Cellulose sulfate, or CS, is being studied as an experimental HIV microbicide called Ushercell. Microbicides are substances that protect the body from infection by microorganisms such as bacteria, viruses, and fungi. Microbicides work by either destroying the microbes or preventing them from establishing an infection.
HIV/AIDS-Related Uses
Cellulose sulfate is an investigational medicine that is not yet approved by the FDA for use outside of clinical trials. It was being studied for the prevention of HIV infection and other sexually transmitted diseases. This medicine does not cure HIV infection or AIDS and was being studied to reduce the risk of passing the virus to other individuals.Two Phase III studies in HIV uninfected women were stopped in January 2007, because preliminary results at some trial sites indicated that use of cellulose sulfate could lead to an increased risk of HIV infection in women who use this microbicide. In a detailed review of the final trial data, cellulose sulfate displayed no preventive effect on HIV transmission and increased the risk of HIV infection. It will no longer be studied for use as a microbicide to prevent HIV transmission.
Dosage Form/Administration
Cellulose sulfate comes in a topical gel form in prefilled 3.5 mL applicators and is applied vaginally. In clinical trials, cellulose sulfate 6% gel has been applied once or twice daily.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine.
Possible Side Effects
Along with its desired effects, cellulose sulfate may cause some unwanted effects. While not all of these effects are known, vaginal leaking of gel and slight stinging have been reported.
Drug and Food Interactions
A doctor should be notified of any other medications being taken, including prescription, nonprescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Cellulose sulfate.
Manufacturer Information
Cellulose sulfate
Polydex Pharmaceuticals Ltd
Sandringham House
83 Shirley Street
Nassau,
Bahamas
Ushercell
Polydex Pharmaceuticals Ltd
Sandringham House
83 Shirley Street
Nassau,
Bahamas
Last Updated: July 31, 2009
Drug Description
Cellulose sulfate, also known as CS, is a high molecular weight carboxymethylcellulose-based polymer. [1] It is a noncytotoxic, antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. [2]
References
[1] Contraception 2004 Nov;70(5):415-22
[2] Contraception 2006 Aug;74(2):1330-40
HIV/AIDS-Related Uses
Extensive Phase III clinical trials were conducted to further explore the preclinical laboratory results indicating cellulose sulfate's HIV prevention potential, but in January 2007, those trials were halted when an interim review of the data revealed that cellulose sulfate was likely no more effective at preventing HIV than the placebo (inactive gel) being used in the trials. [1] One trial in HIV uninfected women being conducted in South Africa, Benin, Uganda, and India was halted because preliminary results at some trial sites indicated using the microbicide could lead to potential increased risk of HIV infection in these women. Simultaneously, a Nigerian study of cellulose sulfate was halted. Although the second study did not detect an increased risk of HIV infection associated with the microbicide, the trial was halted as a precautionary measure in light of the preliminary results from the first study. [2] At interim analysis of the first trial, 24 women using cellulose sulfate and 11 women using placebo developed HIV. Possible causes for the increased infection rate include inflammatory reactions, local immune dysfunction, or vaginal flora disruption. [3] [4] After the final study visit, conducted in May 2007, analysis showed no statistically significant difference in onset of HIV infection (25 women using cellulose sulfate and 16 using placebo) and no potential to prevent HIV transmission. [5] The final study report concludes that cellulose sulfate has no role as an HIV prevention method. [6]
References
[1] Polydex Pharm Polydex Research and Development: Ushercell Worlds Ahead. Available at: http://www.polydex.com/v2/research/ushercell_indepth.html. Accessed 07/26/09.
[2] Polydex Pharm Polydex News: Polydex Pharmaceuticals Reports Phase III Trial of Ushercell for HIV Prevention Halted, 01/31/07. Available at: http://www.polydex.com/v2/news/07-01-31.html. Accessed 07/26/09.
[3] IAS Conf on HIV Pathogenesis and Treatment 4th, 2007. Abstract WESS301.
[4] Aidsmap.com IAS News: Cellulose sulphate microbicide fails to prevent vaginal HIV transmission and may even increase risk. Available at: http://www.aidsmap.com/en/news/975D8513-921B-4D32-B4BC-9D772F2CB275.asp. Accessed 07/26/09.
[5] HIV and Hepatitis.com Conference Coverage: IAS 2007. Ushercell Microbicide Provides No Protection against HIV Transmission, but VivaGel Yields Promising Early Data. Available at: http://www.hivandhepatitis.com/2007icr/ias/docs/081007_a.html. Accessed 07/26/09.
[6] Polydex Pharm Polydex News: Polydex Announces Final Report From Phase III Study of Ushercell, 08/01/08. Available at: http://www.polydex.com/v2/news/1-08-08.html. Accessed 07/26/09.
Dosing Information
Mode of Delivery
Intravaginal. [1]
Dosage Form
Cellulose sulfate 6% vaginal gel in a 3.5 mL prefilled applicator for insertion prior to sexual intercourse. [2] [3]
Cellulose sulfate 200-mg vaginal tablets containing excipients generally regarded as safe (GRAS). Tablets disintegrate in less than 30 seconds in 10 mL of fluid to form a smooth, homogenous, viscous, and bioadhesive dispersion. [4]
Cellulose sulfate 6% vaginal gel has been tested in women up to four times daily for up to 14 consecutive days. [5] [6] [7]
Cellulose sulfate 0.1% vaginal gel has been tested for contraceptive use. [8]
Because the optimal applied volume of gel is not known, volumes ranging from 2.5 to 5 mL have been tested. [9]
References
[1] AIDS 2006 May 12;20(8):1109-16
[2] Microbicides Conf 1st, 2004. Abstract 02629_2.
[3] Microbicides Conf 1st, 2004. Abstract 02585.
[4] Microbicides Conf 1st, 2004. Abstract 02629_2.
[5] Microbicides Conf 1st, 2004. Abstract 02249.
[6] Microbicides Conf 1st, 2004. Abstract 02343_2.
[7] Microbicides Conf 1st, 2004. Abstract 02597.
[8] Contraception 2004 Nov;70(5):415-22
[9] Microbicides Conf 1st, 2004. Abstract 0220_1.
Pharmacology
In vitro, cellulose sulfate blocks cell surface receptors, inhibits HIV binding and penetration of epithelial layers and dendritic cells, blocks the gp120-CD4 coreceptor interaction, and acts against coreceptors CCR5 and CXCR4 in primary isolates and laboratory strains. [1] Cellulose sulfate gel 6% has been shown to stimulate acrosomal loss, inhibit hyaluronidase, and impede sperm penetration into cervical mucus in vitro. [2] Cellulose sulfate inhibits HIV entry and sperm-egg interaction in vitro, reaching 95% or greater inhibition of sperm binding capacity at a concentration of 1 mg/mL. Cellulose sulfate does not affect sperm motility and is not cytotoxic. [3] [4] Cellulose sulfate inhibits HIV-1 strains with a 50% inhibitory concentration (IC50) of 50 ug/mL. It is especially effective against HSV-1 and -2 at an IC50 of 0.12 to 0.25 ug/ml. [5]
Linear gel spread, as evaluated in a study of 2.5 mL and 3.5 mL gel volumes inserted vaginally, takes place primarily in the first 5 minutes after gel insertion. Lateral spreading (surface contact) appears to continue after linear spreading slows or stops. Upright patient movement has a greater effect on gel distribution than gel volume does. Using a larger gel volume increases linear spreading but provides less consistent lateral spreading. The greatest linear and lateral spreading have been noted 50 minutes after insertion in women using 3.5 mL of gel who have walked around after insertion. Even under these conditions, women had bare spots in coverage, particularly in the proximal vagina. Thus, the spreading of cellulose sulfate without intercourse did not result in complete vaginal coverage, even at 50 minutes after product insertion. [6]
Vaginal cellulose sulfate tablet inhibition of sperm enzyme and of HIV, HSV, and Chlamydia appears comparable to that of the gel formulation. Cellulose sulfate tablets do not inhibit Lactobacillus in vitro. [7]
In rabbit models, cellulose sulfate 6% gel was active as a contraceptive for at least 18 hours after application and was partially active for at least 24 hours. A gel concentration as low as 0.1% was an effective contraceptive when applied within 30 minutes of insemination. [8]
References
[1] Antimicrob Agents Chemother 2005;49:3607-15
[2] Microbicides Conf 1st, 2004. Abstract 02496.
[3] Microbicides Conf 1st, 2004. Abstract 02585.
[4] Intl AIDS Conf 1st, 2001. Abstract 253.
[5] Intl AIDS Conf 1st, 2001. Abstract 253.
[6] Microbicides Conf 1st, 2004. Abstract 02420_1.
[7] Microbicides Conf 1st, 2004. Abstract 02629_2.
[8] Contraception 2004 Nov;70(5):415-22
Adverse Events/Toxicity
The most common adverse events reported in one of the halted phase III clinical trials studying cellulose sulfate gel as an HIV prevention method were infections and infestations, including bacterial vaginitis, candidiasis, respiratory tract infection, malaria, and genital infections. Common noninfectious reproductive-system adverse events included pruritus, metrorrhagia, and vaginal discharge. [1]
Previous results from 11 cellulose sulfate studies sponsored by CONRAD have indicated the microbicide is safe, acceptable, and effective as currently marketed spermicides and sexual lubricants. These 11 studies include 5 safety studies in women,2 safety studies in men, 2 contraceptive effectiveness studies, and studies testing the safety of the microbicide when used with a diaphragm and MRI. [2]
Cellulose sulfate 6% gel administered vaginally four times daily for 14 days did not differ with respect to epithelial disruption, candidiasis, BV, and acceptability from K-Y jelly placebo. [3] A blinded crossover study of 6% gel was conducted with 2.5 and 3.5 mL volumes. Each woman used each gel volume twice; after one application, women had restricted upright movement, and after the other, they were allowed to walk around. Excessive leakage was not noted with either volume. [4]
In a safety and acceptability study conducted in the United States and the Dominican Republic, HIV uninfected women used cellulose sulfate 6% gel or K-Y jelly placebo twice daily for 14 days. Some level of product leakage was reported by all study participants. There was no noticeable difference in the proportion of overall vaginal leakage of moderate or severe intensity between the cellulose sulfate and K-Y jelly placebo groups. [5]
In a Phase I, two-part cohort study of 180 women in India, Nigeria, and Uganda using cellulose sulfate 6% gel or K-Y jelly placebo, the majority of women had no problem with either gel, and most found the gels easy to use. Fewer women using cellulose sulfate than using K-Y jelly placebo reported genital symptoms in Cohort 1; new colposcopic findings were detected in only 9% of women using cellulose sulfate, compared to 21% of women using K-Y jelly. In Cohort 2, fewer women using cellulose sulfate than using K-Y jelly placebo reported genital symptoms; 11% in each group had new colposcopy findings. Differences between the groups were not considered to be statistically significant. [6]
In a survey study of HIV infected women using 6% gel once or twice daily for 14 days, women liked the gel's color, smell, and consistency somewhat to a lot. Overall, 31% of women reported that the gel soiled clothing or bed linens. In women using the gel once daily, 4 out of 7 reported leakage during sex; 4 out of 7 also reported leakage after sex. Many women reported that they would prefer a microbicide that could go unnoticed by a sex partner. Primary issues with the gel were soiling of clothes and leakage of gel during sex. [7]
In a Phase I trial in which men directly applied either cellulose sulfate gel or an active control containing nonoxynol-9 for 7 consecutive days, the cellulose sulfate gel was not more irritating than the active control. Symptoms reported by one patient after using cellulose sulfate included slight stinging and mild tingling. [8]
One South African clinical trial tested the safety of the Ortho All flex diaphragm when used with cellulose sulfate gel or with K-Y jelly, compared with cellulose gel use alone, over 6 months in HIV uninfected women. Very few of the participants in this study had ever used diaphragms before. This combination was found to be safe with no serious adverse events or adverse events related to diaphragm use reported. Colposcopic findings were observed in 60% to 80% of study participants. Seven severe findings were observed in those using the microbicide in combination with the diaphragm; however, these differences were not statistically significant. The location of these findings on the external genitalia suggest that they may have been due to trauma following diaphragm insertion. [9]
Cellulose sulfate vaginal tablets are not cytotoxic. The gel formulation has shown an acceptable safety profile in macaques. [10] [11]
References
[1] N Engl J Med Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV Transmission. 2008 Jul;359(5):463-72.
[2] Polydex Pharm Polydex Pharmaceuticals Reports Phase III trial of Ushercell for HIV Prevention Halted. Available at: http://www.polydex.com/v2/news/07-01-31.html. Accessed 07/26/09.
[3] Microbicides Conference 1st, 2004. Abstract 02249.
[4] Microbicides Conference 1st, 2004. Abstract 02420_1.
[5] Contraception 2006 Aug;74(2):133-40
[6] AIDS 2005 Dec 2;19(18):2157-63
[7] AIDS 2006 May 12;20(8):1109-16
[8] Contraception 2001 Dec;64(6):377-81
[9] AIDS Therapies 2006 Oct 13;3:25
[10] Microbicides Conference 1st, 2004. Abstract 02629_2.
[11] Microbicides Conference 1st, 2004. Abstract 02343_2.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Sulfato de celulosa.
Chemistry
CAS Name
Cellulose, hydrogen sulfate [1]
CAS Number
9032-43-3 [2]
Physical Description
Cellulose sulfate is a thick and odorless gel with a slightly hazy, light brown tint. [3]
Stability
Vaginal tablets stored in accelerated stability conditions recommended by the International Council on Harmonization (ICH) for Zone IV countries were stable for a period of 3 months. [4]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/26/09.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/26/09.
[3] Microbicides Conf 1st, 2004. Abstract 02585.
[4] Microbicides Conf 1st, 2004. Abstract 02629_2.
Further Reading
Anderson RA, Feathergill K, Diao XH, Chany C 2nd, Rencher WF, Zaneveld LJ, Waller DP. Contraception by Ushercell (cellulose sulfate) in formulation: duration of effect and dose effectiveness. Contraception. 2004 Nov;70(5):415-22.
Cheshenko N, Keller MJ, MasCasullo V, Jarvis GA, Cheng H, John M, Li JH, Hogarty K, Anderson RA, Waller DP, Zaneveld LJ, Profy AT, Klotman ME, Herold BC. Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread. Antimicrob Agents Chemother. 2004 Jun;48(6):2025-36.
D'Cruz OJ, Uckun FM. Clinical development of microbicides for the prevention of HIV infection. Curr Pharm Des. 2004;10(3):315-36. Review.
El-Sadr WM, Mayer KH, Maslankowski L, Hoesley C, Justman J, Gai F, Mauck C, Absalon J, Morrow K, Masse B, Soto-Torres L, Kwiecien A. Safety and acceptability of cellulose sulfate as a vaginal microbicide in HIV-infected women. AIDS. 2006 May 12;20(8):1109-16.
Schwartz JL, Mauck C, Lai JJ, Creinin MD, Brache V, Ballagh SA, Weiner DH, Hillier SL, Fichorova RN, Callahan M. Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study. Contraception. 2006 Aug;74(2):133-40. Epub 2006 May 2.
Manufacturer Information
Cellulose sulfate
Polydex Pharmaceuticals Ltd
Sandringham House
83 Shirley Street
Nassau,
Bahamas
Ushercell
Polydex Pharmaceuticals Ltd
Sandringham House
83 Shirley Street
Nassau,
Bahamas
Last Updated: July 31, 2009