDA]] Arthritis Advisory Committee by Hemispherx - [http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM334430.pdf (PDF File)] *2013, [http://slightlyalive.blogspot.se/2013/03/ampligen-and-biomarkers-my-testimony-to.html AmpligenĀ® and] [[Diagnostic biomarker | biomarker]]s: my testimony to [[FDA]] Dec 2012 *2013, [http://pomerantzlawfirm.com/assets/complaints/hemispherx.pdf Hemispherx Biopharma,Inc sued in a class action brought by stock holders claiming the company misrepresented whether Ampligen would be] [[FDA]] approved. The stockholders prevailed. *2015, [[FDA]] Response Letter Regarding Approval of AmpligenĀ® for ME/CFS - [http://www.fda.gov/Drugs/NewsEvents/ucm337750.htm (Letter)] *2015, [http://www.meaction.net/2015/08/10/ampligen-price-increases-substantially-available-soon-in-europe/ AmpligenĀ® price more than doubles - Available soon in Europe] *2015, [[FDA]] Approval of MS Drug Puts AmpligenĀ® Back In Play - [http://www.cortjohnson.org/blog/2015/02/04/fda-ms-drug-ampligen-chronic-fatigue/ (Article)] *2016, [http://cdn2.hubspot.net/hubfs/150154/docs/Hemispherx-Executive-Informational-Overview-11-27-16.pdf?__hssc=75734090.1.1482434979170&__hstc=75734090.d484bcfed76166643c7e8f36a0c76637.1482434979170.1482434979170.1482434979170.1&__hsfp=4187238277&hsCtaTracking=afde00a7-b0f3-44d3-b072-5febf480affb%7Cb8ddd437-9009-4bb9-a8fe-65a376fff33f Executive Informational Overview by Crystal Research Associates]<ref name="Crystal, 2016" /> *2016, [http://mobile.in-pharmatechnologist.com/Ingredients/Hemispherx-hires-Avrio-as-Ampligen-CMO-while-it-tries-to-win-US-approval Hemispherx hires Avrio as AmpligenĀ® CMO while it tries to win US approval] *2016, [http://simmaronresearch.com/2016/06/making-case-ampligen-chronic-fatigue-syndrome-me/ Making the Case for AmpligenĀ® in Chronic Fatigue Syndrome (ME/CFS)] *2016, [https://cfsremission.wordpress.com/2016/04/07/ampligen-and-cfs/ AmpligenĀ® and CFS] *2016, [http://www.streetinsider.com/Corporate+News/Hemispherx+Biopharma+%28HEB%29+Comments+on+Recent+Meeting+with+NIH+for+MECFS+Research+Advancement/11408291.html Hemispherx Biopharma (HEB) Comments on Recent Meeting with NIH for ME/CFS Research Advancement] (see also [[NIH Post-Infectious ME/CFS Study]]) *2016, [http://www.cortjohnson.org/forums/threads/ampligen-co-inventor-head-of-hemispherx-biopharma-fired-implications-for-me-cfs-drug-unclear.3729/ AmpligenĀ® Co-Inventor / Head of] [[Hemispherx Biopharma]] Fired: Implications for ME/CFS Drug Unclear *2018, [https://ammes.org/experimental-treatments/ Experimental treatments]<ref name="experimental">{{Cite web | url = https://ammes.org/experimental-treatments/ | title = Experimental treatments | last = | first = | date = | website = [[American Myalgic Encephalomyelitis and Chronic Fatigue Syndrome Society]]|language=en-US|archive-url=|archive-date= | access-date = 2021-03-18}}</ref> - Ampligen'''Ā®''' doesn't appear to suppress the immune system. Instead, it's believed to change the way your immune system works.<ref name="experimental" /> *2019, [https://www.newyorker.com/culture/personal-history/a-town-for-people-with-chronic-fatigue A Town for People with Chronic Fatigue Syndrome] - New Yorker - written by an Ampligen patient ==See also== *[[AIM ImmunoTech]] (formerly Hemispherx Biopharma) *[[Nancy Kaiser]] patient 00 ==References== <references> <ref name="Ablashi, 1994">{{Citation | last1 = Ablashi | first1 = DV | author-link1 = Dharam Ablashi | last2 =Berneman | first2 = ZN | author-link2 = | last3 =Williams | first3 = M | author-link3 = | last4 = Strayer | first4 = D | author-link4 = David Strayer | last5 = Kramarsky | first5 = B | author-link5 = | last6 = Suhadolnik | first6 = RJ | author-link6 =Robert Suhadolnik | last7 =Reichenbach | first7 = N | author-link7 = | last8 = Hiltzges | first8 = P | author-link8 = | last9 = Komaroff | first9 = AL | author-link9 = Anthony Komaroff | title = Ampligen inhibits human herpesvirus-6 in vitro | journal =In Vivo | volume = 8 | issue = 4 | page = 587-91 | date = 1994 | pmid = 7893986 | doi = | url=| pages=|chapter=|edition=|isbn=}}</ref> <ref name="Crystal, 2016">{{citation | author= Crystal Research Associates | title = Hemispherx Biopharma, Inc. | type = Executive Informational Overview | date = 27 Nov 2016 | url = http://cdn2.hubspot.net/hubfs/150154/docs/Hemispherx-Executive-Informational-Overview-11-27-16.pdf }}</ref> <ref name="Strayer, 2015">{{Citation | last1 = Strayer | first1 = David R | author-link1 = David Strayer | last2 = Stouch | first2 = Bruce C | author-link2 = | last3 = Stevens | first3 = Staci R. | author-link3 = Staci Stevens | last4 = Bateman | first4 = Lucinda| author-link4 = Lucinda Bateman | last5 = Lapp | first5 = Charles W | author-link5 = Charles Lapp | last6 = Peterson | first6 = Daniel L | author-link6 = Daniel Peterson | last7 = Carter | first7 = William A | author-link8 = William Carter | last8 = Mitchell | first8 = William M | author-link8 = William Mitchell | title = Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod | journal =Journal of Drug Research and Development | volume = 1 | issue = 1 | date = August 8, 2015 | doi = 10.16966/2470-1009.103 | url = https://sciforschenonline.org/journals/drug/article-data/JDRD-1-103/JDRD-1-103.pdf }}</ref> <ref name="Padalko,2004">{{Citation | last1 = Padalko | first1 = Elizaveta | author-link1 = | last2 = Nuyens | first2 = Dieter| author-link2 = | last3 = De Palma | first3 = Armando| author-link3 = | last4 = Verbeken | first4 = Erik | author-link4 = | last5 = Aerts | first5 = Joeri L. | author-link5 = | last6 = De Clercq | first6 = Erik | author-link6 = | last7 = Carmeliet | first7 = Pete | author-link7 = | last8 = Neyts1 | first8 = Johan | author-link8 = | title = The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis | journal =Antimicrobial Agents and Chemotherapy | volume = 48 | issue = 1 | pages = 267ā274 | date = 2004 | pmid = 14693549 | doi = 10.1128/AAC.48.1.267-274.2004 }}</ref> <ref name="Suhadolnik,1994">{{Citation | last1 = Suhadolnik | first1 = RJ | author-link1 =Robert Suhadolnik | last2 = Reichenbach | first2 = NL | author-link2 = | last3 =Hitzges | first3 = P | author-link3 = | last4 = Sobol | first4 = RW | author-link4 = | last5 = Peterson | first5 = DL | author-link5 = Daniel Peterson | last6 = Henry | first6 = B | author-link6 = | last7 = Ablashi | first7 = DV | author-link8 = Dharam Ablashi | last8 = MĆ¼ller | first8 = WE | author-link8 = | last9 =Schrƶder | first9 = HC | author-link9 = | last10= Carter | first10 = WA | author-link10 = William Carter | title = Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. | journal =Clinical Infectious Disease | volume = 18 | issue = Suppl 1 | page = S96-104 | date = January 1994 | pmid = 8148461 | url=| pages=|chapter=|edition=|isbn=}}</ref> <ref name="HemBio,2012">{{Cite web | last1 = Hemispherx Biopharma, Inc. | title = AmpligenĀ® for the Treatment of Chronic Fatigue Syndrome | date = Dec 20, 2012 | url = http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM334430.pdf }}</ref> <ref name="Strayer,1994">{{Cite journal | last1 = Strayer | first1 = DR | author-link1 = David Strayer | last2 = Carter | first2 = WA | author-link2 = William Carter | last3 = Brodsky | first3 = I | author-link3 = | last4 = Cheney | first4 = P | author-link4 = Paul Cheney | last5 = Peterson | first5 = D | author-link5 = Daniel Peterson | last6 = Salvato | first6 = P | author-link6 = | last7 = Thompson | first7 = C | author-link7 = | last8 = Loveless | first8 = M | author-link8 = | last9 = Shapiro | first9 = DE | author-link9 = | last10 = Elsasser | first10 = W | author-link10 = | title = A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome | journal = Clinical Infectious Diseases | volume = 18 | issue = Suppl 1 | pages = S88-95 | date = 1994 | pmid = 8148460 }}</ref> <ref name="Strayer,1995">{{Cite journal | last1 = Strayer | first1 = DR | author-link1 = David Strayer | last2 = Carter | first2 = W | author-link2 = William Carter | last3 = Strauss | first3 = KI | author-link3 = Kenneth Strauss | last4 = Brodsky | first4 = I | author-link4 = | last5 = Suhadolnik | first5 = R | author-link5 = Robert Suhadolnik | last6 = Ablashi | first6 = D | author-link6 = Dharam Ablashi | last7 =Henry | first7 = B | author-link7 = | last8 = Mitchell | first8 = WM | author-link8 = William Mitchell | last9 = Bastien | first9 = S | author-link9 = | last10 = Peterson | first10 = D | author-link10 = Daniel Peterson | title = Long Term Improvements in Patients with Chronic Fatigue Syndrome Treated with Ampligen | journal = Journal of Chronic Fatigue Syndrome | volume = 1 | issue = 1 | pages = 35-53 | date = 1995 | url = http://www.tandfonline.com/doi/citedby/10.1300/J092v01n01_04?scroll=top&needAccess=true }}</ref> <ref name="Strayer, 2012">{{Citation | last1 = Strayer | first1 = DR | author-link1 = David Strayer | last2 = Carter | first2 = WA | author-link2 = William Carter | last3 = Stouch | first3 = BC | author-link3 = | last4 = Stevens | first4 = SR | author-link4 = Staci Stevens | last5 = Bateman | first5 = L | author-link5 = Lucinda Bateman | last6 = Cimoch | first6 = PJ | author-link6 = | last7 = Lapp | first7 = CW | author-link8 = Charles Lapp | last8 = Peterson | first8 = DL | author-link8 = Daniel Peterson | last9 =Chronic Fatigue Syndrome AMP-516 Study Group | author-link9 = | last10= Mitchell | first10 = WM | author-link10 = William Mitchell | title = A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. | journal = PLoS One | volume = 7 | issue = 3 | pages = e31334 | date = 2012 | pmid = 22431963 | doi = 10.1371/journal.pone.0031334 }}</ref> </references> [[Category:Potential treatments]] [[Category:Antivirals]] [[Category:Immunomodulators]]
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