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{{Short description|Medication}} |
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{{drugbox |
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{{Drugbox |
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| verifiedrevid = 396290045 |
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| verifiedrevid = 420793656 |
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| IUPAC_name = 5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1) |
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| IUPAC_name = 5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1) |
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| image = |
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| image = |
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| width = 200 |
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| width = 200 |
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<!--Clinical data--> |
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| tradename = Ampligen |
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| routes_of_administration = IV |
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<!--Identifiers--> |
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| CAS_number = 38640-92-5 |
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| ATC_prefix = none |
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| UNII = 94325AJ25N |
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| PubChem = |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 34908 |
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| ChemSpiderID = |
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| NIAID_ChemDB = 000136 |
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| InChI = 1/C10H13N4O8P.C9H14N3O8P.C9H13N2O9P/c15-6-4(1-21-23(18,19)20)22-10(7(6)16)14-3-13-5-8(14)11-2-12-9(5)17;10-5-1-2-12(9(15)11-5)8-7(14)6(13)4(20-8)3-19-21(16,17)18;12-5-1-2-11(9(15)10-5)8-7(14)6(13)4(20-8)3-19-21(16,17)18/h2-4,6-7,10,15-16H,1H2,(H,11,12,17)(H2,18,19,20);1-2,4,6-8,13-14H,3H2,(H2,10,11,15)(H2,16,17,18);1-2,4,6-8,13-14H,3H2,(H,10,12,15)(H2,16,17,18)/t4-,6-,7-,10-;2*4-,6-,7-,8-/m111/s1 |
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| KEGG = D09661 |
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| InChIKey = KNUXHTWUIVMBBY-JRJYXWDABE |
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<!--Chemical data--> |
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| molecular_weight = |
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| smiles = O=P(O)(O)OC3O(n1c2N\C=N/C(=O)c2nc1)(O)3O.O=C1/N=C(/N)\C=C/N12O(COP(=O)(O)O)(O)2O.O=C/1NC(=O)N(\C=C\1)2O((O)2O)COP(=O)(O)O |
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| smiles = O=P(O)(O)OC3O(n1c2N\C=N/C(=O)c2nc1)(O)3O.O=C1/N=C(/N)\C=C/N12O(COP(=O)(O)O)(O)2O.O=C/1NC(=O)N(\C=C\1)2O((O)2O)COP(=O)(O)O |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = KNUXHTWUIVMBBY-JRJYXWDASA-N |
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| StdInChIKey = KNUXHTWUIVMBBY-JRJYXWDASA-N |
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| synonyms = PolyI:PolyC12U |
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| CAS_number = 38640-92-5 |
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| ATC_prefix = none |
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| ATC_suffix = |
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| PubChem = |
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| DrugBank = |
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| molecular_weight = |
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| synonyms = PolyI:PolyC12U |
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| density = |
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| bioavailability = |
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| metabolism = |
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| excretion = |
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| pregnancy_AU = |
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| pregnancy_category = |
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| legal_AU = |
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| routes_of_administration = IV |
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}} |
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}} |
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'''Rintatolimod''', sold under the tradename '''Ampligen''', is a medication intended for treatment of ] (ME/CFS).<ref name=Smith2015/> There is some evidence it may improve some ME/CFS symptoms.<ref name=Smith2015/> |
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'''Ampligen''', also known as '''poly I:poly C12U''', is an experimental ]y ] ] developed by ] of ], Pennsylvania. Ampligen was first synthesized in the 1970s and has been proposed and tested as a treatment for ]es including ] (CFS) and ] (AIDS). |
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It is an ]y ] drug similar to the prototypical RNA ]. It was first synthesized in the 1970s and is manufactured by ] (formerly known as Hemispherx Biopharma).<ref>{{cite web |url=https://aimimmuno.com/ |title=Official website of AIM ImmunoTech |access-date=May 17, 2021 }}</ref> |
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Hemispherx reports that it completed a ] ] for CFS in 2004 and filed a ] (NDA) with the ] (FDA) to market and sell Ampligen for the treatment of CFS,<ref name="Hemispherx"></ref> but this was rejected in December 2009 because the FDA concluded that the two RCTs "did not provide credible evidence of efficacy."<ref name="PBJ2010-02-12">{{Cite web |
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| last = George |
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| first = John |
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| title = FDA rejects Hemispherx's chronic fatigue drug Ampligen |
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| work = |
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| publisher = Philadelphia Business Journal |
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| date = Modified: Thursday, December 3, 2009 |
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| url = http://philadelphia.bizjournals.com/philadelphia/stories/2009/11/30/daily23.html |
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| format = html |
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| accessdate = 2010-02-12 }}</ref><ref name="thestreet_dec09">http://www.thestreet.com/_yahoo/story/10636318/1/hemispherxs-ampligen-dealt-fda-blow.html</ref> |
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==History== |
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Although Ampligen was initially cleared for use in Canada in 1997,<ref name="Ostrom 1997">{{cite web |url=http://wwcoco.com/cfids/ampligen2.html |title=Ampligen Finally Breaks Free of Red Tape – in Canada |year=1997 | vauthors = Ostrom N |access-date=May 17, 2021 |work=Stone-Cold Decade }}</ref> and obtained ] status for treatment of ME/CFS in the European Union in 2000, it is approved for use only in Argentina.<ref name="cfsfacts.org">{{cite web |url=http://www.cfsfacts.org/2009/12/facts-about-ampligen-research-in-cfs.html |title=12 Facts about Ampligen research in CFS |access-date=2015-02-08 |archive-date=2016-10-09 |archive-url=https://web.archive.org/web/20161009181454/http://www.cfsfacts.org/2009/12/facts-about-ampligen-research-in-cfs.html |url-status=dead }}</ref><ref name=Globe2018 /> Its status in Canada, per later information, is as a Special Use Program.<ref name=Globe2018>{{cite news |url=https://www.globenewswire.com/news-release/2018/04/04/1459981/0/en/Hemispherx-Expands-Ampligen-Early-Access-Programme-to-Canada-to-Treat-ME-CFS-Patients.html |title=Hemispherx Expands Ampligen Early Access Programme to Canada to Treat ME/CFS Patients |date=April 4, 2018 |work=Globe News Wire |access-date=May 17, 2021 |quote=... special access activities in Canada to include managing the supply of Ampligen® for the treatment of ME/CFS, for which there is currently no approved product in Canada. Ampligen is approved only in Argentina for severe ME/CFS.}}</ref> Rintatolimod has not yet been approved as a legally-prescriptible medication to treat any formally-defined health conditions, diseases, or symptoms in the United States of America; it is still classified by the ] (FDA) as an experimental drug. |
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Ampligen was developed in the 1960s after ] synthesized a double-stranded ] compound composed of inosinic and cytidylic acid residues (poly I:poly C or poly I:C). Poly I:C inhibited tumor growth by inducing ] production. In the mid-1970s, William A. Carter, a post-doctoral researcher at ], modified the ] molecule by adding uridylic acid molecules at specific interval along the RNA chain. The new compound, called Ampligen (for AMPLIfied GENetic activity) stimulated interferon production like poly I:C, but was less toxic.<ref name="kitei">Kitei, Mindy. ." ''Philadelphia Magazine.'' October 1994. Retrieved on February 25, 2007.</ref> |
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A new research project is about to commence on the use of Ampligen in the treatment of ME/CFS (chronic fatigue syndrome ). Key physicians have been recruited in this treatment project, Derek Enlander MD, New York, Charles Lapp MD, Carolina, Lucinda Bateman MD , Salt Lake City, Nancy Klimas MD Miami, and Dr Peterson MD Reno. |
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The project is due to start in May 2011. |
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Carter founded a company based upon the compound and licensed it from Johns Hopkins. By the late 1980s, Carter and his company, HEM Research, Inc., were pursuing human therapeutic uses for Ampligen, as well as non-therapeutic uses, such as diagnostic testing for ] and protecting plants from pathogens.<ref name="hemospherx">"" 1986. Retrieved on February 25, 2007.</ref> |
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In 2007, Hemispherx filed a ] with the U.S. Food and Drug Administration (FDA) to market and sell rintatolimod for the treatment of CFS,<ref name="Hemispherx2007NDA">{{cite web |url=http://www.hemispherx.net/content/investor/default.asp?goto=315 |title=Hemispherx Biopharma Files New Drug Application for Ampligen as Treatment of Chronic Fatigue Syndrome NDA of investigational drug includes four well-controlled trials, more than 1,200 trial subjects and 90,000 doses |access-date=2007-11-07 |archive-date=2015-09-24 |archive-url=https://web.archive.org/web/20150924025648/http://www.hemispherx.net/content/investor/default.asp?goto=315 |url-status=dead }}</ref> but this was rejected in December 2009, because the FDA concluded that the two ]s "did not provide credible evidence of efficacy"<ref name="PBJ2010-02-12">{{cite news |title=FDA rejects Hemispherx's chronic fatigue drug Ampligen |newspaper= Philadelphia Business Journal |url=https://www.bizjournals.com/philadelphia/stories/2009/11/30/daily23.html |date=December 3, 2009 | vauthors = George J |access-date= February 12, 2010 }}</ref><ref name="thestreet_dec09">{{cite news |url=https://www.thestreet.com/investing/stocks/hemispherxs-ampligen-dealt-fda-blow-10636318 |title=Hemispherx's Ampligen Dealt FDA Blow | vauthors = Feuerstein A |work=The Street |date=December 2009 |access-date=May 17, 2021}}</ref> and "because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies."<ref name="fda1">{{cite web |url=https://www.fda.gov/Drugs/NewsEvents/ucm337759.htm |archive-url=https://wayback.archive-it.org/7993/20170113030412/http://www.fda.gov/Drugs/NewsEvents/ucm337759.htm |title=Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS): Questions and Answers |work=] |date=February 26, 2016 |archive-date=January 13, 2017 |access-date=May 17, 2021}}</ref> The FDA requested Hemispherx conduct at least one additional controlled trial to demonstrate efficacy in treating ME/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.<ref name="fda1" /> There are two open-label uses in the US, under Dr. Dan Peterson in Nevada and Dr. Charles Lapp in North Carolina.<ref name=BioSpace2020 /> |
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Ampligen was tested in clinical trials in America beginning in 1988, after ] invested ]30 million in Hemispherx. Initial success in a small trial for ] treatment was followed by difficulties in persuading the FDA to permit large scale trials. By 1991, it was thought that the chance of approval for a large trial being conducted in the USA had gone. Hemispherx then began to move clinical trials to ] and ].<ref name="johnson">Johnson, Hillary. "." 1996. ''].'' Retrieved on February 25, 2007.</ref> |
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Ampligen continues to be evaluated, and as of May 2021 is the subject of phase 2 and phase 3 trials to potentially treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and several cancers. |
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In Belgium, Ampligen has been available for use since the drug's trial beginning in May 1996. It has also been available under Canada's Emergency Drug Release Program for both ] (CFS) and HIV treatment since 1996, with marketing rights controlled by ].<ref name="biovail">Melnyk, Eugene; Howling, Kenneth G. "." ''].'' February 11, 2000. Retrieved on February 25, 2007.</ref> An agreement between the Spanish company ] and Hemispherx in 2002 gave Esteve the rights to perform clinical trials at their own cost in ], ], and ].<ref name="esteve">"." January 14, 2003. Retrieved on February 25, 2007.</ref> ], a ] based company, was granted the exclusive marketing rights to Ampligen in the ], ], and several countries in the Southern Hemisphere.<ref name="bioclones">"." ''Drugs in R&D.'' February 1, 2002. Retrieved on February 26, 2007.</ref> |
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The marketing agreement with Bioclones was terminated in 2005.<ref |
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name="sec3">"</ref> |
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Over its developmental history, Ampligen has received various designations, including “orphan drug product” and “emergency compassionate cost recovery sales authorization” both from the FDA and "promising" clinical outcome recognition based on the evaluation of certain summary clinical reports (AHRQ, Agency Health Research Quality).<ref name="sec2">"</ref> |
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==Medical uses== |
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On December 3, 2007, the FDA deemed the NDA submitted by the company on October 10, 2007 to be incomplete. Specifically, eleven deficiencies were noted in the Clinical Section and three in the Pre-Clinical Section. |
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As of 2021, there is limited scientific evidence supporting the therapeutic efficacy of rintatolimod in treating CFS. The number of double-blinded, placebo-controlled human trial studies published in well-regarded peer-reviewed journals is very sparse. However, there is a small amount of evidence from preliminary clinical studies of limited scope indicating that administration of rintatolimod may improve the daily quality of life of people diagnosed with CFS.<ref name=Smith2015>{{cite journal | vauthors = Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, Fu R, Nelson HD | display-authors = 6 | title = Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop | journal = Annals of Internal Medicine | volume = 162 | issue = 12 | pages = 841–850 | date = June 2015 | pmid = 26075755 | doi = 10.7326/M15-0114 | doi-access = free }}</ref> Rintatolimod was designed with the therapeutic intention of preserving the healthy functioning of human cells by enhancing each cell's immunoresistance to actively-invasive viruses and uncontrollably-proliferating tumorous human cells, e.g. cancerous growths. Therefore, if rintatolimod is proven effective in its originally-intended role as a compound to enhance human cells' resistance to viruses and tumors, it is hypothesized by some medical professionals that it could act synergistically with other antiviral drugs in preventing human infections from ] if coadministered with them.<ref name="Alibek">{{cite journal | vauthors = Alibek K, Liu G | title = Biodefense shield and avian influenza | journal = Emerging Infectious Diseases | volume = 12 | issue = 5 | pages = 873–875 | date = May 2006 | pmid = 16710964 | pmc = 3374437 | doi = 10.3201/eid1205.051480 | publisher = Emerg Infect Dis | version = Letter }}</ref><ref name="Hemispherx_Avian">{{cite news | title = Hemispherx Presents Evidence of Ampligen Synergies with Existing Antivirals at International Avian Influenza Conference| publisher =Business Wire | date = 2007-06-04 | url = http://www.bio-medicine.org/medicine-technology/Hemispherx-Presents-Evidence-of-Ampligen-Synergies-with-Existing-0AAntivirals-at-International-Avian-Influenza-Conference-453-1/| access-date = 2008-04-26}}</ref> |
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In 2009, William Carter said that Ampligen could be a booster for a flu vaccine to the ] flu and fight the ].<ref name="street"></ref> |
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==Side effects== |
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The FDA postponed an announcement about Ampligen scheduled for May 25, 2009 for "one to two weeks." In July, 2009, a report said that the FDA's decision would not be announced until later in 2009.<ref> John George, Philadelphia Business Journal, July 22, 2009</ref> Critics said that Hemispherx is regularly using "an eight year old government report to assure investors the company's chronic fatigue syndrome drug will be approved soon."<ref></ref> |
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An independent review of rintatolimod trials in CFS was published in the December 2006 issue of the ''Journal of Clinical Virology''.<ref>{{Cite journal|url=http://www.journalofclinicalvirology.com/article/S1386-6532(06)70079-8/abstract|doi = 10.1016/S1386-6532(06)70079-8|title = 60: Review of Ampligen clinical trials in chronic fatigue syndrome|year = 2006| vauthors = Mitchell W |journal = Journal of Clinical Virology|volume = 37|pages = S113}}</ref> 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 about 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."<ref>{{cite journal | vauthors = Mitchell W | title = Review of Ampligen clinical trials in Chronic Fatigue Syndrome | journal = Journal of Clinical Virology | volume = 37 | issue = supp. 1 | pages = S113 |date=December 2006 | url = http://www.immunesupport.com/library/showarticle.cfm/id/7638/searchtext/ampligen | access-date = 2007-02-26 | doi = 10.1016/S1386-6532(06)70079-8 }}</ref> A mild ] reaction has occurred in about 15% of patients, and more rarely reported ] include ], ], ], ], ], and ]. Some of these side effects may be attributed to a temporary ] in response to pathogen die-off. According to Hemispherx and patient testimonials, side effects, when they occur, usually subside within 3–4 months or less.<ref>{{cite web | title = Ampligen for Chronic Fatigue Syndrome | url = http://chronicfatigue.about.com/od/treatingfmscfs/p/ampligen.htm | vauthors = Dellwo A | veditors = Ozeri D | date = 25 September 2020 }}</ref><ref name="sec">{{cite web |url= https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166046.pdf |archive-url=https://web.archive.org/web/20090710121009/https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166046.pdf |title=FDA Letter Section: Abstracts of Patient Session on Ampligen (1998) |work=] |date=July 7, 2000 |archive-date=July 10, 2009 |url-status= dead |access-date=June 17, 2021}}</ref> |
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==Mechanism of action== |
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The drug was rejected by FDA in December 2009.<ref name="PBJ2010-02-12">{{Cite web |
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| last = George |
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| first = John |
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| title = FDA rejects Hemispherx's chronic fatigue drug Ampligen |
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| work = |
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| publisher = Philadelphia Business Journal |
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| date = Modified: Thursday, December 3, 2009 |
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| url = http://philadelphia.bizjournals.com/philadelphia/stories/2009/11/30/daily23.html |
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| format = html |
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| doi = |
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| accessdate = 2010-02-12 }}</ref><ref name="thestreet_dec09">http://www.thestreet.com/_yahoo/story/10636318/1/hemispherxs-ampligen-dealt-fda-blow.html</ref> |
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One mode of action of this drug is to stimulate the ], also called the nonspecific immune system, and the first line of defense. According to a study published in the '']''<ref name="J Immuno">{{cite journal | vauthors = Gowen BB, Wong MH, Jung KH, Sanders AB, Mitchell WM, Alexopoulou L, Flavell RA, Sidwell RW | display-authors = 6 | title = TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules | journal = Journal of Immunology | volume = 178 | issue = 8 | pages = 5200–5208 | date = April 2007 | pmid = 17404303 | doi = 10.4049/jimmunol.178.8.5200 | doi-access = free }}</ref> and reflected in a press release by Hemispherx,<ref name="Hemispherx2007MoA">{{cite web | author = Hemispherx Biopharma, Inc. | date = 1 May 2007 | url = https://pipelinereview.com/index.php/2007050111449/DNA-RNA-and-Cells/New-Report-Illuminates-AmpligenRs-Unique-Mechanism-of-Action.html| title = New Report Illuminates Ampligen's Unique Mechanism of Action Hemispherx | quote = Biopharma's Proprietary Experimental Therapeutic Activates TLR-3 Receptor to Potentiate Broad-Spectrum Immune Response }}</ref> rintatolimod stimulates the innate immune system by binding to ], and activating the TLR-3 receptors for broad-spectrum immune response. TLR-3 receptors are located intracellular at the membranes of endosomes. They are part of a family of "pattern recognition" receptors that detect pathogens immediately, long before the slower ] can intervene against foreign invaders. These receptors are critical to the first line of immunological defense against a broad range of pathogens, including viruses and cancer.{{cn|date=January 2023}} |
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==Hypothesized mechanism of action== |
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The mechanism of rintatolimod in relation to CFS is not certain, but is thought to include the ] enzyme.<ref name="pmid7893988">{{cite journal | vauthors = ], Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE | display-authors = 6 | title = Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome | journal = In Vivo | volume = 8 | issue = 4 | pages = 599–604 | year = 1994 | pmid = 7893988 }}</ref> Rintatolimod is a dsRNA, and when TLR-3 senses a dsRNA, it is thought to relay a message to cells to produce ].<ref>{{cite journal | vauthors = Liang SL, Quirk D, Zhou A | title = RNase L: its biological roles and regulation | journal = IUBMB Life | volume = 58 | issue = 9 | pages = 508–514 | date = September 2006 | pmid = 17002978 | doi = 10.1080/15216540600838232 | doi-access = free }}</ref> IFNs are a group of ] 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 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.<ref name="deMeirleir">{{cite journal | vauthors = Nijs J, De Meirleir K | title = Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome | journal = In Vivo | volume = 19 | issue = 6 | pages = 1013–1021 | year = 2005 | pmid = 16277015 }}</ref> |
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The manufacturer says ampligen acts by stimulating the innate immune system. Cells normally encounter double-stranded RNA molecules like Ampligen and poly I:C only during infection with RNA ]es. A receptor on the cell surface called Toll-like receptor 3 (TLR3) is part of an evolutionarily conserved family of “pattern recognition” receptors that detect pathogens immediately, even those the body has not yet encountered, long before ] can intervene against foreign invaders. These molecules are critical to the first line of immunological defense against a broad range of pathogens, such as viruses, and even various forms of cancer. |
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==History== |
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When TLR3 senses a dsRNA, it relays a message to the cell to produce interferon, a small protein that serves as a signal. Interferon alerts other cells that an infection is present and produces a series of responses in nearby cells and the interferon-producing cell. These include changes in gene regulation, for example stimulating production of the 2'-5' oligoadenylate synthetase-dependent enzyme ] (''Ribonuclease, latent''). This protein degrades viral RNA. It can also degrade the cell's own RNA, leading to the ] (programmed cell death) of virally compromised cells. |
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Rintatolimod development evolved from a 1960s synthesis by ], 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 IFN production, but was too toxic to use. In the mid-1970s, William A. Carter, a postdoctoral researcher at ], modified the ] 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.<ref name="kitei">{{cite web | vauthors = Kitei M | url = http://www.cfs-news.org/kitei.htm | title = A History of Ampligen: The AIDS Drug No One Can Have. | archive-url = https://web.archive.org/web/20080122073726/http://www.cfs-news.org/kitei.htm | archive-date = 22 January 2008 | work = Philadelphia Magazine. | date = October 1994 | access-date = 25 February 2007 }}</ref> It is also known as "poly I:poly C12U". |
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Dr. Carter founded a company based upon the compound, and licensed it from Johns Hopkins. By the late 1980s, Carter and his company, HEM Research, Inc., were pursuing human therapeutic uses for rintatolimod, as well as nontherapeutic uses, such as diagnostic testing for ] and protecting plants from pathogens.<ref name="hemospherx">"" 1986. Retrieved on February 25, 2007.</ref> |
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The mechanism of Ampligen in relation to CFS is not known but it is thought to involve ].<ref name="pmid7893988">{{cite journal |author=Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE |title=Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome |journal=In Vivo (Athens, Greece) |volume=8 |issue=4 |pages=599–604 |year=1994 |pmid=7893988 |doi= |url=}}</ref> Accumulation of an inactive form of RNase L may be associated with CFS.<ref name="deMeirleir">{{cite journal |author=Nijs J, De Meirleir K |title=Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome |journal=In Vivo |volume=19 |issue=6 |pages=1013–21 |year=2005 |pmid=16277015 }}</ref> According to a Hemispherx press release<ref name="Hemispherx"></ref> summarizing findings<ref name="J Immuno">{{cite journal |author=Gowen BB, Wong MH, Jung KH, ''et al.'' |title=TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules |journal=J. Immunol. |volume=178 |issue=8 |pages=5200–8 |year=2007 |month=April |pmid=17404303 |doi= |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=17404303}}</ref> published in the ], Ampligen requires TLR-3 to work, in contrast to other synthetic dsRNA molecules that are detected by multiple cellular sensors. |
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Rintatolimod was tested in clinical trials in the United States beginning in 1988, after ] invested $30 million in Hemispherx. Initial success in a small trial for ] treatment was followed by difficulties in persuading the FDA to permit large-scale trials. By 1991, the chance of approval for a large trial being conducted in the USA was thought to be gone. Hemispherx then began to move clinical trials to ] and ].<ref name="johnson">{{cite book | vauthors = Johnson H | title = Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic | year = 1996 | publisher = ] | pages = 647–49 | isbn = 978-0517703533 }}</ref> |
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==Clinical trials and approval status== |
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In Belgium, rintatolimod has been available for use since the drug's trial beginning in May 1996. It has also been available under Canada's Special Access Program for both CFS and HIV treatment since 1996, with marketing rights controlled by Biovail Corporation International.<ref name="biovail">Melnyk, Eugene; Howling, Kenneth G. "." ''Biovail Corporation International|Biovail.'' February 11, 2000. Retrieved on February 25, 2007.</ref> An agreement between the Spanish company ] and Hemispherx in 2002 gave Esteve the rights to perform clinical trials at their own cost in ], ], and ].<ref name="esteve">"." January 14, 2003. Retrieved on February 25, 2007.</ref> Bioclones (PTY) Ltd, a ] based company, was granted the exclusive marketing rights to rintatolimod in the ], ], and several countries in the Southern Hemisphere.<ref name="bioclones">"." ''Drugs in R&D.'' February 1, 2002. Retrieved on February 26, 2007.</ref> The marketing agreement with Bioclones was terminated in 2005.<ref name="HEMISPHERX-BIOPHARMA-INC-Mar-2007-10-K">{{cite web|url=http://edgar.secdatabase.com/2780/114420407013492/filing-main.htm |title=Hemispherx Biopharma Inc, Form 10-K, Annual Report, Filing Date Mar 19, 2007 |publisher=secdatabase.com |access-date =May 15, 2018}}</ref> |
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A randomized study of Ampligen (AMP 516 ] ] for treatment of CFS) in the USA was completed in 2004.<ref></ref> The AMP 511 open-label study of Ampligen in CFS is still recruiting participants.<ref></ref> Open-label studies are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained.<ref></ref> Hemispherx management had missed several target deadlines for new drug application (NDA) filing in the past, including the end of 2005, the third quarter of 2006, and the first quarter of the year 2007.<ref></ref> In October 2007, the US ] (FDA) Ampligen NDA was filed.<ref name="Hemispherx"/><ref name="Hemispherx1">{{cite web | last = | first = | title = Ampligen | publisher = Hemispherx Biopharma | date = | url = http://www.hemispherx.net/content/rnd/drug_candidates.htm | accessdate =2008-04-26}}</ref> In December 2009 the FDA issued a CRL refusing Hemisherx's new drug application for Ampligen's treatment of CFS. The FDA concluded that the two RCTs "did not provide credible evidence of efficacy." The agency recommends a minimum of one additional six month 300 patient study, and rodent carcinogenicity studies. The company reports it is currently working with the FDA to address these concerns.<ref name="PBJ2010-02-12"/><ref name="thestreet_dec09"/> |
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Over its developmental history, rintatolimod has received various designations, including "orphan drug product" and "emergency compassionate cost recovery sales authorization", both from the FDA, and "promising" clinical outcome recognition based on the evaluation of certain summary clinical reports (AHRQ, Agency Health Research Quality).<ref name="sec2">"</ref> |
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According to the US National Academy of Sciences Institute of Medicine, "Chronic fatigue syndrome is a disease characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion of any sort. CFS can severely impair patients' ability to conduct their normal lives."<ref></ref> In October 2007, Hemispherx BioPharma submitted their first new drug application (NDA) to the FDA for rintatolimod to treat CFS. In December 2007, the agency deemed the application incomplete, citing deficiencies including lack of dose ranging, statistical analysis plans inconsistent with protocols, database discrepancies, and lack of clinical pharmacology and ]icity data.<ref name="fda1" /> In early 2009, Hemispherx again submitted rintatolimod for FDA approval for CFS treatment. The FDA scheduled their decision for May 25th of that year and twice postponed.<ref></ref><ref> John George, Philadelphia Business Journal, July 22, 2009</ref> The company received a ] from the agency on rintatolimod's NDA in December 2009, requesting further data.<ref></ref> |
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Ampligen is received ]. It is generally administered twice weekly for periods of one year or greater. Two toxicology studies were recently completed that establish the safety of intranasal and intramucosal methods of Ampligen administration.<ref name="sec">http://sec.gov/Archives/edgar/data/946644/000114420407023929/v074337_10q.htm, p. 20</ref> Hemispherx states it is currently researching an oral drug that uses nucleic acid technology related to Ampligen.<ref name="Oragen">http://www.hemispherx.net/content/rnd/drug_candidates.htm</ref> |
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In 2007, and again during the ], Carter said that rintatolimod could also be used as an ] flu vaccine booster, citing ''in vitro'' studies with Ampligen and neuraminidase inhibitors oseltamivir and zanamivir (brand names Tamiflu and Relenza).<ref> (June 4, 2007) Retrieved February 21, 2015</ref> |
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==Impact== |
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Approximately 760 patients have received Ampligen as part of clinical trials in the US, representing about 75,000 doses. Some chronic fatigue syndrome patients have reported a complete recovery, with others reporting clear and measurable improvements, <ref></ref> although success has not been universal. More common benefits include improved ] skills, an increase in energy and greater oxygen uptake. These improvements can be measured on the ].<ref>{{cite journal |author=Suhadolnik RJ, Reichenbach NL, Hitzges P, ''et al.'' |title=Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome |journal=In Vivo |volume=8 |issue=4 |pages=599–604 |year=1994 |pmid=7893988 |doi= |url=}}</ref><ref>{{cite journal |author=Strayer DR, Carter WA, Brodsky I, ''et al.'' |title=A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome |journal=Clin. Infect. Dis. |volume=18 Suppl 1 |issue= |pages=S88–95 |year=1994 |month=January |pmid=8148460 |doi= |url=}}</ref> |
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Hemispherx Biopharma continues to work with the FDA on rintatolimod approval for CFS treatment. On December 20, 2012, an FDA Advisory Committee voted in favor of rintatolimod's safety for commercial use (vote 8 to 5), but not in favor of its efficacy (4 to 9).<ref></ref> The ] asked for more study data prior to rintatolimod approval.<ref name="fda1" /> |
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==Side effects and safety== |
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On January 12, 2015, the company released new ''in vitro'' study findings showing that low natural killer cell function associates with greater CFS disease symptom severity, and that rintatolimod treatment increases average NK cell activity over 100%. The new study report, "Low Natural Killer (NK) Activity Observed Across the Chronic Fatigue Syndrome (CFS) Disease Spectrum," has been submitted as a scientific paper for peer review and publication. In addition to the new study findings, the paper summarizes six supportive publications of results with more than 150 CFS patients, correlating increased debility of CFS and low NK cell activity.<ref name="hemispherx.net"></ref> Clinical testing is currently under way to determine whether NK cell activity augmentation by rintatolimod ''in vivo'' associates with lessened CFS disease severity and increased physical endurance and performance measures.<ref name="hemispherx.net"/> |
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Hemispherx consider that Ampligen has been "generally well tolerated", with a "low incidence of clinical toxicity", particularly when compared to 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."<ref>{{cite journal | last = Mitchell | first = W. | title = Review of Ampligen clinical trials in Chronic Fatigue Syndrome | journal = Journal of Clinical Virology | volume = 37, supp. 1 | pages = S113 | month = December | year = 2006 | url = http://www.immunesupport.com/library/showarticle.cfm/id/7638/searchtext/ampligen | accessdate = 2007-02-26 | doi = 10.1016/S1386-6532(06)70079-8 }}</ref> A mild ] reaction has occurred in about 15% of patients, and other reported ] include ], ], ], ], ] and ]. A full list is available on the Hemispherx website.<ref> - official Hemispherx site</ref> The extent of these side-effects is unknown. According to Hemispherx, side-effects usually subside within "several months".{{Citation needed|date=August 2009}} |
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==Status around the world as of 2022== |
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==Controversy== |
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Hemispherx has on two occasions received warning letters from the FDA regarding its promotion of Ampligen as safe and effective before approval from the FDA.<ref></ref><ref></ref> |
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Although Ampligen was initially cleared for use in Canada in 1997,<ref name="Ostrom 1997"/> and obtained ] status for treatment of CFS in the European Union in 2000, it is approved for use only in Argentina.<ref name="cfsfacts.org"/><ref name=Globe2018 /> Its status in Canada, is as a Special Access Program, via the My Tomorrows program set up in Amsterdam.<ref name=Globe2018/><ref>{{cite news |url=https://www.bizjournals.com/philadelphia/news/2018/02/26/heb-ampligen-pancreatic-cancer-canada-mytomorrows.html |title=Hemispherx's Ampligen drug is coming to Canada | vauthors = George J |date=February 28, 2018 |work=Philadelphia Business Journal |access-date=May 17, 2021 }}</ref> It is so far without FDA approval, and is classed as experimental in the United States.{{cn|date=November 2022}} |
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], an investment adviser who reports on companies he considers to be overvalued, has criticized Hemispherx and its Ampligen results,<ref name="aegis"></ref> alleging a variety of ] including accusations of refusing to supply Ampligen after clinical trials have ended,<ref></ref> and issuing misleading results to widen markets for Ampligen.<ref name="aegis" /> |
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It was approved for use in Argentina and will soon be ready for commercial sales. Interest rose in that country after an increase in the number of ME/CFS cases following its SARS epidemic in 2002–2003. Argentina anticipates a similar rise in ME/CFS cases from SARS-CoV-2.<ref name=BioSpace2020>{{cite news |url=https://www.biospace.com/article/aim-immunotech-provides-update-on-commercial-launch-of-ampligen-r-in-argentina-for-the-treatment-of-chronic-fatigue-syndrome/ |title=AIM ImmunoTech Provides Update on Commercial Launch of Ampligen(R) in Argentina for the Treatment of Chronic Fatigue Syndrome |work=Bio Space |date=June 15, 2020 |access-date=May 17, 2021 |quote= Dr. Dan Peterson, M.D. ... is currently an investigator in an FDA authorized open-label expanded access treatment protocol of Ampligen. }}</ref> |
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In 2007, Hemispherx filed a ] with the ] (FDA) to market and sell rintatolimod for the treatment of CFS,<ref name="Hemispherx2007NDA"/> but this was rejected in December 2009, because the FDA concluded that the two ]s "did not provide credible evidence of efficacy"<ref name="PBJ2010-02-12"/><ref name="thestreet_dec09"/> and "because of clinical, statistical, clinical pharmacology, nonclinical, product quality, and facilities inspection deficiencies."<ref name="fda1" /> The FDA requested Hemispherx conduct at least one additional controlled trial to demonstrate efficacy in treating CFS.{{cn|date=November 2022}} |
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In August 2012, Hemispherx submitted further analyses of the original clinical trial data to FDA, 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.<ref name="fda1" /> |
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Work continues on the drug, and there has been no approval by the US FDA, as of May 2021. There is open-label use in the US, under Dr. Dan Peterson in Nevada.<ref name=BioSpace2020 /> |
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As of 2022, rintatolimod was approved in Argentina and is ready to "Launch pending FDA export authorization" <ref>https://aimimmuno.com/products/ "Official Website of AIM ImmunoTech Retrieved March 23, 2022</ref> |
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==Controversy== |
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In 1998 and 2000, Hemispherx received notices of violation from the FDA for promoting rintatolimod as safe and effective before FDA approval, in violation of the ].<ref> – FDA, 7 July 2000,</ref><ref> – FDA, 15 Oct 1998</ref> |
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Also in the late 1990s, ] reported on Hemispherx, saying the company was overvalued. He criticized Hemispherx and its rintatolimod results,<ref name="aegis.com"> {{webarchive |url=https://web.archive.org/web/20060828141002/http://www.aegis.com/NEWS/PR/1999/PR990509.html |date=August 28, 2006 }}</ref> alleging a variety of ], including accusations of refusing to supply rintatolimod after clinical trials have ended,<ref> {{webarchive |url=https://web.archive.org/web/20070204071235/http://www.cfs-news.org/amposler.htm |date=February 4, 2007 }}</ref> and issuing misleading results to widen markets for rintatolimod.<ref name="aegis.com"/> |
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In 1998, Hemispherx Biopharma filed a complaint against Asensio and his company, alleging defamation, conspiracy and interference with its business relations through a ] plot. After a jury rejected the defamation claims against Asensio, a mistrial was declared. Hemispherx announced in 2006 that they anticipated a new trial date to be set.<ref></ref> |
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In 1998, Hemispherx Biopharma filed a complaint against Asensio and his company, alleging defamation, conspiracy, and interference with its business relations through a short-selling plot.<ref name="HEMISPHERX-BIOPHARMA-INC-Mar-2007-10-K"/> After a jury rejected the defamation claims against Asensio, a mistrial was declared.<ref></ref> |
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On November 2, 1999, Mary Schweitzer, a chronic fatigue syndrome patient who had been treated with Ampligen, raised the question of why Ampligen had never been fast-tracked by the US public health authorities at the Chronic Fatigue Syndrome Co-ordinating Committee of the ].<ref></ref> |
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On November 2, 1999, Mary Schweitzer,<!--NOT Mary Higby Schweitzer--> a CFS patient who had been treated with rintatolimod, raised the question of why Ampligen has never been fast-tracked by the US public health authorities at the Chronic Fatigue Syndrome Co-ordinating Committee of the ].<ref></ref> Grassroots activism for FDA approval of Ampligen grew and continues. Efforts in 2015 to spur FDA approval of Ampligen include petitions, appeal for congressional hearing,<ref>{{cite web | title = Congressional Hearing To Remove Roadblocks to Ampligen Approval at FDA | vauthors = Johnson C | date = 5 February 2015 | work = Health Rising | url = https://www.healthrising.org/blog/2015/02/05/congressional-hearing-ampligen-roadblocks-fda-called/ }}</ref> and popular social media group organizing.<ref>{{cite web | url = https://www.facebook.com/groups/ampligen/ | title = Ampligen | work = Facebook Page }}</ref><ref>{{cite web | url = https://www.facebook.com/HungerStrikeForAmpligen | title = Hunger Strike for Ampligen | work = Facebook Page }}</ref><ref>{{cite web | url = https://www.youtube.com/watch?v=fkucpprXmvc | title = Why No Antivirals & Ampligen? | date = 2011 | work = YouTube Video }}</ref><ref>{{cite web | url = https://www.youtube.com/watch?v=kliPho9dJ1o | title = Ampligen patient speaking to an FDA representative | date = 2013 | work = YouTube Video }}</ref> |
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In June 2009, ] alleged Hemispherx was "seeking to divert investors' attention away from the delayed approval of Ampligen as a treatment for chronic fatigue syndrome" by issuing three press releases in seven days about research from 2007 into possible applications for Ampligen as a flu vaccine booster. Hemispherx stated that Ampligen could be used against the H1N1 swine flu. The Street also alleged the Hemispherx press releases were misleading because they imply the research had been done in 2009.<ref name="street"/> Hemispherx's attempts to put Ampligen in the H1N1 market were unsuccessful. The company stated they were "shut out of the U.S. government's efforts to stockpile vaccine against the H1N1 flu."<ref name=StreetH1N1> Adam Feuerstein, The Street, July 14, 2009</ref> |
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Adam Feuerstein, a journalist for ],<ref></ref> has published several articles harshly critical of Hemispherx BioPharma, Inc. In June 2009, Feuerstein alleged the company was "seeking to divert investors' attention away from the delayed approval of Ampligen as a treatment for chronic fatigue syndrome" by issuing three press releases in seven days about research from 2007 into possible applications for Ampligen as a flu vaccine booster, in which Hemispherx stated that Ampligen could be used against the H1N1 swine flu.<ref></ref> This article also alleged the press releases were misleading, because they implied the research had been done in 2009. When Hemispherx offered Ampligen as a potential H1N1 vaccine or vaccine booster, the U.S. government turned them down, and Feuerstein wrote, "Hemispherx Biopharma has been shut out of the U.S. government's efforts to stockpile vaccine against the H1N1 flu."<ref> Adam Feuerstein, The Street, July 14, 2009</ref> |
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==Other uses== |
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The manufacturer says Ampligen can be used for ]<ref name="Hemispherx_Avian">{{cite news | last = | first = | title = Hemispherx Presents Evidence of Ampligen Synergies with Existing Antivirals at International Avian Influenza Conference| work = | pages = | language = | publisher = BUSINESS WIRE | date = 2007-06-04 | url = http://www.bio-medicine.org/medicine-technology/Hemispherx-Presents-Evidence-of-Ampligen-Synergies-with-Existing-0AAntivirals-at-International-Avian-Influenza-Conference-453-1/| accessdate = 2008-04-26}}</ref><ref name="Alibek"> {{cite paper |author=Alibek K, Liu G. |title=Biodefense shield and avian influenza |version=Letter |publisher=Emerg Infect Dis |date=2006 May |url=http://www.cdc.gov/ncidod/EID/vol12no05/05-1480.htm |accessdate=2007-12-14}}</ref><ref></ref> and ],<ref></ref><ref></ref> although studies have been limited.<ref></ref> Other suggested uses include ] and ].<ref></ref> |
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==See also== |
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==Research== |
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Rintatolimod has been studied in humans since 1994.<ref>{{cite journal | vauthors = Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W | display-authors = 6 | 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–S95 | date = January 1994 | pmid = 8148460 | doi = 10.1093/clinids/18.supplement_1.s88 }}</ref> In early 2015, the AMP 511 ] of rintatolimod in CFS was still recruiting participants.<ref>{{ClinicalTrialsGov|NCT00215813|Study of Ampligen in Chronic Fatigue Syndrome}}</ref> Open-label studies are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the investigational drug until marketing approval is obtained.<ref></ref> Hemispherx management had missed several target deadlines for NDA filing in the past, including the end of 2005, the third quarter of 2006, and the first quarter of 2007.<ref name="HEMISPHERX-BIOPHARMA-INC-Jan-2006-8-K">{{cite web|url=http://edgar.secdatabase.com/1775/94664406000001/filing-main.htm |title=HEMISPHERX BIOPHARMA INC, Form 8-K, Current Report, Filing Date Jan 3, 2006 |publisher=secdatabase.com |access-date =May 14, 2018}}</ref> In October 2007, the US FDA Ampligen NDA was filed.<ref name="Hemispherx2007NDA"/><ref name="Hemispherx1">{{cite web |title=Ampligen |publisher=Hemispherx Biopharma |url=http://www.hemispherx.net/content/rnd/drug_candidates.htm |access-date=2008-04-26}}</ref> In December 2009, the FDA issued a complete response letter refusing Hemispherx's new drug application for rintatolimod's treatment of CFS. The FDA concluded that the two RCTs "did not provide credible evidence of efficacy." The agency recommended a minimum of one additional six-month, 300-patient study, and rodent carcinogenicity studies.{{cn|date=November 2022}} |
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Rintatolimod is administered ]. It is generally administered twice weekly for periods of one year or longer. Two toxicology studies had been completed as of 2007, which established the safety of intranasal and intramucosal methods of Ampligen administration as a vaccine immunostimulant.<ref name="sec" />{{rp|20}} Hemispherx has conducted research on a by mouth versions of rintatolimod using nucleic acid technology related to rintatolimod.<ref></ref><ref>{{cite journal | title = Mismatched double-stranded RNA: polyI:polyC12U | journal = Drugs in R&D | volume = 5 | issue = 5 | pages = 297–304 | year = 2004 | pmid = 15357629 | pmc = 7100700 | doi = 10.2165/00126839-200405050-00006 | author1 = Adis Editorial }}</ref> |
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==References== |
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{{Reflist}} |
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==External links== |
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== References == |
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