UC-781 is a type of medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is being studied as a microbicide. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. NNRTIs block reverse transcriptase, a protein that HIV needs to make more copies of itself. Microbicides work by either destroying the microbes or preventing them from establishing an infection.
HIV/AIDS-Related Uses
UC-781 is an investigational medicine that is not yet approved by the FDA for use outside of clinical trials. It is being studied for the prevention of sexual transmission of HIV infection. This medicine does not cure HIV infection or AIDS and is being studied to reduce the risk of passing the virus to other people.
Dosage Form/Administration
UC-781 comes in a topical gel form and is applied vaginally.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine.
Possible Side Effects
Along with its desired effects, UC-781 may cause some unwanted effects. UC-781 has not yet been fully studied in clinical trials, so these effects are not yet known. In laboratory studies, UC-781 was not harmful to human tissue samples.
Drug and Food Interactions
A doctor should be notified of any other medications being taken, including prescription, non-prescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use UC-781.
Manufacturer Information
UC-781
Cellegy Pharmaceuticals, Inc
3490 Oyster Point Boulevard
Suite 200
South San Francisco, CA 94080
Phone: 650-616-2200
Last Updated: February 12, 2008
Drug Description
UC-781 is a thiocarboxanilide non-nucleoside reverse transcriptase inhibitor (NNRTI). [1]
References
[1] J Virol 2005;79(17):11179-86
HIV/AIDS-Related Uses
UC-781 is an NNRTI currently being developed as a vaginal microbicide to prevent HIV transmission. UC-781 has been studied in animal models and has entered a Phase I clinical trial in humans. UC-781 is now in Phase II trials in the United States and in Thailand. [1] [2]
References
[1] CONRAD New Licensing Agreement to Maximize AIDS Drug Development [press release], February 1, 2006. Available at: http://www.conrad.org/press/02012006.htm. Accessed 2/12/08.
[2] ClinicalTrials.gov Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
Dosing Information
Mode of Delivery
Intravaginal. [1] Rectal. [2]
Dosage Form
Topical gel in 0.1%, 0.25%, or 1.0% concentrations. [3] [4] UC-781 has been studied in once-daily dosages for up to 7 days and in twice-daily dosages for up to 14 days. [5] [6]
References
[1] ClinicalTrials.gov Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[2] ClinicalTrials.gov Safety and Acceptability Study of the UC-781 Microbicide Gel Applied Rectally. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00408538. Accessed 2/12/08.
[3] Microbicides Conference 2nd, 2006. Abstract PA58.
[4] ClinicalTrials.gov Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[5] ClinicalTrials.gov Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[6] ClinicalTrials.gov Safety and Acceptability Study of the UC-781 Microbicide Gel Applied Rectally. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00408538. Accessed 2/12/08.
Pharmacology
In vitro studies have shown UC-781 to be a rapid, tight-binding inhibitor of HIV-1 reverse transcriptase. [1] It is effective against transmission of both free-floating HIV particles and cell-associated HIV. UC-781 has an intracellular antiviral protective effect and a half-life of 5.5 days. [2] [3]
In vitro exposure of human cervical tissue to UC-781 for 30 minutes has resulted in 95% reduction of subsequent HIV infection. Furthermore, greater concentrations of UC-781 pretreatment have resulted in total protection of the cervical tissue from both X4- and R5-tropic HIV-1 isolates as well as from cell-associated HIV-1 infection. Twenty-minute incubation with UC-781 has completely protected the cervical tissue up to 48 hours post-treatment without associated tissue toxicity. [4]
UC-781 administered to cellular and tissue explant models as a 0.1% carbopol gel formulation has demonstrated a potent, dose-dependent effect against R5- and X4-tropic HIV infections in T cells. In human cervical explant cultures, UC-781 was able to not only inhibit direct infection of mucosal tissue but also to prevent dissemination of virus by migratory cells. UC-781 retained significant activity against direct tissue infection and migratory cell infection. UC-781 demonstrated prolonged inhibitory effects able to prevent both localized and disseminated infections up to 6 days post-treatment. In addition, a 2-hour exposure to UC-781 prevented infection of lymphoid tissue when challenged up to 2 days later. Although a greater dose of UC-781 was required to inhibit infections of lymphoid versus cervical explant, that dose, equivalent to a 1:3.000 dilution, was less than the full dose provided in a 0.1% formulation. [5]
The prolonged protective effect of UC-781, characterized as a memory effect that continues to protect drug-treated cells from HIV-1 replication, has been demonstrated for up to 12 days. [6]
UC-781 has been studied with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine in vitro. A 1:1 molar combination of zidovudine plus UC-781 showed high-level synergy in inhibiting replication of a zidovudine-resistant clinical isolate of HIV. When a 1:1 molar combination of zidovudine and UC-781 was compared to use of either drug alone, HIV resistance development was significantly slower. [7]
The microbicidal activity of UC-781 has been studied in vitro against strains of HIV-1 resistant to UC-781 (UCR), efavirenz (EFVR), and nevirapine (NVPR). UC-781 was 10- to 100-fold less effective against resistant strains than wild-type virus. The drug was more effective against NVPR strains than UCR strains, and was less effective against EFVR strains than UCR strains. Efficacy of UC-781 was dose-dependent; 25 mcM UC-781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wild-type virus. UC-781 formulations under current development contain concentrations approximately 100-fold greater than the 25 mcM concentration necessary for efficacy. [8]
References
[1] Antimicrob Agents Chemother 2005 May;49(5):1830-6
[2] J Virol 1997 Apr;71(4):3023-30
[3] AIDS 2003 Mar 28;17(5):653-61
[4] Conf Retroviruses Opportunistic Infect 9th, 2002. Abstract 780-W.
[5] J Virol 2005 Sep;79(17):11179-86
[6] Microbicides Conference 1st, 2004. Abstract 02460.
[7] Antimicrob Agents Chemother 1999 Feb;43(2):259-63
[8] J Virol 2006 May;80:4440-6
Drug and Food Interactions
UC-781 exhibits synergy with the NRTI zidovudine in vitro. [1] The combination of UC-781 and another candidate microbicide, cellulose acetate 1,2-benzenedicarboxylate, resulted in effective synergy for inhibition of HIV-1 in vitro and in peripheral blood mononuclear cells. Concomitant administration provided complementary mechanisms of action and protected ex vivo lymphoid tissues from HIV infection. [2]
References
[1] Antimicrob Agents Chemother 1999 Feb;43(2):259-63
[2] Antimicrob Agents Chemother 2005;49(5):1830-6
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use UC-781.
Chemistry
CAS Name
3-Furancarbothioamide, N-(4-chloro-3-((3-methyl-2-butenyl)oxy)phenyl)-2-methyl- [1]
CAS Number
178870-32-1 [2]
Molecular Formula
C17-H18-Cl-N-O2-S
Elemental Composition
C60.8%, H5.4%, Cl10.6%, N4.2%, O9.5%, S9.5%
Molecular Weight
335.5
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 2/12/08.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/08/06.
Further Reading
Liu S, Lu H, Neurath AR, Jiang S. Combination of candidate microbicides cellulose acetate 1,2-benzenedicarboxylate and UC-781 has synergistic and complementary effects against human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother. 2005 May;49(5):1830-6.
Patton DL, Sweeney YT, Balkus JE, Rohan LC, Moncla BJ, Parniak MA, Hillier SL. Preclinical safety assessments of UC-781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother. 2007 May;51(5):1608-15.
Roth S, Monsour M, Dowland A, Guenthner PC, Hancock K, Ou CY, Dezzutti CS. Effect of topical microbicides on infectious human immunodeficiency virus type 1 binding to epithelial cells. Antimicrob Agents Chemother. 2007 Jun;51(6):1972-8.
Sassi AB, Isaacs CE, Moncla BJ, Gupta P, Hillier SL, Rohan LC. Effects of physiological fluids on physical-chemical characteristics and activity of topical vaginal microbicide products. J Pharm Sci. 2007 Oct 5 [Epub ahead of print].
Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, Lewi P, Vanham G, Janssen P. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother. 2004 Jan;48(1):337-9.
ClinicalTrals.gov- Phase I Study of Safety and Persistence of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00441909?term=NCT00441909&rank=1. Accessed 02/12/08.
Manufacturer Information
UC-781
Cellegy Pharmaceuticals, Inc
3490 Oyster Point Boulevard
Suite 200
South San Francisco, CA 94080
Phone: 650-616-2200
Last Updated: February 12, 2008