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Poly(I)-Poly(C12U)
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Brand Name: Ampligen  Audio
Drug Class: Opportunistic Infection and Other Drugs

Drug Description
Poly(I)-poly (C12U), a specifically mismatched double stranded RNA (dsRNA) nucleic compound, is a biological response modifier with anti-HIV activity.[1]

HIV/AIDS-Related Uses
Poly(I)-poly(C12U) is in Phase IIb studies for the treatment of HIV as monotherapy or as an addition to failing regimens of highly active antiretroviral therapy (HAART).[2][3] Poly(I)-poly(C12U) is also being evaluated for its role in lengthening the duration of structured treatment interruptions (STIs) of HAART therapy.[4]

Non HIV/AIDS-Related Uses
Poly(I)-poly(C12U) has widespread antiviral activity, including activity against West Nile virus and other flaviviruses.[5] Poly(I)-poly(C12U) is also being studied for the treatment of hepatitis B and C infection, renal cell carcinoma, and malignant melanoma. Phase III studies evaluating the drug for treatment of chronic fatigue syndrome have recently been completed as well.[6]

Dosing Information

Mode of Delivery
Intravenous.[7]

Dosage Form
In clinical trials, poly(I)-poly(C12U) 400 mg is administered intravenously twice weekly.[8][9]

Pharmacology
Poly(I)-poly(C12U) provides broad activity by activating otherwise dormant cellular defenses against viruses and tumors. Specifically, poly(I)-poly(C12U) activates intracellular antiviral mediators 2-5A synthetase/RNase.[10][11] The drug's cell-mediated immunomodulatory properties produce a delayed hypersensitivity response, which may delay viral rebound during structured treatment interruptions (STIs) of HAART.[12]

STI is based on the premise that immune function may recover in stable HIV infected patients by temporarily withdrawing HAART, allowing viral rebound to stimulate the immune response. However, efforts to date have produced conflicting results. When given during the interruption period, poly(I)-poly(C12U) appears to stabilize patients and allows a longer duration of interrupted therapy.[13]

In a Phase IIb study of poly(I)-poly(C12U) for treatment of HIV during STI, 22 patients with viral loads less than 50 copies/ml and CD4 counts of at least 400 cells/mm3 were randomized to receive poly(I)-poly(C12U) 400 mg IV twice weekly or no treatment during STIs over 64 weeks. STIs continued until the viral load rebounded to at least 5,000 copies/ml for 3 consecutive weeks or 50,000 copies/ml at least once. After 9 months, therapy with poly(I)-poly(C12U) significantly prolonged the duration of STI from a mean 13 weeks without treatment to a mean 27 weeks with the drug. Additionally, the number of CD8 cells significantly increased in patients receiving poly(I)-poly(C12U), destroying additional cells infected with the virus.[14]

During in vitro testing, poly(I)-poly(C12U) was equally active against wild-type HIV and HIV resistant to the following: nevirapine, protease inhibitors, or nucleoside analogue reverse transcriptase inhibitors.[15]

Ampligen 400 mg currently is being studied in AMP 720, an open-label randomized trial, for its use prolonging the structured treatment interruption of existing highly active antiretroviral therapy in HIV infected adults with plasma HIV RNA levels less than 50 copies/ml and CD4 counts of at least 400 cells/mm3.[16][17]

Adverse Events/Toxicity
Poly(I)-poly(C12U) appears generally well tolerated as monotherapy or as concomitant anti-HIV therapy in clinical studies. In a 9-month trial of poly(I)-poly(C12U) in HIV infected patients, adverse effects were primarily mild and self-limiting. To date, lactic acidosis, insulin resistance, and hyperlipidemia have not been noted in relation to poly(I)-poly(C12U) therapy.[18][19]

In clinical trials of poly(l)-poly(C12U) for various treatments, a low level of clinical toxicity has been observed. An infusion rate-related mild flushing reaction, at time accompanied by tachycardia, shortness of breath, or anxiety, has occurred in approximately 15% of patients. Other adverse effects noted in trials include diarrhea, itching, rash, hypotension, anemia, elevation of kidney function tests, dizziness, and confusion. Mild flu-like symptoms, such as chills, fever, nausea, vomiting, headache, and fatigue, have also been reported but appear to resolve within several months of treatment initiation.[20]

Drug And Food Interactions
Poly(I)-poly(C12U) is synergistic with zidovudine in decreasing CD4 counts in patients receiving combination therapy for more than a year. Poly(I)-poly(C12U) also appears to resensitize zidovudine-resistant HIV when given concomitantly.[21] In addition, in vitro studies have demonstrated poly(I)-poly(C12U) synergy with the following antiretroviral medications: abacavir, amprenavir, didanosine, efavirenz, indinavir, ritonavir, nelfinavir, stavudine, zalcitabine, and zidovudine.[22]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Poly%20OR%20I-Poly%20OR%20C12U.

Chemistry

CAS Name
5'-Inosinic acid, homopolymer, complex with 5'-cytidylic acid polymer with 5'-uridylic acid (1:1)[23]

CAS Number
38640-92-5[24]

Molecular Formula
(C10-H13-N4-O8-P)x-.(C9-H14-N3-O8-P.C9-H13-N2-O9-P)x-[25]

Further Reading
PMID/15357629 Mismatched double-stranded RNA: polyI:polyC12U. Drugs R D. 2004;5(5):297-304. PMID: 15357629

Safety and Efficacy of Ampligen in the Treatment of HIV Patients Failing HAART. Available at: http://www.clinicaltrials.gov/ct/show/NCT00035581. Accessed 01/08/09.

The Role of Ampligen in Strategic Therapeutic Intervention (STI) of HAART. Available at: http://www.clinicaltrials.gov/ct/show/NCT00035893. Accessed 01/08/09.

Manufacturer Information
Poly(I)-Poly(C12U)
  Hemispherx Biopharma, Inc
  One Penn Ctr
  1617 JFK Blvd, 6th Floor
  Philadelphia,  PA  19103
  (215) 988-0080
    

Ampligen
  Hemispherx Biopharma, Inc
  One Penn Ctr
  1617 JFK Blvd, 6th Floor
  Philadelphia,  PA  19103
  (215) 988-0080
    

References
[1] Intl AIDS Conf - 14th, 2002. Abstract LbPeB9011.
[2] Hemispherx Biopharma, Inc. - Research and Development: Product Candidates Under Development. Available at: http://www.hemispherx.net/content/rnd/product_candidates.htm. Accessed 01/08/09.
[3] Hemispherx Biopharma, Inc. - Research and Development: Drug Candidates-Ampligen. Available at: http://www.hemispherx.net/content/rnd/drug_candidates.htm. Accessed 01/08/09.
[4] Hemispherx Biopharma, Inc. - Clinical Development: Product Candidates Under Development. Available at: http://www.hemispherx.net/content/rnd/product_candidates.htm. Accessed 01/08/09.
[5] Drugs R D - 2004;5(5):297-304
[6] Hemispherx Biopharma, Inc. - Research and Development: Drug Candidates-Ampligen. Available at: http://www.hemispherx.net/content/rnd/drug_candidates.htm. Accessed 01/08/09.
[7] Hemispherx Biopharma, Inc. - Research and Development: Drug Candidates-Ampligen. Available at: http://www.hemispherx.net/content/rnd/drug_candidates.htm. Accessed 01/08/09.
[8] Intl AIDS Conf - 14th, 2002; Abstract LbPeB9011.
[9] IAS Conf on HIV Pathogenesis and Treatment - 2nd, 2003; Abstract 596.
[10] Hemispherx Biopharma, Inc. - Research and Development: Drug Candidates-Ampligen. Available at: http://www.hemispherx.net/content/rnd/drug_candidates.htm. Accessed 01/08/09.
[11] Intl AIDS Conf - 14th, 2002. Abstract LbPeB9011.
[12] IAS Conf on HIV Pathogenesis and Treatment - 2nd, 2003. Abstract 596.
[13] AEGIS - AIDSWeekly - Treatment Interruption: Ampligen use in HIV treatment show promise [press release], May 19, 2003. Available at: http://www.aegis.com/pubs/aidswkly/2003/AW030508.html. Accessed 01/08/09.
[14] IAS Conf on HIV Pathogenesis and Treatment - 2nd, 2003. Abstract 596.
[15] Antiviral Res - 2001 Sep;51(3):189-202
[16] Hemispherx Biopharma, Inc. - Research and Development: Clinical Trials Info. Available at: http://www.hemispherx.net/content/rnd/clinical_trials_hiv_720.htm. Accessed 01/08/09.
[17] ClinicalTrials.gov - The Role of Ampligen in Strategic Therapeutic Intervention (STI) of HAART. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00035893. Accessed 01/08/09.
[18] IAS Conf on HIV Pathogenesis and Treatment - 2nd, 2003; Abstract 596.
[19] Eur J Clin Microbiol Infect Dis - 1996 Jul;15(7):580-7
[20] Hemispherx Biopharma, Inc. - Research and Development: Drug Candidates-Ampligen. Available at: http://www.hemispherx.net/content/rnd/drug_candidates.htm. Accessed 01/08/09.
[21] In Vivo - 1994 May-Jun;8(3):375-81
[22] Antiviral Res - Sep;51(3):189-202
[23] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 02/14/08.
[24] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/08/09.
[25] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/08/09.
Updated January 8, 2009