Tag: Ampligen

Individualizing medical treatment in chronic fatigue syndrome/ myalgic encephalomyelitis: Evidence for effective medications and possible relevance to “Long-Hauler Syndrome” in Covid-19 affected patients

Abstract:

Large controlled studies of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) have shown no effective medical treatment for this disorder. There are individual patients, however, with dramatic responses to some medications.

We report two patients with clear responses to rintatolimod and galantamine characterized by rapid reduction of symptoms on starting treatment and return of symptoms on withdrawal.

As in cancer, CFS/ME is a heterogeneous disorder but unlike most cancers, such as melanoma, breast cancer, and B-cell lymphoma, CFS/ME has no known biological marker that can distinguish between subtypes.

We suggest an approach to medical treatment of CFS/ME that could be utilized by primary caregivers that offer the possibility of more rapid and complete recovery from this debilitating disorder.

Current studies indicate that prolonged symptomatic recovery from infection with Covid-19 (“long hauler syndrome” or PASC, for post-acute sequelae of Covid-19) represents a severe form of CFS/ME and thus may also be amenable to personalized medicine with specific medications.

Source: Levine PH, Ajmera KM, Bjorke B, Peterson D. Individualizing medical treatment in chronic fatigue syndrome/myalgic
encephalomyelitis: Evidence for effective medications and possible relevance to “Long-Hauler Syndrome” in Covid-19 affected
patients. J Clin Images Med Case Rep. 2022; 3(1): 1681. https://jcimcr.org/pdfs/JCIMCR-v3-1681.pdf (Full text)

 

Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials.

Methods and findings: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets.

Conclusion/significance: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2.

Source: Strayer DR, Young D, Mitchell WM. Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One. 2020 Oct 29;15(10):e0240403. doi: 10.1371/journal.pone.0240403. PMID: 33119613. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403 (Full text)

Hemispherx Successfully Completes Commercial Scale Demonstration Batch of Ampligen® at Contract Manufacturer

NEW BRUNSWICK, N.J., Dec. 20, 2017 (GLOBE NEWSWIRE) — Hemispherx Biopharma (NYSE American:HEB) said, its Contract Manufacturing Organization (CMO) for Ampligen® has  completed a commercial scale demonstration/engineering manufacturing run,  along with the re-qualifications of analytical methods that were agreed upon during a previous successful Pre-Approval Inspection (PAI) as necessary prior to the production of commercial lots of Ampligen®.

This accomplishment, in addition to completing all qualification operations to address new equipment and new container closure/vial components, allows the manufacture of current Good Manufacturing Practice (cGMP) clinical product in March 2018 following a scheduled shut down of the CMO for its bi-annual maintenance program.  Completion of the demonstration/engineering manufacturing run provides confidence that the clinical product will meet the stringent quality control release and stability testing prior to release and should be available to patients by the end of the second quarter 2018.  The manufacture of a second clinical lot of Ampligen® is being scheduled to assure maintenance of the clinical supply inventory.

  • Ampligen® has been approved in Argentina for severely debilitated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. Hemispherx recently reported that discussions are underway with the U.S. FDA on the next steps regarding a New Drug Application (NDA) for Ampligen® in ME/CFS, which afflicts more than one million people in this country, according to the Centers for Disease Control (CDC). Ampligen® is the only drug to have completed a Phase 3 clinical trial in the U.S. in ME/CFS.
  • Earlier this year Hemispherx began supplying Ampligen® for pancreatic cancer patients in an Early Access Program (EAP) in the Netherlands.  In addition, work is underway at two leading U.S. cancer centers to define Ampligen®’s potential role in enhancing the effectiveness of PD-1 and PD-L1 checkpoint inhibitors in the fast-growing field of immuno-oncology.

Continue reading “Hemispherx Successfully Completes Commercial Scale Demonstration Batch of Ampligen® at Contract Manufacturer” →

Chronic fatigue syndrome patients need an effective therapeutic, leading expert argues

Ampligen, the first drug ever seeking approval to treat chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), recently hit another roadblock with the U.S. Food and Drug Administration (FDA). In its long quest to treat 1 million Americans suffering from this debilitating illness, the FDA advisory panel did not recommend the drug to be sold on the market, largely because CFS/ME doesn’t have clear biomarkers such as blood tests to define patients who most likely to respond to the drug. Data from clinical trials of Ampligen has not convinced the FDA so far.

Nancy Klimas, M.D., one of the world’s leading researchers and clinicians in chronic fatigue syndrome/myalgic encepahalomyelitis (CFS/ME), is the director the NSU Institute for Neuro Immune Medicine. “The real loser is not Ampligen, but CFS/ME patients whose daily suffering continues to be unabated,” she says. “CFS/ME feels like you’ve been run over by a truck — pain, inflammation, utter exhaustion and trouble concentrating.”

Klimas has been caring for patients with CFS/ME for 26 years now. “It’s heartbreaking seeing them struggle and suffer from this serious illness that has been trivialized by science and society. One of the early controversies quickly disproven suggested that CFS/ME is a form of depression. This led to enduring public policies that allowed insurance companies to limit coverage to CFS/ME to either mental health or exercise therapy, neither get to the root cause of CFS/ME,” she explains.

“CFS/ME researchers, including myself, have seen major advances in our understanding of the biology of CFS/ME. It seems to resemble an illness we know how to treat like multiple sclerosis (MS), chronic viral diseases and autoimmune diseases.”

Around since the late 1980s, this drug is not new to science and medicine. Two phase 3 clinical studies have been completed. The data shows that a subgroup of CFS/ME patients showed marked improvement, even recovery on the drug.

“Yet, that’s not enough evidence for the FDA advisory committee to approve because they would like to see a conclusive biomarker,” notes Klimas. “As a physician, I could live with this decision if I had other effective therapies to treat my CFS/ME patients. But I do not. Moreover, it defies common logic in used in drug approval for other complex immune mediated diseases.”

Take for example, MS: Its earliest approved treatments had opposite immune effects. One interferon increased immune activity and a second interferon quieted immune activity. In the studies that led to approval, MS drugs, like Ampligen, had about a 40 percent success rate.

Clinical research for these early MS drugs produced no biomarkers other than a patient’s successful response to therapy, such as the case of Ampligen. The biomarker the FDA relied on for approval of MS — seeing if the lesions in a patient’s brain decreased — had no correlation to the patient’s improvement.

Why would the FDA approve MS drugs before there were concrete biomarkers to determine success? The answer is simple, Klimas says. The advisory panel saw MS as a serious disease that required interventions ASAP, and were willing to accept that clinicians would better understand where to use the first drugs with more experience using them. Now there are seven approved drugs for MS that have significantly improved quality of life for patients. But they are not willing to use the same logic for Ampligen.

“With or without a biomarker, the FDA should recognize the seriousness of CFS/ME and approve Ampligen, and open the door for other targeted therapies now,” she says.

 

Source: Nova Southeastern University. “Chronic fatigue syndrome patients need an effective therapeutic, leading expert argues.” ScienceDaily. ScienceDaily, 24 January 2013. https://www.sciencedaily.com/releases/2013/01/130124183448.htm

 

Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Abstract:

Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA).

Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2′-5′ adenylate synthetase, protein kinase R).

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. The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed.

 

Source: Mitchell WM. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Expert Rev Clin Pharmacol. 2016 Jun;9(6):755-70. Doi: 10.1586/17512433.2016.1172960. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917909/ (Full article)

 

A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a severely debilitating disease of unknown pathogenesis consisting of a variety of symptoms including severe fatigue. The objective of the study was to examine the efficacy and safety of a TLR-3 agonist, rintatolimod (Poly I: C(12)U), in patients with debilitating CFS/ME.

METHODS AND FINDINGS: 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.

CONCLUSIONS/SIGNIFICANCE: Rintatolimod produced objective improvement in ET and a reduction in CFS/ME related concomitant medication usage as well as other secondary outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00215800.

 

Source: 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.Collaborators (12). A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. doi: 10.1371/journal.pone.0031334. Epub 2012 Mar 14.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303772/ (Full article)

 

TLR3 agonists as immunotherapeutic agents

The interaction of innate and adaptive immune responses is extremely complex and just beginning to be understood in detail. The tendency for biomedical research to establish reproducible models, cell systems and receptor pathways, and then to focus on these systems can sometimes result in opportunity that is not appreciated. The Toll-like receptor (TLR)3 pathway as a therapeutic target falls into this category. There is an immense body of data that has been developed for more than 40 years; all of which is highly relevant to the TLR3 story and yet most of which predates the elucidation of the TLR pathways. A new recognition of TLR3, its unique properties that distinguish it from other TLR pathways, the specificity of relevant and long-available TLR agonists, and new studies of this biology utilizing modern assay methodology suggest that this target may be especially valuable as an adjunct to multiple immunotherapy strategies currently in use or in development.

You can read the rest of this article here: http://www.futuremedicine.com/doi/full/10.2217/imt.10.8 (Full article)

 

Source: Christopher F Nicodemus and Jonathan S Berek. TLR3 agonists as immunotherapeutic agents. Immunotherapy, March 2010 ,Vol. 2, No. 2, Pages 137-140 , DOI 10.2217/imt.10.8 (doi:10.2217/imt.10.8)  http://www.futuremedicine.com/doi/full/10.2217/imt.10.8 (Full article)

Mismatched double-stranded RNA: polyI:polyC12U

Abstract:

Ampligen [polyI:polyC12U] is a mismatched double-stranded RNA that acts by inducing interferon production (immunomodulator) and by activating an intracellular enzyme (RNase-L) against viral RNA transcripts (antiviral). Ampligen, currently under development by Hemispherx Biopharma in the US, acts on the immunological system through T-lymphocyte stimulation and is indicated for the treatment of chronic fatigue syndrome and acquired immunodeficiency deficiency syndrome (AIDS), as part of the combined therapy. Ampligen is available for licensing worldwide.

In February 2004, Fujisawa Deutschland GmbH, a subsidiary of Fujisawa Pharmaceutical Co., entered into an option agreement with Hemispherx Biopharma with the intent of becoming a distributor for Ampligen for the potential treatment of chronic fatigue syndrome in Germany, Switzerland and Austria. An option fee of 400,000 euros was paid pursuant to the terms of the option agreement and upon execution of the Distribution Agreement, Fujisawa will pay Hemispherx fees and milestone payments with a potential worth of several millions of dollars.

In September 2003, Hemispherx Biopharma Inc. entered into an agreement with Guangdong Medicine Group Corporation to organise clinical trials, marketing, sales and distribution for both of its lead compounds, Ampligen and Alferon N in the People’s Republic of China. The agreement stipulates that the Guangdong Medicine Group Corporation (GMC) will conduct clinical trials with Ampligen for the treatment of HIV. All costs related to the trials are to be covered by GMC. Additionally, GMC has to develop and implement marketing and promotional programmes.

In May 2003, Hemispherx Biopharma and the Center for Cell and Gene Therapy entered into a research project agreement that will see Ampligen implemented in a protocol used in patients with relapsed EBV-positive Hodgkin’s Lymphoma.

In March 2002, Esteve and Hemispherx Biopharma entered into a collaborative agreement under which Esteve will be the sole distributor of Ampligen in Spain, Portugal and Andorra for the treatment of chronic fatigue syndrome. Under this agreement, in addition to other terms, Esteve will also collaborate in the drug product development by conducting clinical studies in Spain in patients coinfected with HIV/HCV.

In July 2001 Hemispherx Biopharma announced that it had formed a strategic alliance with Empire Health Resources for clinical trials of Ampligen in the treatment of HIV and hepatitis C virus infections. Empire Health Resources, a healthcare management firm, will be responsible for accrual and retention of patients for HIV trials, and protocols for trials in patients with hepatitis C or both HIV and hepatitis C infections.

Hemispherx has entered into a collaboration with RED Laboratories, and RED Laboratories NV expects that this will facilitate the continued development of Ampligen. Hemispherx has also entered into an agreement with Schering Plough to use a Schering facility as its principal manufacturing platform in the US. This agreement may be expanded to include other territories. Hemispherx and AOP Orphan Pharmaceuticals have signed a marketing agreement for Ampligen for the treatment of chronic fatigue syndrome for Austria, the Czech Republic, Poland and Hungary. In an arrangement between Hemispherx and Bioclones, Bioclones has certain marketing rights for Ampligen in the Southern Hemisphere, UK and Ireland.

In the US, Ampligen has been granted orphan drug status for the treatment of AIDS, renal cell carcinoma (phase II, completed), chronic fatigue syndrome (phase III) and invasive/metastatic malignant melanoma (phase II).

In August 2004, Hemispherx announced that it intends to use the proceeds from the private placement of company stock to complete the clinical work for its immunotherapeutics/ antivirals Ampligen and Oragens. Previously, Hemispherx submitted an application to the EMEA for the approval of Ampligen for the treatment of chronic fatigue syndrome; the first stage of th;) for the treatment of chronic fatigue syndrome; the first stage of the regulatory review has been cleared.

In 2000, Hemispherx Europe (Hemispherx) obtained orphan drug status for Ampligen for the treatment of chronic fatigue syndrome in the EU, providing Hemispherx with 10 years of marketing exclusivity following the launch of the drug, as well as potential financial research benefits for the agent.

In February 2000, Crystaal Corporation (now Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to Ampligen in Canada, where it submitted an NDA for the agent for the treatment of chronic fatigue syndrome. In the meantime, Ampligen has been available since May 1996 under the Canadian Emergency Drug Release Programme for the treatment of chronic fatigue syndrome and immune dysfunction syndrome by Rivex Pharma (Helix BioPharma).

Bioclones has initiated clinical studies with Ampligen for the treatment of chronic fatigue syndrome in Australia. The active substance for Ampligen is manufactured by F.H. Faulding Ltd.

Clinical treatment programmes for chronic fatigue syndrome in other Pacific Rim countries are planned. Ampligen is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa. Hemispherx has developed a ‘ready-to-use’ liquid formulation of the drug and has begun treating patients with chronic fatigue syndrome in ongoing clinical trials. Hemispherx has also developed an oral version of the drug (Oragen), which is undergoing preclinical evaluation.

In February 2001, Hemispherx Biopharma announced that it was initiating phase II/III trials of Ampligen in the treatment of late-stage, multidrug-resistant strains of HIV in the European Union. Patients treated in these studies will have exhausted all other treatment options.

In July 2001, Hemispherx stated that Ampligen was being evaluated in a phase IIb trial in patients with HIV in the US. The trial, comprising two studies, REARMI and REARMII (Research/Evaluation of Ampligen for Retroviral Mutations I and II), will evaluate the ability of Ampligen to prevent the emergence of mutated, drug-resistant strains of the virus. ‘Several hundred’ patients currently on antiretroviral therapy and at risk of viral relapse will be enrolled at centres in Connecticut, New York, Florida and California.

A second phase IIb study evaluating the effect of Ampligen on structured treatment interruptions (STI) is also underway. Final results from this study were reported in December 2002. NIH sponsored studies of potential therapies for SARS have identified Ampligen as having unusually high and consistent antiviral activity against human coronavirus, the pathogen implicated as the causative agent of the disease. Ampligen demonstrated very high potency at very low concentrations (0.4 microg/mL) and had a favourable safety profile.

In October 2003, Hemispherx announced that, based on these promising new results, the company will stockpile injectible and/or oral formats of Ampligen and Alferon N. Independent researchers have demonstrated the antiviral activity of Ampligen against flaviviruses (West Nile virus, Equine Encephalitis virus, Dengue fever virus and Japanese Encephalitis virus) as well as virus classes associated with bioterrorism. In an animal study, Ampligen was shown to prevent destruction of nerve cells, reduce virus concentrations in the brain and blood stream and increase survival rates. Researchers at the Rega Institute in Belgium have published results from an animal study demonstrating that Ampligen was superior at protecting mice against coxsackie B3 virus-induced myocarditis compared with pegylated interferon.

In May 2004 Hemispherx announced that it had filed an expanded US patent application covering the use of Ampligen for the potential treatment and prevention of severe acute respiratory syndrome (SARS) and dreaded emerging viruses.

Copyright 2004 Adis Data Information BV

Source: [No authors listed] Mismatched double-stranded RNA: polyI:polyC12U. Drugs R D. 2004;5(5):297-304. http://www.ncbi.nlm.nih.gov/pubmed/15357629

 

 

Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome

Abstract:

Latent 2′, 5′-oligoadenylate (2-5A) synthetase activity, bioactive 2-5A and RNase L activity were measured in extracts of peripheral blood mononuclear cells (PMBC) before and during a randomized, multicenter, placebo-controlled, double-blind study of poly(I)-poly(C12U) in individuals with chronic fatigue syndrome (CFS) as defined by the Centers for Disease Control and Prevention. The mean values for bioactive 2-5A and RNase L activity were significantly elevated at baseline compared to controls (p < .0001 and p = .001, respectively). In individuals that presented with elevated RNase L activity at baseline, therapy with poly(I)-poly(C12U) resulted in a significant decrease in both bioactive 2-5A and RNase L activity (p = .09 and p = .005, respectively). Decrease in RNase L activity in individuals treated with poly(I)-poly(C12U) correlated with cognitive improvement (p = .007). Poly(I)-poly(C12U) therapy resulted in a significant decrease in bioactive 2-5A and RNase L activity in agreement with clinical and neuropsychological improvements (Strayer DR, et al., Clin. Infectious Dis. 18:588-595, 1994). The results described show that poly(I)-poly(C12U) is a biologically active drug in CFS.

 

Source: Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Müller WE, et al. Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome. In Vivo. 1994 Jul-Aug;8(4):599-604. http://www.ncbi.nlm.nih.gov/pubmed/7893988

 

Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome

Abstract:

Levels of 2′,5′-oligoadenylate (2-5A) synthetase, bioactive 2-5A, and RNase L were measured in extracts of peripheral blood mononuclear cells (PBMCs) from 15 individuals with chronic fatigue syndrome (CFS) before and during therapy with the biological response modifier poly(I).poly(C12U) and were compared with levels in healthy controls.

Patients differed significantly from controls in having a lower mean basal level of latent 2-5A synthetase (P < .0001), a higher pretreatment level of bioactive 2-5A (P = .002), and a higher level of pretherapy RNase L activity (P < .0001). PBMC extracts from 10 persons with CFS had a mean basal level of activated 2-5A synthetase higher than the corresponding control value (P = .009). All seven pretherapy PBMC extracts tested were positive for the replication of human herpesvirus 6 (HHV-6).

Therapy with poly(I).poly(C12U) 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. The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS. The response to therapy suggests direct or indirect antiviral activity of poly(I).poly(C12U) in this situation.

 

Source: Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Müller WE, Schröder HC, Carter WA, et al. Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S96-104. http://www.ncbi.nlm.nih.gov/pubmed/8148461