- Protegrin structure and activity against Neisseria gonorrhoeae
Qu, X-D; Harwig, SSL; Shafer, WM; Lehrer, RI*
Infection and Immunity [Infect. Immun.], vol. 65, no. 2, pp. 636-639, Feb 1997
Protegrin 1 (PG-1) is a broad-spectrum antimicrobial peptide that contains 18 amino acid residues (RG GRLCYCRRRFCVCVGR) and has two intramolecular cystine disulfide bonds. To determine the minimal structure responsible for protegrin-mediated activity against Neisseria gonorrhoeae, we synthesized 15 protegrin variants and tested them against two well-characterized gonococcal strains. The MICs of PG-1 were 0.61 mu M (1.31 mu g/ml) for the serum-sensitive strain F 62 and 0.98 mu M (2.11 mu g/ml) for the serum-resistant strain FA 19. Six amino acid residues (Arg sub(1), Gly sub(2), Gly sub(3), Arg sub(4), Gly sub(17), and Arg sub(18)) and either disulfide bond could be deleted from PG-1 without impairing its potency against strain F 62. In contrast, only Gly sub(17) and Arg sub(18) could be removed without decreasing its activity against FA 19. Protegrin congener 64a (PC-64a; LTYCRRRFCVTV), a variant of PG-1 with 12 amino acid residues and one disulfide bond, displayed MICs of 0.45 mu M (0.68 mu g/ml) for strain F 62 and 1.37 mu M (2.07 mu g/ml) for strain FA 19, which approximated those of intact PG-1. Serum-sensitive sac-1 super(+) and sac-3 super(+) transformants of N. gonorrhoeae FA 19 and two FA 19 derivatives with truncated lipooligosaccharide structures were more susceptible to PG-1 and variants with altered disulfide structures. These data suggest that structurally simpler protegrin variants, such as PC-64a, could be used as topical microbicides for N. gonorrhoeae. They also suggest that the cystine-stabilized antiparallel beta -sheet formed by PG-1 residues 5 to 16 is principally responsible for its activity against gonococci.
- Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: Potential applications to microbicide development
Boyd, MR; Gustafson, KR; McMahon, JB; Shoemaker, RH; O'Keefe, BR; Mori, T; Gulakowski, RJ; Wu, L; Rivera, MI; Laurencot, CM; Currens, MJ; Cardellina, JH II; Buckheit, RW Jr; Nara, PL; et al.
Antimicrobial Agents & Chemotherapy [Antimicrob. Agents Chemother.], vol. 41, no. 7, pp. 1521-1530, Jul 1997
We have isolated and sequenced a novel 11-kDa virucidal protein, named cyanovirin-N (CV-N), from cultures of the cyanobacterium (blue-green alga) Nostoc ellipsosporum. We also have produced CV-N recombinantly by expression of a corresponding DNA sequence in Escherichia coli. Low nanomolar concentrations of either natural or recombinant CV-N irreversibly inactivate diverse laboratory strains and primary isolates of human immunodeficiency virus (HIV) type 1 as well as strains of HIV type 2 and simian immunodeficiency virus. In addition, CV-N aborts cell-to-cell fusion and transmission of HIV-1 infection. Continuous, 2-day exposures of uninfected CEM-SS cells or peripheral blood lymphocytes to high concentrations (e.g., 9,000 nM) of CV-N were not lethal to these representative host cell types. The antiviral activity of CV-N is due, at least in part, to unique, high-affinity interactions of CV-N with the viral surface envelope glycoprotein gp120. The biological activity of CV-N is highly resistant to physicochemical denaturation, further enhancing its potential as an anti-HIV microbicide.
- Effect of undecylenic acid as a topical microbicide against genital herpes infection in mice and guinea pigs
Bourne, N; Ireland, J; Stanberry, LR; Bernstein, DI
Antiviral Research [Antiviral Res.], vol. 40, no. 3, pp. 139-144, 1 Jan 1999
There is increasing interest in the use of topical microbicides to help prevent the spread of sexually transmitted diseases (STD). Undecylenic acid (UA), a monosaturated fatty acid, is the active ingredient in a number of over-the-counter (OTC) antifungal spray powders, that also exhibits in vitro antibacterial and antiviral activity, including herpes simplex virus (HSV) activity. We, therefore, evaluated UA as a topical microbicide against genital HSV infection using the murine and guinea pig models of genital herpes. Mice were administered a 20% solution of UA in polyethylene glycol (PEG) vehicle, vehicle alone or phosphate buffered saline (PBS) intravaginally immediately prior to vaginal challenge with HSV-2. Pre-treatment with UA decreased the number of mice that became infected (P<0.001 vs. PBS or vehicle control), developed symptoms (P<0.001) or died (P<0.001). However, when treatment was extended to either 5 min prior to or after viral inoculation, protection was lost. Similar findings were found using the guinea pig model, where UA treatment completely prevented HSV-2 vaginal infection when given immediately prior to HSV-2 inoculation (P<0.001 vs. PBS or vehicle control). Thus, UA, an approved OTC medication, provided significant protection against HSV disease and infection only when applied immediately before viral inoculation, indicating that better formulations were needed to extend the duration of protection.
- Bile salts: Natural detergents for the prevention of sexually transmitted diseases
Herold, BC; Kirkpatrick, R; Marcellino, D; Travelstead, A; Pilipenko, V; Krasa, H; Bremer, J; Dong, LJ; Cooper, MD
Antimicrobial Agents & Chemotherapy [Antimicrob. Agents Chemother.], vol. 43, no. 4, pp. 745-751, Apr 1999
The development of new, safe, topical microbicides for intravaginal use for the prevention of sexually transmitted diseases is imperative. Previous studies have suggested that bile salts may inhibit human immunodeficiency virus infection; however, their activities against other sexually transmitted pathogens have not been reported. To further explore the potential role of bile salts in preventing sexually transmitted diseases, we examined the in vitro activities and cytotoxicities of select bile salts against Chlamydia trachomatis, herpes simplex virus (types 1 and 2), Neisseria gonorrhoeae, and human immunodeficiency virus in comparison to those of nonoxynol-9 and benzalkonium chloride using both primary cells and cell lines derived from the human female genital tract. We found that taurolithocholic acid 3-sulfate and a combination of glycocholic acid and taurolithocholic acid 3-sulfate showed excellent activity against all of the pathogens assayed. Moreover, taurolithocholic acid 3-sulfate alone or in combination was less cytotoxic than nonoxynol-9 and benzalkonium chloride. Thus, taurolithocholic acid 3-sulfate alone or in combination warrants further evaluation as a candidate topical microbicidal agent.
- Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2
Bourne, KZ; Bourne, N; Reising, SF; Stanberry, LR
Antiviral Research [Antiviral Res.], vol. 42, no. 3, pp. 219-226, 1 Jul 1999
There is considerable interest in developing topical microbicides; products to be used intravaginally by women for protection against sexually transmitted diseases. Many compounds derived from plants have been shown to have antimicrobial properties. We examined 19 such compounds in vitro by plaque reduction assay to determine their activity against a common sexually transmitted pathogen, herpes simplex virus type 2. Compounds with an ED sub(50) less than or equal to 7.0 mg/ml were tested for efficacy in vivo. Four compounds, carrageenan lambda type IV, cineole, curcumin, and eugenol, provided significant protection (P<0.05) in a mouse model of intravaginal HSV-2 challenge. Eugenol, which provided the greatest protection in mice was also evaluated using the guinea pig model of genital HSV-2 infection where it also demonstrated significant protection. Based on these results, several plant-derived compounds appear to warrant further evaluation as potential microbicides.
- Hydrogels Containing Monocaprin Prevent Intravaginal and Intracutaneous Infections With HSV-2 in Mice: Impact on the Search for Vaginal Microbicides
Neyts, J; Kristmundsdottir, T; De Clercq, E; Thormar, H
Journal of Medical Virology [J. Med. Virol.], vol. 61, no. 1, pp. 107-110, May 2000
Hydrogel formulations containing the 1-mono-glyceride of capric acid (monocaprin) possess potent in vitro microbicidal activity against HIV and HSV, Chlamydia trachomatis and Neisseria gonorrhoeae. These formulations were studied to determine whether they prevent intracutaneous and intravaginal infections of mice with HSV-2, a virus that is in vitro as sensitive to the virucidal action of the compound as is HIV. In mice intravaginal infection with HSV-2 and the associated mortality was prevented completely when the infection was carried out in the presence of a 20 mM monocaprin containing gel formulation. Similarly, virtually complete protection of lesion development and associated mortality was observed when mice were infected intracutaneously with HSV-2 in the presence of gels containing 10 or 20 mM monocaprin. No irritation or toxicity was observed following application of the gel to the skin or the vaginal mucosa. Hydrogel formulations of monocaprin could thus be pursued as vaginal microbicides for the prevention of sexual transmission of HSV, HIV and other infectious pathogens.
- Dendrimers, a new class of candidate topical microbicides with activity against herpes simplex virus infection
Bourne, N; Stanberry, LR; Kern, ER; Holan, G; Matthews, B; Bernstein, DI
Antimicrobial Agents & Chemotherapy [Antimicrob. Agents Chemother.], vol. 44, no. 9, pp. 2471-2474, Sep 2000
Dendrimers are large highly branched macromolecules synthesized from a polyfunctional core. They have shown a variety of biological properties, including, in some instances, antiviral activity. In this study, five dendrimers were evaluated for in vitro activity against herpes simplex virus (HSV) types 1 and 2 by cytopathic effect (CPE) inhibition and plaque reduction (PR) assay in human foreskin fibroblast cells. All of the compounds were active against both virus types in the CPE inhibition assay, in which drug was added to the cells prior to the addition of virus. Antiviral activity was reduced or lost in the PR assays, in which the cells were incubated with the virus before the drug was added. The prophylactic efficacy suggested that the dendrimers might have potential as topical microbicides, products intended to be applied to the vaginal or rectal mucosa to protect against sexually transmitted infections. Three dendrimers were evaluated for this application against genital HSV infection in mice. Two of the compounds, BRI-2999 and BRI-6741, significantly reduced infection rates when 15 mu l of a 100-mg/ml solution was administered immediately prior to intravaginal challenge, and the most effective compound, BRI-2999, provided significant protection even when applied 30 min before challenge. This is the first report of microbicidal activity by dendrimers in vivo.
- Transgenic commensals as mucosal protectants
Whaley, KJ; Zeitlin, L
Nature Biotechnology [Nat. Biotechnol.], vol. 18, no. 10, pp. 1038-1039, Oct 2000
As our first line of defense against the majority of infections, mucosal surfaces in the genitourinary, oral, gastrointestinal, and respiratory systems are obvious sites for delivering protective agents for preventing infectious disease. Unfortunately, the technology for mucosal protection is severely limited; for example, the world community has had few options for preventing sexual transmission of HIV. With the report by Beninati et al. in this issue of Nature Biotechnology, an additional option may be realized. The authors used a single-chain antibody fragment (scFv) for treating vaginal Candida albicans infections in a rat model. What makes this report distinctive is the combination of a novel use of an antibody (antiidiotype scFv) and a unique delivery system (transgenic commensal bacteria expressing the scFv).
- In vitro inactivation of Chlamydia trachomatis and of a panel of DNA (HSV-2, CMV, adenovirus, BK virus) and RNA (RSV, enterovirus) viruses by the spermicide benzalkonium chloride
Belec, L; Tevi-Benissan, C; Bianchi, A; Cotigny, S; Beumont-Mauviel, M; Si-Mohamed, A; Malkin, J-E
Journal of Antimicrobial Chemotherapy [J. Antimicrob. Chemother.], vol. 46, no. 5, pp. 685-693, Nov 2000
Kinetics of inactivation by the detergent spermicide benzalkonium chloride (BZK) of Chlamydia trachomatis and of a panel of DNA viruses [herpes simplex virus hominis type 2 (HSV-2), cytomegalovirus (CMV), adenovirus (ADV) and BK virus (BKV)] and RNA [respiratory syncytial virus (RSV) and enterovirus (ENV)] were established in accordance with a standardized in vitro protocol. After a 5 min incubation, inactivation of >95% of HSV-2 and CMV was obtained at a concentration of 0.0025% (w/v) (25 Ig/L); concentrations as low as 0.0005%, 0.0050% and 0.0125%, induced a 3.0 log10 reduction in infectivity of HSV-2 and CMV, RSV and ADV, respectively. After a 60 min incubation, concentrations of 0.0125% and 0.050% provided a 3.0 log10 reduction in infectivity of ENV and BKV, respectively. These features indicate that sensitivity to BZK was very high (HSV-2 and CMV) or high (RSV) for enveloped viruses, intermediate (ADV) or low (ENV and BKV) for non-enveloped viruses. Furthermore, BZK had marked antichlamydial activity, showing >99% killing after only a 1 min incubation at a concentration of 0.00125%. BZK demonstrates potent in vitro activity against the majority of microorganisms causing sexually transmitted infectious diseases, including those acting as major genital cofactors of human immunodeficiency virus transmission. These attributes qualify BZK as a particularly attractive candidate for microbicide development.
- Candidate Microbicides Block HIV-1 Infection of Human Immature Langerhans Cells within Epithelial Tissue Explants
Kawamura, T; Cohen, SS; Borris, DL; Aquilino, EA; Glushakova, S; Margolis, LB; Orenstein, JM; Offord, RE; Neurath, AR; Blauvelt, A*
Journal of Experimental Medicine [J. Exp. Med.], vol. 192, no. 10, pp. 1491-1500, 20 Nov 2000
Initial biologic events that underlie sexual transmission of HIV-1 are poorly understood. To model these events, we exposed human immature Langerhans cells (LCs) within epithelial tissue explants to two primary and two laboratory-adapted HIV-1 isolates. We detected HIV-1 sub(Ba-L) infection in single LCs that spontaneously emigrated from explants by flow cytometry (median of infected LCs= 0.52%, range = 0.08-4.77%). HIV-1-infected LCs downregulated surface CD4 and CD83, whereas MHC class II, CD80, and CD86 were unchanged. For all HIV-1 strains tested, emigrated LCs were critical in establishing high levels of infection (0.1-1 mu g HIV-1 p24 per milliliter) in cocultured autologous or allogeneic T cells. HIV-1 sub(Ba-L) (an R5 HIV-1 strain) more efficiently infected LC-T cell cocultures when compared with HIV-1 sub(IIIB) (an X4 HIV-1 strain). Interestingly, pretreatment of explants with either aminooxypentane-RANTES (regulated upon activation, normal T cell expressed and secreted) or cellulose acetate phthalate (potential microbicides) blocked HIV-1 infection of LCs and subsequent T cell infection in a dose-dependent manner. In summary, we document HIV-1 infection in single LCs after exposure to virus within epithelial tissue, demonstrate that relatively low numbers of these cells are capable of inducing high levels of infection in cocultured T cells, and provide a useful explant model for testing of agents designed to block sexual transmission of HIV-1.
- Thermoreversible gel as a candidate barrier to prevent the transmission of HIV-1 and herpes simplex virus type 2.
Piret J; Gagne N; Perron S; Desormeaux A; Tremblay MJ; Gourde P; Omar RF; Bergeron AM
Sexually transmitted diseases., 2001 Aug, 28(8):484-91
BACKGROUND: Sexually transmitted diseases (STDs) caused by HIV, herpes simplex virus (HSV), and other pathogens are spreading dramatically. The need to develop active products and vehicles to reduce this epidemic is urgent. GOAL: The efficacy of a thermoreversible gel formulation as a possible barrier to prevent the transmission of pathogens causing STDs was evaluated. STUDY DESIGN: This evaluation investigated the ability of the gel formulation to prevent infection of susceptible cells by HIV-1 and HSV-2 in vitro, the diffusion of radiolabeled herpes virus and micelles of polymer through an insertion membrane, and the electron microscopic appearance of herpes virus and gel alone or mixed together. RESULTS: The gel formulation prevents infection of susceptible cells by HIV-1 and HSV-2. It acts as an effective artificial physical barrier against the herpes virus within the first 4 hours of incubation. Herpes virus is coated by the gel or entrapped within micelles of the gel, which could hinder its attachment to target cells and inhibit its infectivity. CONCLUSION: This thermoreversible gel formulation represents an attractive matrix for the incorporation of microbicides to prevent the spread of STDs.
- Preclinical evaluation of docusate as protective agent from herpes simplex viruses
Gong, Y*; Wen, A; Cheung, D; Wong, M; Sacks, SL
Antiviral Research [Antiviral Res.], vol. 52, no. 1, pp. 25 - 32, 1 Oct 2001
Prevention of sexually transmitted infections (STIs) is key to public health efforts to control these diseases. An effective vaginal microbicide could provide topical, broad-spectrum prevention against the transmission of several STI pathogens. Docusate is a sulfated surfactant and, as such, may inactivate viral pathogens by disrupting viral envelopes and/or denaturing/disassociating proteins. Accordingly, the in vitro efficacy and toxicity of docusate (dioctyl sodium sulfosuccinate; Zorex; Meditech Pharmaceuticals, Inc., Scottsdale, Arizona) against herpes simplex viruses (HSV) were evaluated. Docusate was effective in vitro against wild type and drug-resistant strains of HSV type 1 and 2 with EC sub(90-100) (effective concentration giving 90-100% virus yield reduction) of approximately 0.005% (w/v). Sodium dodecyl sulfate (SDS) was equipotent, however, docusate was somewhat less toxic to uninfected Vero cells compared with SDS after 2 days incubation (docusate CC sub(50) similar to 0.01% vs. SDS similar to 0.005%). The cytotoxicity profiles of docusate were time- and dose-dependent and thus associated with the frequency of use. Kinetics of inactivation examined by pre-mixing virus and drug in a time-course experiment demonstrated that docusate could reach its EC sub(90-100) within 30 min. Docusate pretreatment of cells was associated with a 45% reduction in infectivity of those cells, despite a triple washing procedure. Once infected, an approximate 30% plaque reduction was observed with treatment.
- In vitro and in vivo evaluations of sodium lauryl sulfate and dextran sulfate as microbicides against herpes simplex and human immunodeficiency viruses
Piret, J; Lamontagne, J; Bestman-Smith, J; Roy, S; Gourde, P; Desormeaux, A; Omar, RF; Juhasz, J; Bergeron, MG*
Journal of Clinical Microbiology [J. Clin. Microbiol.], vol. 38, no. 1, pp. 110-119, Jan 2000
The efficacy of sodium lauryl sulfate (SLS), a sulfated anionic chaotropic surfactant, and dextran sulfate (DS), a polysulfated carbohydrate, against herpes simplex virus (HSV) and human immunodeficiency virus (HIV) infections was evaluated in cultured cells and in different murine models of HSV infection. Results showed that both SLS and DS were potent inhibitors of the infectivities of various HSV-1 and HSV-2 strains. Pretreatment of HIV-1 (strain NL4-3) with SLS also reduced its infectivity to 1G5 cells. DS prevented the binding of HSV to cell surface receptors and therefore its entry into cells. Pretreatment of HSV-1 (strain F) with 50 mu M SLS resulted in a complete loss of virus infectivity to Vero cells. However, viruses were able to enter into cells and to produce in the nuclei capsid shells devoid of a DNA core. The amount of the glycoprotein D gene produced in these cells remained unchanged compared to controls, suggesting that SLS could interfere with the maturation of the virus. At a higher SLS concentration (100 mu M), HSV was highly damaged by SLS pretreatment and only a few viral particles could enter into cells to produce abnormal capsids. Although DS was a more potent inhibitor of HSV infectivity in vitro, it was unable to provide any protection in murine models of HSV infection. However, SLS conferred a complete protection of animals infected cutaneously with pretreated viruses. In addition, skin pretreatment of mice with a polymer formulation containing SLS completely prevented the development of cutaneous lesions. More interestingly, intravaginal pretreatment of mice with SLS in a buffered solution also completely protected against lethal HSV-2 infection. Taken together, our results suggest that SLS could thus represent a candidate of choice as a microbicide to prevent the sexual transmission of HIV, HSV, and possibly other pathogens that cause sexually transmitted diseases.
- Sodium lauryl sulfate abrogates human immunodeficiency virus infectivity by affecting viral attachment
Bestman-Smith, J; Piret, J; Desormeaux, A; Tremblay, MJ; Omar, RF; Bergeron, MG*
Antimicrobial Agents & Chemotherapy [Antimicrob. Agents Chemother.], vol. 45, no. 8, pp. 2229-2237, Aug 2001
The microbicidal activity of sodium lauryl sulfate (SLS) against human immunodeficiency virus type 1 (HIV-1) was studied in cultured cells. Pretreatment of HIV-1 sub(NL4-3) with SLS decreased, in a concentration-dependent manner, its infectivity when using 1G5 as target cells. In the absence of a viral pretreatment period or when 1G5 cells were pretreated with SLS, the surfactant-induced inactivation of viral infectivity was less pronounced, especially at concentrations between 375 and 550 mu M. SLS had no effect on HIV-1 when the virus was adsorbed to 1G5 cells by a 2-h incubation period. SLS almost completely inhibited the fusion process by decreasing the attachment of HIV-1 to target cells. SLS also inhibited the infectivity of HIV-1-based luciferase reporter viruses pseudotyped with the amphotropic murine leukemia virus envelope (which enters cells in a CD4-, CCR5-, and CXCR4-independent manner), indicating that SLS may inactivate other envelope viruses. In contrast, no effect was seen with vesicular stomatitis virus envelope glycoprotein G (which enters cells through receptor-mediated endocytosis) pretreated with up to 700 mu M SLS. SLS also decreased, in a dose-dependent manner, the HIV-1-dependent syncytium formation between 1G5 and J1.1 cells after a 24-h incubation. The reduction of luciferase activity was more pronounced when J1.1 cells (which express HIV-1 proteins on their surface) were pretreated with SLS rather than 1G5 cells. Taken together, our results suggest that SLS could represent a candidate of choice for use in vaginal microbicides to prevent the sexual transmission of HIV and possibly other pathogens causing sexually transmitted diseases.
- A broad-spectrum microbicide with virucidal activity against sexually transmitted viruses
Howett, MK; Neely, EB; Christensen, ND; Wigdahl, B; Krebs, FC; Malamud, D; Patrick, SD; Pickel, MD; Welsh, PA; Reed, CA; Ward, MG; Budgeon, LR; Kreider, JW
Antimicrobial Agents & Chemotherapy [Antimicrob. Agents Chemother.], vol. 43, no. 2, pp. 314-321, Feb 1999
Sodium dodecyl sulfate (SDS), an alkyl sulfate surfactant derived from an organic alcohol, possesses surfactant properties but also denatures and unfolds both monomeric and subunit proteins. In preliminary experiments, we demonstrated that SDS is a potent inactivator of herpes simplex virus type 2 and human immunodeficiency virus type 1 at concentrations comparable to those used for the surfactant nonoxynol-9. We hypothesized that SDS might be capable of denaturing the capsid proteins of nonenveloped viruses. In this report, we demonstrate inactivation of rabbit, bovine, and human papillomaviruses after brief treatment with dilute solutions of SDS. Effective concentrations were nontoxic to rabbit skin and to split-thickness grafts of human foreskin epithelium. This is the first report of a microbicidal surfactant that will inactivate papillomaviruses. We propose that SDS is now a candidate microbicide for formulation and testing with humans.
- Design of a "Microbicide" for Prevention of Sexually Transmitted Diseases Using "Inactive" Pharmaceutical Excipients
Neurath, AR; Strick, N; Li, Y; Lin, K; Jiang, S
Biologicals, vol. 27, no. 1, pp. 11-21, Mar 1999
The human immunodeficiency virus (HIV-1) pandemic has been driven primarily by the sexual transmission of the virus, and facilitated by prior infections with other sexually transmitted disease (STD) pathogens. Although treatment of these STDs has been proposed as a means to decrease the rate of HIV-1 sexual transmission, preventive measures effective against both HIV-1 and other STD pathogens are expected to have a larger impact. These measures include topically applied mechanical and chemical (i.e. microbicidal) barriers. Microbicides of preference should have a broad specificity against diverse STD pathogens and a well established safety record, considering their repeated use over decades. Here, we report that cellulose acetate phthalate (CAP), an "inactive" pharmaceutical excipient, commonly used in the production of enteric tablets and capsules: (1) has antiviral activity against HIV-1 and several herpesviruses (HSV); and (2) when appropriately formulated, in micronized form, inactivates HIV-1, HSV-1, HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi and Chlamydia trachomatis but does not affect Lactobacilli , components of the natural vaginal flora contributing to resistance against STDs. Thus, the CAP formulations meet the criteria for preferred microbicides and warrant further evaluation in vivo in humans.
- Effect of a cellulose acetate phthalate topical cream on vaginal transmission of simian immunodeficiency virus in rhesus monkeys
Manson, KH; Wyand, MS*; Miller, Ch; Neurath, AR
Antimicrobial Agents & Chemotherapy [Antimicrob. Agents Chemother.], vol. 44, no. 11, pp. 3199-3202, Nov 2000
Human immunodeficiency virus type 1 (HIV-1) infection continues to spread in developing countries, mostly through heterosexual transmission. The development of a safe and cost-effective topical microbicide, effective against a range of STDs including HIV-1, would greatly impact the ongoing epidemic. When formulated in a vehicle, a micronized form of cellulose acetate phthalate (CAP), which is an inactive pharmaceutical excipient, has been shown to inactivate HIV-1, herpes simplex virus types 1 and 2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi, and Chlamydia trachomatis in vitro. Formulated CAP was also shown to be effective against herpes simplex virus type 2 in vivo. Here we show that a formulation of CAP protected four of six rhesus monkeys from vaginal infection with simian immunodeficiency virus. Thus, CAP may be a candidate for use as a topical microbicide for preventing HIV-1 infection in humans.
- Preliminary safety and acceptability of a carrageenan gel for possible use as a vaginal microbicide.
Coggins C; Blanchard K; Alvarez F; Brache V; Weisberg E; Kilmarx PH; Lacarra M; Massai R; Mishell D Jr; Salvatierra A; Witwatwongwana P; Elias C; Ellertson C
Sex Transm Infect, 2000 Dec, 76(6):480-3
OBJECTIVE: We sought to determine the safety and acceptability of vaginal gel formulation PC-503 among low risk, abstinent women. The active ingredient was 2% pharmaceutical grade lambda carrageenan, a sulphated polymer that is generally recognised as safe by the US Food and Drug Administration. METHODS: 35 women in five sites applied 5 ml of the PC-503 gel vaginally once a day for 7 days while abstaining from sexual intercourse. Visual vaginal examinations were performed on days 1, 4, and 8. STI testing and vaginal pool Gram stain preparations were done on days 1 and 8. Participants were asked about product acceptability. RESULTS: 34 of the 35 women enrolled completed 7 days' use. Following product use, five reported mild symptoms including "bladder fullness," "genital warmth," or discomfort, and lower abdominal pain, and one had moderate pale yellow cervical discharge. Using the Nugent criteria, three women had bacterial vaginosis (BV) before and after use; three had BV before but not after, and two had BV after but not before. Most of the women found PC-503 to be pleasant or neutral in feel and smell and considered extra lubrication to be an advantage; however, one third found it to be messy. CONCLUSIONS: Vaginal use of PC-503 gel did not cause significant adverse effects in a small number of low risk, sexually abstinent women. Further testing in larger numbers of sexually active women is planned. A smaller volume of gel may be more acceptable to some women.
- Tests of Buffergel for contraception and prevention of sexually transmitted diseases in animal models.
Zeitlin L; Hoen TE; Achilles SL; Hegarty TA; Jerse AE; Kreider JW; Olmsted SS; Whaley KJ; Cone RA; Moench TR
Sexually transmitted diseases., 2001 Jul, 28(7):417-23
BACKGROUND: BufferGel is a novel spermicidal and microbicidal gel formulated to maintain the natural protective acidity of the vagina by acidifying semen, which otherwise alkalinizes the vagina. GOAL: To test the efficacy of BufferGel for preventing sexually transmitted infections and pregnancy in animal models. STUDY DESIGN: Animals were challenged with pathogens or sperm after pretreatment with both test and control agents, or after no pretreatment, then evaluated for infection or pregnancy using standard methods. RESULTS: BufferGel provided significant contraceptive efficacy in the rabbit, and significant protection against vaginal and rectal transmission of herpes simplex virus type 2 (HSV-2) in the mouse, vaginal transmission of Chlamydia trachomatis in the mouse, and skin transmission of cottontail rabbit papillomavirus in the rabbit. It did not protect against vaginal transmission of Neisseria gonorrhoeae in the mouse. CONCLUSIONS: The protective efficacy of BufferGel in five of the six animal models suggests that this microbicide warrants clinical evaluation for both contraception and disease prevention.
- Phase 1 Trial of the Topical Microbicide BufferGel: Safety Results From Four International Sites
Van De Wijgert, J; Fullem, A; Kelly, C; Mehendale, S; Rugpao, S; Kumwenda, N; Chirenje, Z; Joshi, S; Taha, T; Padian, N; Bollinger, R; Nelson, K
JAIDS Journal of Acquired Immune Deficiency Syndromes [Jaids J. Acquired Immune Defic. Syndromes], vol. 26, no. 1, pp. 21-27, Jan 2001
To evaluate the safety of BufferGel (ReProtect LLC, Baltimore, MD), a spermicidal microbicide that acidifies semen and maintains the protective acidity of the vagina, in a high-dose tolerance trial. HIV/STD negative, sexually abstinent, and sexually active women in India, Thailand, Malawi, and Zimbabwe were asked to insert one applicator ( similar to 5 ml) of BufferGel vaginally twice per day for 14 days. Sexually active women agreed to have sex (while using BufferGel and nonlubricated condoms) at least twice per week. In total, 98 women (30 sexually abstinent and 68 sexually active) were enrolled. Overall compliance with product use was 93%. Epithelial abnormalities detected by pelvic examination or colposcopy were uncommon (8 cases in 271 examinations). Irritation was reported by approximately one quarter of the women (0.58 events per woman-week) but was generally mild and of short duration. The prevalence of bacterial vaginosis (BV) fell significantly, from 30% at enrollment to 6% at one week, and 7% at two weeks of BufferGel use. Thirty-two women acquired microscopically detectable yeast during BufferGel exposure, but only 3 developed symptomatic vaginitis. BufferGel appears to be safe and well tolerated by the cervicovaginal epithelium. Its effect on BV and yeasts merits further study.
- Safety and Tolerability of BufferGel, a Novel Vaginal Microbicide, in Women in the United States
Mayer, KH; Peipert, J; Fleming, T; Fullem, A; Moench, T; Cu-Uvin, S; Bentley, M; Chesney, M; Rosenberg, Z
Clinical Infectious Diseases [Clin. Infect. Dis.], vol. 32, no. 3, pp. 476-482, 1 Feb 2001
BufferGel (ReProtect, LLC) is a vaginal gel with an acidic buffering action that was designed to prevent vaginal neutralization by semen. The purpose of this study was to evaluate the safety and tolerability of BufferGel (ReProtect, Limited Liability Company) applied vaginally either once or twice daily by 27 women who were at low risk for acquisition of human immunodeficiency virus (HIV). Participants initially used the product once daily for 14 days and then twice daily for 14 days; they underwent colposcopy before and after product exposure. BufferGel was well tolerated, although two-thirds of the participants reported at least 1 mild or moderate adverse experience. The most common adverse events were irritative genitourinary symptoms. Product use was discontinued after 3 adverse events. BufferGel was well tolerated in women at low risk for acquisition of HIV; toxicity was limited and occurred at frequencies similar to those in women who did not use any vaginal product and at levels lower than in women who used detergent-based microbicides.