Ampligen

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Rintatolimod (tradename Ampligen®) is a mismatched, double-stranded RNA molecule with immunomodulatory and antiviral properties. The drug acts as a TLR3 agonist which stimulates the production of interferons and tumor necrosis factors. It is manufactured by Hemispherx Biopharma.

It has been shown to raise natural killer cell function. [1]

History[edit]

Ampligen® was based on a double-stranded RNA (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.[2][3]

William A. Carter, MD, a researcher at John 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 Ampligen®, short for “AMPLIfied GENetic activity.” In the 1980s, while a researcher at Hahnemann University in Philadelphia, Dr. Carter obtained the license for the compound from John Hopkins University. He and several other researchers at Hahnemann University affiliated with a small company, Hemispherx, now called Hemispherx Biopharma to manufacture it.[4]

In the late 1980s, Hemispherx Biopharma partnered with Dupont to start clinical trials for Ampligen®. After a couple years, Dupont severed its business relationship with Hemispherx Biopharma.[5]

Through the years, Dr. Carter's confidence in Ampligen®'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, swine flu, and ebola.[6][7] Hemispherx Biopharma stated: "...we believe that Ampligen® may have broad-spectrum anti-viral and anti-cancer properties."[8]

This over-confidence resulted in a case action suit by stockholders in 2013.[9]

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 is sponsoring Phase I/II studies using Ampligen® as an adjunct treatment in ovarian, peritoneal, and colorectal cancer.[10] Hahnemann University and Hemispherx Biopharma are collaborating on Phase II studies for Ampligen® as a single agent for Renal Cell Carcinoma and Melanoma. Georgia Regents University is in the preclinical stage of testing Ampligen® as part of a combination therapy for Colorectal Cancer and Melanoma.[11]

In late fall 2015, Dr. Francis Collins announced that the NIH was considering the possibility of sponsoring a clinical trial for Ampligen®, as well as Rituximab and other treatments.[12] By the end of 2016, the 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 Hemispherx Biopharma announced "that a retrospective analysis of the AMP-516 Phase III trial of Ampligen® in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), segmented primarily by disease duration, showed that 51% of Ampligen® 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."[13]

Marketing history[edit]

Mechanism of action[edit]

Poly I:C12U Source: Hemispherx Biopharma, Inc

The chemical formation of Ampligen® 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.[14]

Poly I:C is structurally similar to the type of dsRNA present in some viruses. When introduced into the body it stimulants the immune system because the body thinks a virus is present.

Ampligen® 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.[14]

As a result, one strand of the dsRNA is a homopolymer, poly rI and annealed to this strand is a heteropolymer, polyC12U.[14]

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 Ampligen® compound into separate ribonucleotides which are completely natural degradation products the body can easily handle, thus lessening its toxicity.[14]

Ampligen® is a TLR3 agonist.[14] It stimulates the production of toll-like receptor 3 (TLR3), which is a naturally occurring protein. TLR3 recognizes the dsRNA present in some viruses, such as retroviruses, 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 cells (NK cells).

Evidence[edit]

Coxsackie B[edit]

In a mouse model, Ampligen® was found to be protective of Coxsackie B3-induced myocarditis.[15]

HHV6[edit]

  • 1994, A study done by the Department of Biochemistry, Temple University School of Medicine, Philadelphia, using IV therapy of Ampligen® "resulted in a significant decrease in HHV-6 activity (P < .01) and in downregulation of the 2-5A synthetase/RNase L pathway in temporal association with clinical and neuropsychological improvement."[16]

Efficacy in ME/CFS[edit]

  • 2016, 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 Hemispherx Biopharma and a Professor of Pathology, Microbiology and Immunology at Vanderbilt University School of Medicine, Nashville, Tennessee.[17]
  • 2015, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod.
    Abstract: "Methods and Findings: In order to better identify responders to rintatolimod, primary and secondary endpoints have been reexamined post hoc as a function of a pre-specified study baseline ET duration >9 minutes. Analysis of improvement in exercise performance at the ≥ 25% and ≥ 50% levels using [exercise tolerance] ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using the pre-specified baseline exercise stratum (baseline ET duration >9 minutes)...This corresponds to increases of ≥ 186 and ≥ 373 seconds for patients receiving rintatolimod, respectively, at ≥ 25% and ≥ 50% improvement responses. A frequency distribution analysis of ≥ 25% improvement, <25% change, and ≥ 25% deterioration in ET from baseline at 40 weeks for the baseline >9 minutes cohort showed net improvement to be 18.3% for the rintatolimod cohort vs. 4.6% deterioration for placebo (p=0.015)...The KPS and Vitality (SF-36 subscale) quality of life secondary endpoints demonstrated similar clinically significant improvements for the rintatolimod cohort as a function of the same ET dichotomization...Conclusions: Using a modified Bruce ET protocol with reduced physical exertion allowed clear identification of patient responders to rintatolimod with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes in a modified Bruce ET test. Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod."[18]
See Ampligen Exercise Tolerance - graph 1
  • 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 CDC 1988 and 1994 case definitions) to Ampligen® increased Natural Killer cell cytotoxicity 100-178%.[19]
  • 2012, A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome.
    Abstract: "A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF-36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.[20]
The increase of baseline in mean exercise tolerance tests (ETT) improved 95.7% in the group on Ampligen® and 28.2% in the placebo group. (p value= 0.047; slide 81)[21]
A greater percentage of Ampligen® 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)[22]
No Evidence for induction of autoantibodies with Ampligen® 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-dsDNA and one patient (3.7%) developed Rheumatoid Factor autoantibodies. (slide 54)
  • 2004, A study done at the Rega Institute for Medical Research, Belgium on coxsackie B3 virus-induced myocarditis in C3H/HeNHsd mice show Ampligen® markedly reduced the virus titers in the normalized heart electrocardiographic parameters[15]
  • 2001, Chronic Fatigue Syndrome, Ampligen, and Quality of Life: A Phenomenological Perspective
    "Summary - The purpose of this investigation was to identify significant quality-of-life issues for two women previously diagnosed with chronic fatigue syndrome (CFS), and their families. Both women were participants in a cost-recovery, clinical trial of the antiviral and immuno-modulatory drug, Ampligen. A qualitative, case study approach was adopted to access information not normally available from clinical trials. Specifically, semi-structured, in-depth interviews were conducted with the CFS patients, and their spouses, to discover if these families perceived any changes in their patterns of daily living contingent with participation in the Ampligen trial. Patient diaries were also analyzed for the purpose of triangulation. Content analysis of the interview transcripts and diary entries revealed a number of significant quality of life improvements for the women and their families, for which they perceived the drug therapy responsible. After an initial acclimation period, and with the exception of the day when the drug was administered, both women reported a reduction in pain, increased energy levels, and improved cognitive functioning. They each cited numerous cases to illustrate their improvement."[23]
  • 1995, Long Term Improvements in Patients with Chronic Fatigue Syndrome Treated with Ampligen®
    ABSTRACT: "Fifteen patients who fit the CDC definition of chronic fatigue syndrome (CFS) and had evidence of severe reduction in performance levels by low Karnofsky performance scores (KPS) of 20-60 were treated with Ampligen®. At baseline most patients showed evidence of cerebral dysfunction by neuropsychological testing, were antigen positive by cell culture assay for human herpesvirus-6 (HHV-6), and displayed reduced performance during exercise tolerance testing, as measured by oxygen consumption. These patients represented a subset of CFS patients with especially severe and sustained symptomatology. Following 1248 weeks of Ampligen® therapy, sustained improvements were noted in KPS (p < 0.01). Cognitive function improved including IQ and memory. Oxygen uptake and treadmill duration during exercise tolerance testing was also improved after 24 weeks of treatment (p < 0.01). Reduction in HHV-6 expression as measured by the giant cell assay was significant (p < 0.001). Patients continued to show significant improvement late in therapy, taking 8 to 12 weeks as baseline. It was concluded that while receiving Ampligen®, the severely afflicted patients studied here derived long-lasting clinical benefit from the Ampligen® therapy."[24]

Drug approval status[edit]

United States[edit]

Source: Hemispherx Biopharma, Inc, Dec 2012

Ampligen® has been passed through five different FDA review divisions since 1990. Hemispherx Biopharma, Inc, 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, Hemispherx has had the same medical monitor for more than 20 years (Dr. David Strayer)."[14]

Source: FDA website
History of Hemispherx Biopharma’s application to the FDA for Ampligen [25]

Europe[edit]

In 2016 Ampligen® started being made available on a limited basis in Europe.[26]

South America[edit]

Argentina (Argentine Republic) has approved the use of Ampligen® for ME/CFS on August 23, 2016. [27] Approval is limited to ME/CFS patients who are severely disabled and who have been diagnosed for more than one year.[11]

Notable studies[edit]

  • 2016, Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me)
  • 2015, Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop
  • 2012, A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome.
    Abstract: "A Phase III prospective, double-blind, randomized, placebo-controlled trial comparing twice weekly IV rintatolimod versus placebo was conducted in 234 subjects with long-standing, debilitating CFS/ME at 12 sites. The primary endpoint was the intra-patient change from baseline at Week 40 in exercise tolerance (ET). Secondary endpoints included concomitant drug usage, the Karnofsky Performance Score (KPS), Activities of Daily Living (ADL), and Vitality Score (SF 36). Subjects receiving rintatolimod for 40 weeks improved intra-patient placebo-adjusted ET 21.3% (p = 0.047) from baseline in an intention-to-treat analysis. Correction for subjects with reduced dosing compliance increased placebo-adjusted ET improvement to 28% (p = 0.022). The improvement observed represents approximately twice the minimum considered medically significant by regulatory agencies. The rintatolimod cohort vs. placebo also reduced dependence on drugs commonly used by patients in an attempt to alleviate the symptoms of CFS/ME (p = 0.048). Placebo subjects crossed-over to receive rintatolimod demonstrated an intra-patient improvement in ET performance at 24 weeks of 39% (p = 0.04). Rintatolimod at 400 mg twice weekly was generally well-tolerated.[20]
  • 2004, The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis.
    Abstract: "...We evaluated the efficacy of the interferon inducer Ampligen on coxsackie B3 virus-induced myocarditis in C3H/HeNHsd mice. The efficacy of Ampligen was compared with that of the interferon inducer poly(inosinic acid)-poly(cytidylic acid) [poly(IC)], alpha interferon 2b (INTRON A), and pegylated alpha interferon 2b (PEG-INTRON-α-2b)...The observed efficacies of Ampligen and poly(IC) were corroborated by the observation that the drugs also markedly reduced the virus titers in the heart, as detected by (i) quantitative real-time reverse transcription-PCR and (ii) titration for infectious virus content. Whereas the electrocardiograms for untreated mice with myocarditis were severely disturbed, the electrocardiographic parameters were normalized in Ampligen- and poly(IC)-treated mice...."[28]
  • 1995, Long Term Improvements in Patients with Chronic Fatigue Syndrome Treated with Ampligen[24]
  • 1994, Ampligen inhibits human herpesvirus-6 in vitro.
    Abstract: "The recently discovered human herpesvirus-6 (HHV-6) is being associated with an increasing number of conditions in which there is evidence of immunologic dysfunction. A number of widely available antiviral agents have shown little or no activity against the virus. We found that Ampligen [Poly (1): Poly (C12U), a synthetic, mismatched, double-stranded RNA, has potent, previously unexpected antiviral effects. Cells known to allow replication of HHV-6 were infected with the virus and treated with Ampligen under various conditions. When cells were pretreated with Ampligen (concentrations of 100 or 200 micrograms/ml) prior to infection or treated shortly after infection, viral replication was inhibited by 46-98%. At 100 and 200 micrograms/ml, Ampligen also inhibited the DNA polymerase activity of HHV-6 by 42-98%. When lower concentrations of Ampligen (10 and 50 micrograms/ml) were used, only pretreatment of cells, with Ampligen, followed by virus infection and carrying the infected cells with Ampligen, significantly inhibited HHV-6 infection (83.7 and 89.1% respectively). Indirect evidence suggests that Ampligen may inhibit viral attachment to cellular receptors and/or inhibit intracellular maturation of the virus. The above concentrations of Ampligen were not toxic to the cells used in the study. Given these in vitro findings, and the low frequency of toxicity reported with the use of Ampligen, clinical trials of this drug in patients with evidence of reactivated HHV-6 infection would seem to be warranted."[29]
  • 1994, A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome.
    Abstract:" In a randomized, multicenter, placebo-controlled, double-blind study of 92 patients meeting the CFS case definition of the Centers for Disease Control and Prevention, the response of several laboratory and clinical variables to an antiviral and immunomodulatory drug, poly(I).poly(C12U), was determined. Measures of clinical response included Karnofsky performance score, a cognition scale derived from a self-administered instrument assessing symptomatology (SCL-90-R), an activities of daily living scale, and exercise treadmill performance. After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores (P < .03), exhibited a greater ability to do work during exercise treadmill testing (P = .01), displayed an enhanced capacity to perform the activities of daily living (P < .04), had a reduced cognitive deficit (P = .05), and required less use of other medications (P < .05)."[30]

Experiences of patients on Ampligen®[edit]

Talks and interviews[edit]

Learn more[edit]

See also[edit]

References[edit]

  1. 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
  2. http://pomerantzlawfirm.com/assets/complaints/hemispherx.pdf
  3. http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/immune/antivirals-and-immunemodulators/ampligen-rintatolimod/ampligen-i-effectiveness
  4. http://pomerantzlawfirm.com/assets/complaints/hemispherx.pdf
  5. http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/immune/antivirals-and-immunemodulators/ampligen-rintatolimod/ampligen-part-ii-twisted-history
  6. http://www.bio-medicine.org/medicine-technology/Hemispherx-Presents-Evidence-of-Ampligen-Synergies-with-Existing-0AAntivirals-at-International-Avian-Influenza-Conference-453-1/
  7. http://www.wallstreetdaily.com/2014/11/06/hemispherx-biopharma-ebola-vaccine/
  8. http://www.hemispherx.net/
  9. http://pomerantzlawfirm.com/assets/complaints/hemispherx.pdf
  10. http://www.hemispherx.net/pipeline.php
  11. 11.0 11.1 11.2 Crystal Research Associates (27 Nov 2016), Hemispherx Biopharma, Inc. (PDF) (Executive Informational Overview) 
  12. http://www.meaction.net/2015/12/21/nih-considering-ampligen-and-rituximab-trials/
  13. https://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
  14. 14.0 14.1 14.2 14.3 14.4 14.5 14.6 Hemispherx Biopharma, Inc. (20 December 2012), Ampligen® for the Treatment of Chronic Fatigue Syndrome (PDF) 
  15. 15.0 15.1 Padalko, Elizaveta; Nuyens, Dieter; De Palma, Armando; Verbeken, Erik; Aerts, Joeri L.; De Clercq, Erik; Carmeliet, Pete; Neyts1, Johan (2004), "The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis", Antimicrobial Agents and Chemotherapy, 48 (1): 267–274, PMID 14693549, doi:10.1128/AAC.48.1.267-274.2004 
  16. Suhadolnik, RJ; Reichenbach, NL; Hitzges, P; Sobol, RW; Peterson, DL; Henry, B; Ablashi, DV; Müller, WE; Schröder, HC; Carter, WA (January 1994), "Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome.", Clinical Infectious Disease, 18 (Suppl 1): S96-104, PMID 8148461 
  17. https://www.ncbi.nlm.nih.gov/pubmed/27045557
  18. Strayer, David R; Stouch, Bruce C; Stevens, Staci R.; Bateman, Lucinda; Lapp, Charles W; Peterson, Daniel L; Carter, William A; Mitchell, William M (8 August 2015), "Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod" (PDF), Journal of Drug Research and Development, 1 (1), doi:10.16966/2470-1009.103 
  19. 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
  20. 20.0 20.1 Strayer, DR; Carter, WA; Stouch, BC; Stevens, SR; Bateman, L; Cimoch, PJ; Lapp, CW; Peterson, DL; Chronic Fatigue Syndrome AMP-516 Study Group; Mitchell, WM (2012), "A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome.", PLoS One, 7 (3): e31334, PMID 22431963, doi:10.1371/journal.pone.0031334 
  21. http://www.ncbi.nlm.nih.gov/pubmed/22431963
  22. http://www.ncbi.nlm.nih.gov/pubmed/22431963
  23. Christopher R. Snell, Staci R. Stevens & J. Mark Vanness. (2001). Chronic Fatigue Syndrome, Ampligen, and Quality of Life: A Phenomenological Perspective. Journal of Chronic Fatigue Syndrome, Vol. 8, Iss. 3-4, pp. 117-121. http://dx.doi.org/10.1300/J092v08n03_11
  24. 24.0 24.1 Strayer, DR; Carter, W; Strauss, KI; Brodsky, I; Suhadolnik, R; Ablashi, D; Henry, B; Mitchell, WM; Bastien, S; Peterson, D (1995), "Long Term Improvements in Patients with Chronic Fatigue Syndrome Treated with Ampligen", Journal of Chronic Fatigue Syndrome, 1 (1): 35-53 
  25. http://www.fda.gov/Drugs/NewsEvents/ucm337759.htm
  26. Hemispherx ships Ampligen® for European chronic fatigue syndrome program
  27. Hemispherx Biopharma Announces Major Breakthrough: Approval for Commercial Sale of Rintatolimod (U.S. Tradename: Ampligen®) to Treat Severe Cases of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the Argentine Republic - NasDaq GlobeNewswire
  28. Elizaveta Padalko, Dieter Nuyens, Armando De Palma, Erik Verbeken, Joeri L. Aerts, Erik De Clercq, Peter Carmeliet, and Johan Neyts1. (2004). The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis, Antimicrobial Agents and Chemotherapy, 48 (1): 267–274. doi: 10.1128/AAC.48.1.267-274.2004 Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC310159/
  29. Ablashi, DV; Berneman, ZN; Williams, M; Strayer, DR; Kramarsky, B; Suhadolnik, RJ; Reichenbach, N; Hiltzges, P; Komaroff, AL (1994), "Ampligen inhibits human herpesvirus-6 in vitro", In Vivo, 8 (4): 587-91, PMID 7893986 
  30. Strayer, DR; Carter, WA; Brodsky, I; Cheney, P; Peterson, D; Salvato, P; Thompson, C; Loveless, M; Shapiro, DE; Elsasser, W (1994), "A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome", Clinical Infectious Diseases, 18 (Suppl 1): S88-95, PMID 8148460 


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