In Vivo 1994 Jul;8(4):599-604

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

Suhadolnik RJ, Reichenbach NL, Hitzges P, Adelson ME, Peterson DL, Cheney P, Salvato P, Thompson C, Loveless M, Muller WE, et al

Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.

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.

Publication Types:

PMID: 7893988, UI: 95201215

Clin Infect Dis 1994 Jan;18 Suppl 1:S96-S104

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

Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Muller WE, Schroder HC, Carter WA, et al

Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.

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.

Publication Types:

PMID: 8148461, UI: 94198387

Clin Infect Dis 1994 Jan;18 Suppl 1:S88-S95

A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome.

Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, Thompson C, Loveless M, Shapiro DE, Elsasser W, et al

School of Medicine, Hahnemann University, Philadelphia, Pennsylvania 19102.

Chronic fatigue syndrome (CFS) is a physically debilitating illness associated with immunologic abnormalities, viral reactivation, and impairment of cognition. 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).

Publication Types:

PMID: 8148460, UI: 94198386

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Ann N Y Acad Sci 1993 Jun 23;685:756-757

RNA drug therapy acting via the 2-5A synthetase/RNase L pathway.

Suhadolnik RJ, Reichenbach NL, Hitzges PM, Ablashi DV, Strayer DR, Carter WA

Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.

Publication Types:

PMID: 8363281, UI: 93370925