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PubMedDate not supplied

Dose-related effects of Ampligen (poly(I).poly(C12U)), a mismatched double-stranded RNA, in a bleomycin-mouse model of pulmonary fibrosis.

The antifibrotic effect of the mismatched double-stranded RNA, Ampligen (poly(I).poly(C12U)), was evaluated in a bleomycin-mouse model of pulmonary fibrosis. Mice received a single intratracheal dose of bleomycin (0.125 U/mouse) or saline (50 microL) at the beginning of the experiment, followed by 5 or 6 intraperitoneal injections of Ampligen (1.0, 5.0, 10.0, 15.0, or 25.0 mg/kg) or saline at regular intervals for 2 weeks. Ampligen did not produce increased mortality or weight loss by itself. However, it produced varying degrees of mortality in combination with bleomycin. Five injections of 10 mg/kg Ampligen or three injections of 25 mg/kg Ampligen plus three injections of 10 mg/kg Ampligen in combination with bleomycin .produced significant reductions in lung collagen accumulation as indicated by lung hydroxyproline content compared to the bleomycin control group. Animals receiving bleomycin plus Ampligen at all dosages had significantly reduced prolyl hydroxylase activity compared to the bleomycin control group. Lipid peroxidation and bronchoalveolar lavage fluid (BALF)-supernatant protein content for the groups receiving bleomycin plus Ampligen were not reduced compared to the bleomycin control group. In the BALF-supernatant, the activity of acid phosphatase, a lysosomal enzyme produced by neutrophils, monocytes, and macrophages, was significantly decreased in the group receiving bleomycin plus 10 mg/kg Ampligen. Also, selected BALF differential immune cell counts were reduced in some of the groups receiving bleomycin plus Ampligen, but not in a consistent or dose-dependent manner. The results of this study indicate that Ampligen can significantly reduce the bleomycin-induced increased collagen accumulation and may be therapeutically useful in the management of lung fibrosis in humans.

Acid Phosphatase↗
PubMedDate not supplied

Ampligen inhibits human herpesvirus-6 in vitro.

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.

Antigens, Viral↗
PubMed1991

Mismatched double-stranded RNA, Ampligen (poly(I): poly(C12U), demonstrates antiviral and immunostimulatory activities in HIV disease.

Mismatched double-stranded RNA (Ampligen) has broad spectrum antiviral and immunomodulatory activities. These activities generate stabilization or improvement in three important surrogate markers of HIV disease progression. Patients with HIV disease treated with Ampligen do not become positive for p24 antigen, in contrast to patients treated with AZT or placebo. Viral burden can also be decreased in patients receiving Ampligen/AZT therapy. In vitro studies indicate that both AZT sensitive and AZT resistant viruses can be inhibited by Ampligen alone and are synergistically inhibited by Ampligen in combination with AZT. The immunomodulatory effects of Ampligen are manifested as a stabilization of CD4 counts. When Ampligen is combined with AZT, an increase in CD4 count is seen. Furthermore, a return or increase in delayed type hypersensitivity to mumps, Candida, and trichophyton was seen in approximately 70% of patients treated with Ampligen. The activity of Ampligen in HIV disease is due to its multifunctional activity as an antiviral and immune stimulating agent. The antiviral effect directly inhibits HIV-infection and other viruses which have been implicated in HIV disease acceleration and progression. The immunomodulatory activity can stabilize, increase, or restore immune function. This enhanced immune function can also lead to the further inhibition of additional infections associated with disease progression. Thus, Ampligen has multiple mechanisms of action against HIV disease.

Adjuvants, Immunologic↗
PubMed1985

Clinical studies with ampligen (mismatched double-stranded RNA).

Results of an ongoing clinical study of a mismatched double-stranded (ds) RNA, termed Ampligen, in patients with metastatic cancer are described. In a pilot study of Ampligen (lot 1) involving mostly hematologic malignancies, patients received cumulative doses up to approximately 450 mg without untoward effects. Evidence of biologic/antitumor effects was observed (3/5 patients) by monitoring tumor-specific markers or tumor cell morphology. In patients with solid tumors receiving lot 2, Ampligen cumulative doses over 4 g were well tolerated. The drug was given by intravenous infusion (10-80 mg/infusion, twice weekly), in some instances for more than 1 year, without clinically significant side effects. Specifically, no evidence of hematologic, liver, or renal toxicity, which was previously noted with other dsRNAs, was observed. Side effects consisted of occasional mild fatigue or flu-like symptoms. Fever, when encountered, was transient and low grade (less than 100.5 degrees F). Importantly, an analysis of patient sera for dsRNA antibodies revealed that no patient had evidence of specific antibodies directed against Ampligen. Other dsRNAs cause up to a 60% incidence of antibody formation. Additionally, a novel method was developed to monitor Ampligen blood levels. In a survey of seven patients, Ampligen had a mean plasma half-life of 23 min. Ampligen administration can also result in activation of both natural killer (NK) cells and a lymphocyte, interferon-associated, intracellular enzyme. Dose-dependent antitumor effects were seen in several solid tumors; in doses of 10-40 mg, 3/9 patients showed stable disease for up to 1 year. At the 80-mg dose level, 2/5 patients showed tumor regressions (mixed and partial responses).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Formation↗
PubMed1985

Preclinical studies with Ampligen (mismatched double-stranded RNA).

Historically, double-stranded (ds) RNAs have been largely over-looked as potentially valuable anticancer/antiviral drugs, primarily because of the many clinical toxicities and lack of efficacy associated with the first clinically tested dsRNA--polyinosinic-polycytidylic acid (rIn X rCn). However, studies summarized herein demonstrate that the therapeutic ratio of dsRNAs can be greatly enhanced by purposeful mispairing of bases. For example, a mispaired dsRNA, termed Ampligen (rIn X r(C12,U)n), shows strong antitumor activity in a variety of relevant test systems with little or none of the toxicities associated with rIn X rCn. Furthermore, Ampligen demonstrates a much wider therapeutic spectrum than that displayed to date by any single type of interferon (natural or recombinant DNA-derived). Importantly, Ampligen, the product of a straight-forward enzymatic synthesis, shows excellent lot-to-lot biological and biophysical specifications, which is often not the case with biologically derived new compounds. Furthermore, a significant fraction of human solid tumors, which are largely unresponsive to conventional chemotherapy or interferon (IFN), is sensitive to Ampligen in a fresh human tumor clonogenic assay. Indeed, whereas 50% of untreated and IFN-treated athymic mice engrafted with human renal cancer cells die within 20-22 weeks, mice treated with Ampligen survive a minimum of 32 weeks (p less than 0.0003). A summary of all animal models tested and human clinical trials to date demonstrates that Ampligen exerts a greater antitumor activity than IFN and has a superior therapeutic ratio compared to rIn X rCn.

Animals↗
PubMedDate not supplied

Mismatched dsRNA (ampligen) induces protection against genomic variants of the human immunodeficiency virus type 1 (HIV-1) in a multiplicity of target cells.

Mismatched double-stranded RNA of the form r(I)n.r(C12-U)n (Ampligen) has been shown to be active against human immunodeficiency virus type 1 (HIV-1) using CEM and C3 cells as targets for infection by the highly similar HIV-1 isolates HTLV-IIIB and LAV (Montefiori, D.C. and Mitchell, W.M., 1987, Proc. Natl. Acad. Sci. U.S.A., 84, 2985-2989). The scope of Ampligen's anti-HIV-1 activity was examined in this study using the genetically divergent HIV-1 isolate HTLV-IIIRF, two additional target T-cell lines, H9 and MT-2, and a monocyte/macrophage cell line, U937. As judged by indirect immunofluorescence, reverse transcriptase activity and vital dye uptake, Ampligen was active against HTLV-IIIRF in H9, MT-2, C3 and U937 cells in addition to being active against HTLV-IIIB in U937 cells. A minimum of 1 h preincubation of cells (MT-2) with Ampligen was required for maximum activity. These results suggest that Ampligen's potential clinical efficacy may not be limited by either the highly variable nature or host cell range of HIV-1.

Antiviral Agents↗
PubMed1993

The use of ampligen alone and in combination with ganciclovir and coumermycin A1 for the treatment of ducks congenitally-infected with duck hepatitis B virus.

Ampligen, a known immunomodulator and interferon inducer, was used alone and in combination with other antiviral agents to treat ducks congenitally-infected with duck hepatitis B virus. These antiviral agents included the conventional nucleoside analogue ganciclovir and the prokaryotic DNA gyrase B inhibitor coumermycin A1. When used alone, ampligen decreased the amount of serum and liver viral DNA, but had no effect on circulating duck hepatitis B surface antigen (DHBsAg). In combination with ganciclovir, the antiviral effect appeared at least additive with a greater inhibition of viral DNA replication within the liver. The combination of ampligen with coumermycin A1 also resulted in inhibition of viral replication but to a lesser extent than ampligen alone. When all three agents were used together, viral DNA replication was again inhibited, but as with previous treatment regimes, serum DHBsAg levels remained unchanged. At the end of the treatment period for all regimes, analysis of viral DNA forms in the liver showed that the viral relaxed circular and supercoiled DNA forms had persisted. Within 1 week of cessation of therapy, viral replication had often returned to pre-treatment levels. Interferon-like activity was detected in the sera of the majority of the treated ducks during the ampligen therapy, but no clear relationship between the presence of interferon and antiviral effect could be established. These observations in the duck hepatitis B model may provide a rational basis for the use of combinations of antiviral and immunomodulatory regimes for the management of chronic hepatitis B infection in man.

Aminocoumarins↗
PubMed1985

Comparative studies of ampligen (mismatched double-stranded RNA) and interferons.

Historically, it has been assumed that double-stranded (ds) RNAs function at a cellular level exclusively via an interferon (IFN) induction mechanism. However, current studies conducted both in the laboratory and at the clinical level reveal that this assumption is incorrect and, indeed, underestimates the intrinsic antitumor activity of certain dsRNAs. A specific dsRNA (Ampligen) shows strong antiproliferative activity against human carcinoid tumor cells in a clonogenic assay when natural alpha- and beta-IFNs were inactive. Similarly, in vivo studies in which human renal cancer cells were transplanted into athymic mice demonstrate a strong antitumor effect of Ampligen whereas such tumors are largely unaffected by alpha-IFN treatment. In a comparative study including many fresh human tumors of various histological types (breast, ovarian, melanoma, renal, and carcinoid) numerous examples were uncovered of Ampligen sensitivity (antiproliferative effect) in the face of relative or complete insensitivity to IFNs. Synergistic effects of Ampligen plus IFN overcame the resistance of some human tumor cells to either biological modifier given alone. It can also be demonstrated that the antitumor action of Ampligen on certain human lung tumor cells is not shared by polyinosinic . polycytidylic acid, thus indicating that different dsRNAs may themselves exhibit dissimilar effects on various human tumors.

Animals↗
PubMed1992

The effect of combinations of ampligen and zidovudine or dideoxyinosine against human immunodeficiency viruses in vitro.

The combinations of ampligen and zidovudine at ratios of 100:1, 25:1, 10:1, and 1:50 acted synergistically to reduce cytopathology caused by HIV in MT-2 cell cultures. Combination indices were less than 1 at all of these ratios representing different combinations of concentrations and at 3 effective doses (ED30, ED50, ED70). Combination of drugs which show synergism at a wide range of ratios of combinations suggest that they may be useful clinically, and that the antiviral efficacy of ZDV may be increased in combination with ampligen. Synergism was also found between ampligen and zidovudine by reduction of HIV-produced plaques in a HeLa cell line expressing CD-4 receptors. However the combination of ampligen and dideoxyinosine against HIV in MT-2 cells was only additive and not synergistic.

Antiviral Agents↗
PubMed1987

Clinical, immunological, and virological effects of ampligen, a mismatched double-stranded RNA, in patients with AIDS or AIDS-related complex.

10 patients with the acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), or lymphadenopathy syndrome (LAS) were given 200-250 mg ampligen, a mismatched double-stranded (ds) RNA with in-vitro antiviral activity against human immunodeficiency virus (HIV), twice a week for up to 18 weeks, without side-effects or toxicity. In all 9 patients who were positive for HIV RNA in peripheral blood mononuclear cells before therapy, levels became undetectable between days 10 and 40 of the start of therapy. 6 of the 7 patients with ARC or LAS also showed a progressive reduction in HIV load as measured by co-culture assays. All 10 patients had augmentation of delayed-type hypersensitivity skin reactions. Other changes noted during ampligen therapy included an increase in or maintenance of numbers of helper-inducer T lymphocytes, improvements in HIV-related symptoms, rises in titre of neutralising antibodies against HIV, and restoration of proper functioning of the natural lymphocyte antiviral dsRNA-dependent (2'-5'-oligoadenylate/RNA-ase L) pathway. Thus, in the short term, ampligen seems to have the dual ability to restore immunological function and to control HIV replication.

AIDS-Related Complex↗
PubMed1987

Mismatched double-stranded RNA (ampligen) reduces concentration of zidovudine (azidothymidine) required for in-vitro inhibition of human immunodeficiency virus.

'Ampligen', a non-toxic, mismatched polymer of double-stranded RNA with antiviral and immunomodulatory activities reduced the concentration of zidovudine (azidothymidine, AZT; 'Retrovir', Wellcome) required for inhibitory activity against human immunodeficiency virus (HIV) in vitro. At the higher doses of AZT tested, the virustatic activity observed seemed to have a synergistic virustatic relation with ampligen. Thus, combined therapy with ampligen and AZT can be expected to be more beneficial than AZT alone to patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex since AZT regimens that seem to be clinically effective are associated with considerable toxicity.

Antiviral Agents↗
PubMed1992

A phase I study of ampligen in human immunodeficiency virus-infected subjects.

Ampligen, poly(I)n:poly(C12U)n, was administered intravenously to 39 human immunodeficiency virus (HIV)-infected subjects, asymptomatic or with early AIDS-related complex (ARC) and with CD4+ cell counts less than 500/mm3 in a phase I dose-escalation study. Six doses ranging from 10 to 570 mg/m2 were administered twice-weekly for 9-25 weeks to groups of 5-7 subjects. There was no significant effect on HIV as measured by serum p24 levels, the proportion of patients from whom HIV could be cocultured from blood, or the concentration of peripheral mononuclear cells positive for the virus. Although patients on 10 and 40 mg/m2 showed a significant decline in CD4+ cell counts, as would be expected in untreated patients, patients who received doses greater than or equal to 120 mg/m2 showed no significant decline in CD4+ cell counts. In addition, there was a significant increase in CD4+ cell counts with respect to dose of ampligen. This effect of ampligen and the fact that it has been shown to act synergistically with zidovudine against HIV in vitro suggest that the combination might be tried clinically in patients.

AIDS-Related Complex↗
PubMedDate not supplied

[Inhibition of alfa interferon and ampligen of human immunodeficiency virus (HIV) replication in monocyte-macrophage subpopulations].

Levels of replication of HIV in two different populations of monocyte/macrophages (M/M) at different stages of maturation were evaluated, as well as the antiviral activity of alpha-interferon (alpha-IFN) and Ampligen (an inductor of endogenous production of alpha-IFN). HIV replication was found to be 5-10 times greater in mature than in young M/M. Furthermore, alpha-IFN and Ampligen showed a substantial anti-HIV activity in young M/M, while little effect was achieved in mature M/M. Finally, HIV replication in chronically-infected M/M was not affected by alpha-IFN. These results suggest that alpha-IFN might be useful in combination with other anti-HIV drugs in the therapy of HIV-related disease.

AIDS-Related Complex↗
PubMed1993

Treatment of lethal Pichinde virus infections in weanling LVG/Lak hamsters with ribavirin, ribamidine, selenazofurin, and ampligen.

A lethal Pichinde (An 4763 strain) virus infection was produced in 3-week-old random-bred Golden Syrian (LVG/Lak strain) hamsters inoculated intraperitoneally with virus, causing mortality in 6-9 days. High virus titers (> or = 10(7.5) cell culture infectious doses/g) were present in visceral organs, serum, brain and salivary glands near the time of death. Intraperitoneal treatments with ribavirin (10 and 32 mg/kg) and ribamidine (32, 100, and 320 mg/kg) for 10 days starting 24 h after virus challenge significantly decreased mortality and reduced virus titers by 100- to > 10,000-fold in liver, spleen, brain, and serum. Serum alanine aminotransferase (an indicator of liver damage) was also reduced in animals treated with the two compounds (ribavirin at 32 mg/kg; ribamidine at 100 and 320 mg/kg). Intraperitoneal selenazofurin (1-100 mg/kg per day for 10 days) and ampligen (0.5 and 5 mg/kg every other day for 5 injections) treatments provided neither protection from the lethal infection nor increased mean survival times. In fact, selenazofurin was overtly toxic, causing death of uninfected hamsters at 32 and 100 mg/kg. The random-bred LVG/Lak hamster appears to be a viable and cost-effective model for evaluating new therapies for arenavirus infections.

Animals↗
PubMed1989

In vitro evaluation of mismatched double-stranded RNA (ampligen) for combination therapy in the treatment of acquired immunodeficiency syndrome.

Multiple drug effect analyses with mismatched double-stranded RNA (mismatched dsRNA or Ampligen) as a core drug were performed to identify other agents and mechanisms through which mismatched dsRNA may potentiate effective therapeutic intervention in human immunodeficiency virus (HIV) infection. Antiviral activities were defined by a microtiter infection assay utilizing MT-2 cells as targets and HTLV-III-B produced in H9 cells as a virus source. The scope of agents tested included rIFN-alpha A, rIFN-beta Ser 17, and rIFN-gamma as cytokines; azidothymidine and phosphonoformate (Foscarnet) as inhibitors of reverse transcription; ribavirin as a putative inhibitor of proper HIV mRNA capping; amphotericin B as a lipophile; and castanospermine as a glycoprotein processing (glucosidase I) inhibitor. Separately, each drug demonstrated dose-dependent anti-HIV activity and, when used in combination with mismatched dsRNA, demonstrated synergism. Although mismatched dsRNA was synergistic with all three IFNs for anti-HIV activity in microtiter infection assays, it did not potentiate the transient inhibition of virus production observed for IFN in cultures of H9/HTLV-III-B cells. The results of these studies suggest that the pleiotropic activities of dsRNAs differ from those of IFN and may provide synergism in combination therapy with a wide range of antiviral drugs for the treatment of the acquired immunodeficiency syndrome (AIDS).

Acquired Immunodeficiency Syndrome↗
PubMed1993

Mode of action of the anti-AIDS compound poly(I).poly(C12U) (Ampligen): activator of 2',5'-oligoadenylate synthetase and double-stranded RNA-dependent kinase.

The mismatched double-stranded RNA (dsRNA), poly(I).poly(C12U), also termed Ampligen, exhibits a strong antiviral and cytoprotective effect on cells (human T-lymphoblastoid CEM cells and human T-cell line H9) infected with the human immunodeficiency virus type 1 (HIV-1). Untreated H9 cells infected with HIV-1 start to release the virus 3 days post-infection, while in the presence of 40 micrograms/ml (80 micrograms/ml) of poly(I).poly(C12U) the onset of virus production and release is retarded and does not occur before day 5 (day 6). We demonstrate that poly(I).poly(C12U) markedly extends the duration of the transient increase of 2',5'-oligoadenylate (2-5A) synthetase mRNA level and activity preceding virus production after infection of cells with HIV-1. Treatment of HeLa cells with poly(I).poly(C12U) was found to cause a significant increase in total (activated plus latent) 2-5A synthetase activity; no evidence was obtained that the level of latent (nonactivated) 2-5A synthetase is changed in cells treated with dsRNA plus interferon (IFN). Poly(I).poly(C12U) is able to bind and to activate 2-5A synthetase(s) from HeLa cell extracts. Addition of poly(I).poly(C12U) to HeLa cell extracts results in production of longer 2-5A oligomers (> or = 3 adenylate residues), which are better activators of RNase L. Both free and immobilized poly(I).poly(C12U) also bind to the dsRNA-dependent protein kinase (p68 kinase), resulting in autophosphorylation of the enzyme. Activation of the kinase by the free RNA occurs within a limited concentration range (10(-7) to 10(-6) grams/ml). Addition of HIV-1 Tat protein does not affect binding and activation of p68 kinase to poly(I).poly(C12U)-cellulose but strongly reduces the binding of the kinase to immobilized TAR RNA of HIV-1. We conclude that poly(I).poly(C12U) may antagonize Tat-mediated down-regulation of dsRNA-dependent enzymes.

2',5'-Oligoadenylate Synthetase↗