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1.  Identification of Personal Lubricants That Can Cause Rectal Epithelial Cell Damage and Enhance HIV Type 1 Replication in Vitro 
AIDS Research and Human Retroviruses  2011;27(9):1019-1024.
Abstract
Over-the-counter personal lubricants are used frequently during vaginal and anal intercourse, but they have not been extensively tested for biological effects that might influence HIV transmission. We evaluated the in vitro toxicity anti-HIV-1 activity and osmolality of popular lubricants. A total of 41 lubricants were examined and compared to Gynol II and Carraguard as positive and negative controls for toxicity, respectively. Cytotoxicity was assessed using the XTT assay. The MAGI assay with R5 and X4 HIV-1 laboratory strains was used to evaluate antiviral activity. The effect of the lubricants on differentiated Caco-2 cell monolayers (transepithelial electrical resistance, TEER) was also measured. None of the lubricants tested showed significant activity against HIV-1. Surprisingly, four of them, Astroglide Liquid, Astroglide Warming Liquid, Astroglide Glycerin & Paraben-Free Liquid, and Astroglide Silken Secret, significantly enhanced HIV-1 replication (p<0.0001). A common ingredient in three of these preparations is polyquaternium-15. In vitro testing of a chemically related compound (MADQUAT) confirmed that this similarly augmented HIV-1 replication. Most of the lubricants were found to be hyperosmolar and the TEER value dropped approximately 60% 2 h after exposure to all lubricants tested. Cells treated with Carraguard, saline, and cell controls maintained about 100% initial TEER value after 2–6 h. We have identified four lubricants that significantly increase HIV-1 replication in vitro. In addition, the epithelial damage caused by these and many other lubricants may have implications for enhancing HIV transmission in vivo. These data emphasize the importance of performing more rigorous safety testing on these products.
doi:10.1089/aid.2010.0252
PMCID: PMC3161103  PMID: 21309617
2.  Rectal Application of a Highly Osmolar Personal Lubricant in a Macaque Model Induces Acute Cytotoxicity but Does Not Increase Risk of SHIV Infection 
PLoS ONE  2015;10(4):e0120021.
Background
Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15.
Methods
Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure.
Results
Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models).
Conclusions
Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission.
doi:10.1371/journal.pone.0120021
PMCID: PMC4390343  PMID: 25853710
3.  In Vitro and Ex Vivo Testing of Tenofovir Shows It Is Effective As an HIV-1 Microbicide 
PLoS ONE  2010;5(2):e9310.
Background
Tenofovir gel has entered into clinical trials for use as a topical microbicide to prevent HIV-1 infection but has no published data regarding pre-clinical testing using in vitro and ex vivo models. To validate our findings with on-going clinical trial results, we evaluated topical tenofovir gel for safety and efficacy. We also modeled systemic application of tenofovir for efficacy.
Methods and Findings
Formulation assessment of tenofovir gel included osmolality, viscosity, in vitro release, and permeability testing. Safety was evaluated by measuring the effect on the viability of vaginal flora, PBMCs, epithelial cells, and ectocervical and colorectal explant tissues. For efficacy testing, PBMCs were cultured with tenofovir or vehicle control gels and HIV-1 representing subtypes A, B, and C. Additionally, polarized ectocervical and colorectal explant cultures were treated apically with either gel. Tenofovir was added basolaterally to simulate systemic application. All tissues were challenged with HIV-1 applied apically. Infection was assessed by measuring p24 by ELISA on collected supernatants and immunohistochemistry for ectocervical explants. Formulation testing showed the tenofovir and vehicle control gels were >10 times isosmolar. Permeability through ectocervical tissue was variable but in all cases the receptor compartment drug concentration reached levels that inhibit HIV-1 infection in vitro. The gels were non-toxic toward vaginal flora, PBMCs, or epithelial cells. A transient reduction in epithelial monolayer integrity and epithelial fracture for ectocervical and colorectal explants was noted and likely due to the hyperosmolar nature of the formulation. Tenofovir gel prevented HIV-1 infection of PBMCs regardless of HIV-1 subtype. Topical and systemic tenofovir were effective at preventing HIV-1 infection of explant cultures.
Conclusions
These studies provide a mechanism for pre-clinical prediction of safety and efficacy of formulated microbicides. Tenofovir was effective against HIV-1 infection in our algorithm. These data support the use of tenofovir for pre-exposure prophylaxis.
doi:10.1371/journal.pone.0009310
PMCID: PMC2824823  PMID: 20174579
4.  Factors Associated with Use of Latex Condom-Compatible Lubricants by Men Who Have Sex with Men in India: Implications for HIV Prevention 
We examined the prevalence and type of rectal lubricants use and factors associated with exclusive use of latex-condom compatible lubricants (water-based lubricants) among men who have sex with men (MSM) using data from a large-scale cross-sectional survey conducted in 2009/10 in three Indian states. Using time-location cluster sampling, 3880 MSM were recruited from cruising sites. We used multiple logistic regression to assess the association between type of lubricants used and sociodemographic and programmatic indicators. Among those who reported using lubricants (64%) more than half (53%) exclusively used water-based lubricants, less than one-tenth used exclusively oil-based lubricants, and nearly 40% used both water-based and oil-based lubricants. Factors associated with exclusive use of water-based lubricants were exposure to HIV prevention interventions (AOR: 6.18, 95% CI 4.82 to 7.92) and kothi-identified MSM—feminine/anal-receptive (AOR: 2.56, 95% CI 2.12 to 3.10). Targeted HIV interventions among MSM need to promote and distribute latex condom-compatible lubricants for use during anal sex—irrespective of their presumed or stated sexual role in anal sex, and educate them not to use oil-based lubricants with condoms.
doi:10.1155/2013/161085
PMCID: PMC4475579  PMID: 26316951
5.  Reformulated tenofovir gel for use as a dual compartment microbicide 
Objectives
Coital use of 1% tenofovir gel was shown to be modestly effective at preventing HIV transmission when applied vaginally in the CAPRISA 004 trial. Because the gel is hyperosmolar, which would reduce the integrity of the epithelium and induce fluid movement into the lumen, rectal use may not be acceptable. This study evaluated the pre-clinical safety and efficacy of a reformulated (reduced osmolality) tenofovir gel product.
Methods
Reduced glycerine (RG)-tenofovir gel was compared with the original tenofovir gel for physiochemical characteristics, product safety and anti-HIV-1 activity.
Results
The formulations were similar in all characteristics except for osmolality and spreadability/firmness. The RG-tenofovir gel had a 73% lower osmolality, a 29.6% increase in spreadability and a 27% decrease in firmness as compared with the original tenofovir gel. When applied to epithelial cell monolayers, tenofovir gel showed a transient reduction in the transepithelial resistance while the RG-tenofovir gel did not. Both gels retained ectocervical and colorectal explant viability. However, tenofovir gel treatment resulted in epithelial stripping that was absent after RG-tenofovir gel treatment of the polarized explants. Anti-HIV-1 activity was confirmed by lack of HIV-1 infection in polarized explants treated with either gel as compared with the control explants.
Conclusions
Reducing the osmolality of the tenofovir gel resulted in improved epithelial integrity, which suggests better safety upon rectal use. The improved gel safety did not compromise drug release or anti-HIV-1 activity. These data support the use of this gel as a dual compartment microbicide.
doi:10.1093/jac/dks173
PMCID: PMC3417689  PMID: 22581908
HIV prevention; rectal microbicide; formulation; preclinical testing; safety
6.  Effects of feminine hygiene products on the vaginal mucosal biome 
Microbial Ecology in Health and Disease  2013;24:10.3402/mehd.v24i0.19703.
Background
Over-the-counter (OTC) feminine hygiene products come with little warning about possible side effects. This study evaluates in-vitro their effects on Lactobacillus crispatus, which is dominant in the normal vaginal microbiota and helps maintain a healthy mucosal barrier essential for normal reproductive function and prevention of sexually transmitted infections and gynecologic cancer.
Methods
A feminine moisturizer (Vagisil), personal lubricant, and douche were purchased OTC. A topical spermicide (nonoxynol-9) known to alter the vaginal immune barrier was used as a control. L. crispatus was incubated with each product for 2 and 24h and then seeded on agar for colony forming units (CFU). Human vaginal epithelial cells were exposed to products in the presence or absence of L. crispatus for 24h, followed by epithelium-associated CFU enumeration. Interleukin-8 was immunoassayed and ANOVA was used for statistical evaluation.
Results
Nonoxynol-9 and Vagisil suppressed Lactobacillus growth at 2h and killed all bacteria at 24h. The lubricant decreased bacterial growth insignificantly at 2h but killed all at 24h. The douche did not have a significant effect. At full strength, all products suppressed epithelial viability and all, except the douche, suppressed epithelial-associated CFU. When applied at non-toxic dose in the absence of bacteria, the douche and moisturizer induced an increase of IL-8, suggesting a potential to initiate inflammatory reaction. In the presence of L. crispatus, the proinflammatory effects of the douche and moisturizer were countered, and IL-8 production was inhibited in the presence of the other products.
Conclusion
Some OTC vaginal products may be harmful to L. crispatus and alter the vaginal immune environment. Illustrated through these results, L. crispatus is essential in the preservation of the function of vaginal epithelial cells in the presence of some feminine hygiene products. More research should be invested toward these products before they are placed on the market.
doi:10.3402/mehd.v24i0.19703
PMCID: PMC3758931  PMID: 24009546
Lactobacillus; L. crispatus; cytokines; Interleukin-8; Nonoxynol-9; vaginal microbiota; vaginal epithelial colonization; mucosal immunity
7.  Effect of Vaginal Lubricants on Natural Fertility 
Obstetrics and gynecology  2012;120(1):44-51.
Objective
Over-the-counter vaginal lubricants have been shown to negatively affect in vitro sperm motility. The objective of this study was to estimate the effect of vaginal lubricant use during procreative intercourse on natural fertility.
Methods
Women aged 30–44 years with no history of infertility who had been trying to conceive for less than 3 months completed a baseline questionnaire on vaginal lubricant use. Subsequently, women kept a diary to record menstrual bleeding, intercourse, and vaginal lubricant use and conducted standardized pregnancy testing for up to 6 months. Diary data were used to determine the fertile window and delineate lubricant use during the fertile window. A proportional hazards model was used to estimate fecundability ratios with any lubricant use in the fertile window considered as a time-varying exposure.
Results
Of the 296 participants, 75 (25%) stated in their baseline questionnaire that they use vaginal lubricants while attempting to conceive. Based on daily diary data, 57% of women never used a lubricant, 29% occasionally used a lubricant, and 14% used a lubricant frequently. Women who used lubricants during the fertile window had similar fecundability to those women who did not use lubricants (fecundability ratio 1.05, 95% CI: 0.59, 1.85) after adjusting for age, partner race, and intercourse frequency in the fertile window.
Conclusion
Lubricants are commonly used by couples during procreative intercourse. Lubricant use during procreative intercourse does not appear to reduce the probability of conceiving.
doi:10.1097/AOG.0b013e31825b87ae
PMCID: PMC3427535  PMID: 22914390
8.  Commercial lubricant use among HIV-negative men who have sex with men in Los Angeles: implications for the development of rectal microbicides for HIV prevention 
AIDS care  2014;26(12):1609-1618.
To inform the development and assess potential use of rectal microbicide gels for HIV prevention among men who have sex with men (MSM), we examined the dynamics and contexts of commercial lubricant use during receptive anal intercourse (RAI) within this population. From 2007–2010, 168 HIV-negative MSM living in Los Angeles who practice RAI completed computer-assisted self-interviews, which collected information on their last sexual event with ≤3 recent partners, at baseline, 3 months, and 1 year study visits. Logistic generalized linear mixed models were used to identify individual- and sexual event-level characteristics associated with commercial lubricant use during RAI at the last sexual event within 421 partnerships reported by participants over the course of follow-up. During RAI at their last sexual event, 57% of partnerships used a condom and 69% used commercial lubricant. Among partnerships that used commercial lubricant, 56% reported lubricant application by both members of the partnership, 66% first applied lubricant during sex, but before penetration, and 98% applied lubricant at multiple locations. The relationship between substance use and commercial lubricant use varied by condom use (interaction p-value=0.01). Substance use was positively associated with commercial lubricant use within partnerships that used condoms during RAI at their last sexual event (adjusted odds ratio [AOR]=4.47, 95% confidence interval [CI]: 1.63–12.28), but no association was observed within partnerships that did not use condoms (AOR=0.66, 95% CI: 0.23–1.85). Commercial lubricant use during RAI was also positively associated with reporting more sexual partners (AOR=1.18, 95% CI: 1.05–1.31), while older age (units= 5 years) (AOR=0.75, 95% CI: 0.61–0.94), homelessness (past year) (AOR=0.32, 95% CI: 0.13–0.76), and having sex with an older (>10 years) partner (AOR=0.37, 95% CI: 0.14–0.95) were negatively associated with commercial lubricant use. These factors should be considered in the development of rectal microbicide gels to enhance their acceptability and use among MSM.
doi:10.1080/09540121.2014.936821
PMCID: PMC4188690  PMID: 25022198
commercial lubricant use; receptive anal intercourse; MSM; MSM partnerships; rectal microbicides; HIV prevention
9.  Effect of lubricants and a vaginal spermicide gel on the detection of prostate specific antigen, a biomarker of semen exposure, using a quantitative (Abbott ARCHITECT) assay☆, ☆☆, ★ 
Contraception  2013;89(2):134-138.
Objectives
Little is known about the effects of commonly used lubricants on detection of biomarkers of semen exposure. We investigated the in vitro effect of Gynol®, K-Y Jelly®, Replens®, Astroglide®, Carbopol, and Silicorel on quantitative detection of prostate specific antigen (PSA).
Study Design
A predetermined concentration of each of the gels was added to serially diluted semen samples. Additionally, serial dilutions of each of the gels were added to three different semen dilutions (high, medium, or low). The resulting samples were tested for PSA on the Abbott ARCHITECT System.
Results
When using the Abbott ARCHITECT system, the only products that inhibited PSA detection were Gynol® and Replens®. The inhibition caused by Gynol® was dose-dependent, but that of Replens was dose-independent. K-Y Jelly®-spiked samples had higher PSA values than controls.
Conclusions
Caution is warranted when using the Abbott quantitative assay for PSA detection as a biomarker of semen exposure in settings where Gynol®, Replens® or K-Y Jelly® might also have been used. Neither Astroglide® nor Silicorel inhibited PSA detection. Additional studies evaluating other vaginal products, including microbicides, and their effects on other assays, are needed. In vivo studies will be especially important to optimize PSA detection from clinical samples.
Implications
Researchers should consider the potential for specific lubricants or any vaginal products to affect the particular assay used for semen biomarker detection. The Abbott ARCHITECT’s total PSA assay should not be used with the product Replens. Caution is warranted when using the assay in settings where Gynol or K-Y jelly may have been used.
doi:10.1016/j.contraception.2013.09.016
PMCID: PMC4554523  PMID: 24314911
Semen biomarkers; Lubricants; Vaginal products; Spermicide; Prostate-specific antigen
10.  Condoms and condiments: compatibility and safety of personal lubricants and their use in Africa 
Previous research on the use of personal lubricants for sexual intercourse is limited and has primarily focused on condom compatibility and breakage, with only recent limited assessment of lubricant safety and possible epidemiologic implications. This article discusses the global evidence of lubricant compatibility with latex condoms and biological safety of lubricants, as well as documentation of lubricant use and current guidelines for HIV prevention programming in Africa. Data on lubricant compatibility with condoms are less available than commonly realized, and many lubricant products may not have been thoroughly tested for safety due to flexible regulatory environments. Recent laboratory and study findings from microbicides research also suggest that some water-based lubricants may have safety issues. Some African populations are using several types of lubricants, especially oil-based petroleum jellies, and receive little evidence-based guidance. More research is needed from the medical community to guide prevention programming.
doi:10.7448/IAS.16.1.18531
PMCID: PMC3708353  PMID: 23841994
lubricants; condoms; HIV prevention; Africa
11.  Comparative evaluation of tableting compression behaviors by methods of internal and external lubricant addition: Inhibition of enzymatic activity of trypsin preparation by using external lubricant addition during the tableting compression process 
AAPS PharmSci  2001;3(3):32-42.
This study evaluated tableting compression by using internal and external lubricant addition. The effect of lubricant addition on the enzymatic activity of trypsin, which was used as a model drug during the tableting compression process, was also investigated. The powder mixture (2% crystalline trypsin, 58% crystalline lactose, and 40% microcrystalline cellulose) was kneaded with 5% hydroxypropyl cellulose aqueous solution and then granulated using an extruding granulator equipped with a 0.5-mm mesh screen at 20 rpm. After drying, the sample granules were passed through a 10-mesh screen (1680 μm). A 200-mg sample was compressed by using 8-mm punches and dies at 49, 98, 196, or 388 MPa (Mega Pascal) at a speed of 25 mm/min. The external lubricant compression was performed using granules without lubricant in the punches and dies. The granules were already dry coated by the lubricant. In contrast, the internal lubricant compression was performed using sample granules (without dry coating) containing 0.5% lubricant. At 98 MPa, for example, the compression level using the external lubricant addition method was about 13% higher than that for internal addition. The significantly higher compressing energy was also observed at other MPas. By comparison, the friction energy for the external addition method calculated based on upper and lower compression forces was only slightly larger. The hardness of tablets prepared using the internal addition method was 34% to 48% lower than that for the external addition method. The total pore volume of the tablet prepared using the external addition method was significantly higher. The maximum ejection pressure using the no-addition method (ie, the tablet was prepared using neither dry-coated granules nor added lubricant) was significantly higher than that of other addition methods. The order was as follows: no addition, external addition, and then internal addition. The ejection energy (EE) for internal addition was the lowest; for no addition, EE was the highest. In the dissolution test, the tablets obtained using external addition immediately disintegrated and showed faster drug release than those prepared using internal addition. This result occurred because the water penetration rate of the tablet using the external addition was much higher. The trypsin activity in tablets prepared using the external addition method was significantly higher than that produced using the internal addition method at the same pressure. All these results suggest that the external addition method might produce a fast-dissolution tablet. Because the drug will be compressed using low pressure only, an unstable bulk drug may be tableted without losing potency.
doi:10.1208/ps030320
PMCID: PMC2751015  PMID: 11741271
Tableting; Trypsin; Preparation; Compression; Dissolution
12.  Interactive Cytokine Regulation of Synoviocyte Lubricant Secretion 
Tissue Engineering. Part A  2009;16(4):1329-1337.
Cytokine regulation of synovial fluid (SF) lubricants, hyaluronan (HA), and proteoglycan 4 (PRG4) is important in health, injury, and disease of synovial joints, and may also provide powerful regulation of lubricant secretion in bioreactors for articulating tissues. This study assessed lubricant secretion rates by human synoviocytes and the molecular weight (MW) of secreted lubricants in response to interleukin (IL)-1β, IL-17, IL-32, transforming growth factor-beta 1 (TGF-β1), and tumor necrosis factor-alpha (TNF-α), applied individually and in all combinations. Lubricant secretion rates were assessed using ELISA and binding assays, and lubricant MW was assessed using gel electrophoresis and Western blotting. HA secretion rates were increased ∼40-fold by IL-1β, and increased synergistically to ∼80-fold by the combination of IL-1β + TGF-β1 or TNF-α + IL-17. PRG4 secretion rates were increased ∼80-fold by TGF-β1, and this effect was counterbalanced by IL-1β and TNF-α. HA MW was predominantly <1 MDa for controls and individual cytokine stimulation, but was concentrated at >3 MDa after stimulation by IL-1β + TGF-β1 + TNF-α to resemble the distribution in human SF. PRG4 MW was unaffected by cytokines and similar to that in human SF. These results contribute to an understanding of the relationship between SF cytokine and lubricant content in health, injury, and disease, and provide approaches for using cytokines to modulate lubricant secretion rates and MW to help achieve desired lubricant composition of fluid in bioreactors.
doi:10.1089/ten.tea.2009.0210
PMCID: PMC2862605  PMID: 19908966
13.  Covert Use, Vaginal Lubrication, and Sexual Pleasure: A Qualitative Study of Urban U.S. Women in a Vaginal Microbicide Clinical Trial 
Archives of sexual behavior  2009;39(3):748-760.
Using data from a U.S. clinical safety trial of tenofovir gel, a candidate microbicide, we explored the intersection of sexual pleasure and vaginal lubrication to understand whether and under what circumstances women would use a microbicide gel covertly with primary partners. This study question emerged from acceptability research in diverse settings showing that even though future microbicides are extolled as a disease prevention method that women could use without disclosing to their partners, many women assert they would inform their primary partner. Participants (N = 84), stratified by HIV-status and sexual activity (active vs. abstinent), applied the gel intra-vaginally for 14 days. At completion, quantitative acceptability data were obtained via questionnaire (N = 79) and qualitative data via small group discussions (N = 15 groups, 40 women). Quantitatively, 71% preferred a microbicide that could not be noticed by a sex partner and 86% experienced greater vaginal lubrication during application of the gel. Based on our analysis of the qualitative data, we suggest that women would find it more acceptable to use a microbicide covertly in primary relationships if they believed that the method was truly unnoticeable. Our findings also showed that women’s assessment of the possibility of discreet, if not covert, use was strongly related to their perception of how a microbicide’s added vaginal lubrication would influence their own and their partner’s pleasure, as well as their partner’s experience of his sexual performance. A microbicide that increases pleasure for both partners could potentially be used without engendering opposition from primary partners.
doi:10.1007/s10508-009-9509-3
PMCID: PMC2855760  PMID: 19636696
Sexual pleasure; HIV/STI prevention; vaginal Microbicide; pregnancy prevention
14.  Pharmacodynamic activity of Dapivirine and Maraviroc single entity and combination topical gels for HIV-1 prevention 
Pharmaceutical research  2015;32(11):3768-3781.
Purpose
Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission.
Methods
0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety.
Results
The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm2/min1/2), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm2/min1/2). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe.
Conclusions
The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.
doi:10.1007/s11095-015-1738-7
PMCID: PMC4600024  PMID: 26078001
HIV prevention; pre-exposure prophylaxis; rectal microbicides; antiretroviral drugs; drug combinations
15.  Hyperosmolar Stress Induces Neutrophil Extracellular Trap Formation: Implications for Dry Eye Disease 
Purpose.
To determine if hyperosmolar stress can stimulate human neutrophils to form neutrophil extracellular traps (NETs) and to investigate potential strategies to reduce formation of NETs (NETosis) in a hyperosmolar environment.
Methods.
Neutrophils were isolated from peripheral venous blood of healthy subjects and incubated in iso-osmolar (280 mOsM) or hyperosmolar (420 mOsM) media for 4 hours. Neutrophil extracellular traps were quantified using a PicoGreen dye assay to measure extracellular DNA. Two known inhibitors of NETosis, staurosporine and anti-β2 integrin blocking antibody, and two proresolution formyl peptide receptor 2 (FPR2) agonists, annexin/lipocortin-1 mimetic peptide and 15-epi-lipoxin A4, were evaluated as possible strategies to reduce hyperosmolarity-induced NETosis.
Results.
The amount of NETs induced by hyperosmolar medium (420 mOsM) increased linearly over time to 3.2 ± 0.3 times that induced by iso-osmolar medium at 4 hours (P < 0.05). NETosis increased exponentially with increasing osmolarity and was independent of the stimulus used to increase osmolarity. Upon neutrophil exposure to hyperosmolar stress, restoration of iso-osmolar conditions decreased NET formation by 52.7% ± 5% (P < 0.05) but did not completely abrogate it. Among the strategies tested to reduce NETosis in a hyperosmolar environment, annexin-1 peptide was the most efficacious.
Conclusions.
Hyperosmolarity induces formation of NETs by neutrophils. This NETosis mechanism may explain the presence of excessive NETs on the ocular surface of patients with dry eye disease. Because they reduce hyperosmolarity-induced NETosis, FPR2 agonists may have therapeutic potential in these patients.
Hyperosmolarity induces formation of neutrophil extracellular traps (NETs) by neutrophils. Hyperosmolarity-induced NETosis may explain why excessive NETs are present on the ocular surface of patients with tear-deficient dry eye disease.
doi:10.1167/iovs.14-15332
PMCID: PMC4263134  PMID: 25406284
dry eye; hyperosmolar stress; extracellular DNA; neutrophil extracellular traps
16.  Associations of sexually transmitted infections with condom problems among young men who have sex with men 
Sexually transmitted diseases  2014;41(7):427-432.
Background
Young men who have sex with men (YMSM) are disproportionately infected with STIs. Condom use is the most widely available means of preventing the transmission of STIs, but effectiveness depends on correct use. Condom errors, such as using an oil-based lubricant, have been associated with condom failures, such as breakage. Little research has been done on the impact of condom problems on the likelihood of contracting an STI.
Methods
Data came from Crew 450, a longitudinal study of HIV risk among YMSM (N = 450). All self-report data were collected using computer-assisted self-interview (CASI) technology and clinical testing was done for gonorrhea, Chlamydia, and HIV.
Results
Nearly all participants made at least one error, with high rates of using oil based lubricant and incomplete use. No differences were found in rates of condom problems during anal sex with a man versus vaginal sex with a woman. Black YMSM reported significantly higher use of oil based lubricants than White and Hispanic YMSM, an error significantly associated with HIV status (AOR = 2.60; 95% CI: 1.04 – 6.51). Participants who reported a condom failure were significantly more likely to have a STI (AOR=3.27; 95% CI: 1.31 – 8.12).
Conclusions
YMSM report high rates of condom problems, and condom failures were significantly associated with STIs after controlling for unprotected sex. Educational programs are needed to enhance correct condom use among YMSM. Further research is needed on the role of oil based lubricants in explaining racial disparities in STIs and HIV.
doi:10.1097/OLQ.0000000000000150
PMCID: PMC4261919  PMID: 24922101
Homosexuality; Male; Condoms; HIV; Sexually Transmitted Diseases; Adolescent
17.  Frequency, Patterns and Preferences of Lubricant Use During Anal Intercourse Within Male Sexual Partnerships in Lima, Peru: Implications for a Rectal Microbicide HIV Prevention Intervention 
AIDS care  2012;25(5):579-585.
Understanding current practices of lubricant use during anal intercourse can help to assess the contexts for the introduction of topical rectal microbicides as an HIV prevention tool for men who have sex with men (MSM). We used quantitative and qualitative methods to assess: current patterns of lubricant use; preferred characteristics of commercial lubricant formulations; and social and behavioral contexts of lubricant use within male sexual partnerships in Lima, Peru. Between 2007 and 2008, we conducted a quantitative behavioral survey with 547 MSM followed by qualitative individual and group interviews with 36 MSM from Lima, Peru. Approximately half of all participants in the quantitative survey (50.3%) reported using commercial lubricant during intercourse occasionally or consistently during the preceding two months, with lack of availability at the time of intercourse the most commonly reported reason for non-use. No clear preferences regarding the color, smell, taste, or viscosity of commercial lubricants were identified, and all participants who reported using a commercial lubricant used the same product (“Love-Lub”). In the qualitative analysis, participants characterized lubricant use as a sexual practice consistently controlled by the receptive partner, who typically obtained and applied lubricant independently, with or without the consent of the insertive partner. Quantitative findings supported this differential pattern of lubricant use, with men who reported sexual identities or roles consistent with receptive anal intercourse, including unprotected receptive intercourse, more likely to report lubricant use than MSM who claimed an exclusively insertive sexual role. Given the social, behavioral, and biological factors contributing to increased vulnerability for HIV and STI acquisition by the receptive partner in anal intercourse, delivery of a topical rectal microbicide as a lubricant formulation could provide an important HIV prevention resource for at-risk MSM in Lima, Peru.
doi:10.1080/09540121.2012.726335
PMCID: PMC3556347  PMID: 23082796
18.  Increasing safer sexual behavior among Lao kathoy through an integrated social marketing approach 
BMC Public Health  2011;11:872.
Background
Although HIV prevalence has remained low in Laos thus far, there is reason to be concerned that Lao male-to-female (MtF) transgender persons (kathoy) and their partners may facilitate the spread of HIV. Little is known about how to most effectively reach kathoy with HIV prevention programming. This paper evaluates an intervention with Lao kathoy with the objective of increasing safe sex with regular and casual partners.
Methods
Quantitative surveys were administered in November 2004 (n = 288) and June 2006 (n = 415) using time location sampling at venues where kathoy were known to congregate. Respondents were aged 15-35 and from three urban centers in Laos. UNIANOVA tests were used to compare baseline and follow-up survey data and to evaluate the impact of PSI's kathoy-specific interventions on items that changed significantly over time.
Results
Exposure to the intervention was associated with higher levels of condom use at last anal sex with casual partners and greater use of water-based lubricant. Exposure was also linked to improved perceptions of product availability for condoms and water-based lubricant. Knowledge about the importance of consistent condom use improved over time as well as the need to use condoms with regular partners. Some HIV knowledge decreased over time and the intention to use condoms with casual partners when water-based lubricant is available also declined.
Conclusions
Study results demonstrate the feasibility of reaching kathoy with an integrated social marketing approach; combining product promotion, peer education, and other types of interpersonal communication. The approach was successful at increasing condom use with casual partners and water-based lubricant use, but the importance of using condoms along with water-based lubricant must be emphasized and modified strategies are required for improving condom use with boyfriends. Future messages should emphasize consistent condom use with all types of partners as well as improve knowledge and correct misconceptions about HIV and AIDS, STIs, condom use, and lubricant use. It is also important that authorities create an enabling environment to support such interventions and help foster behavior change.
doi:10.1186/1471-2458-11-872
PMCID: PMC3257214  PMID: 22087632
19.  Oxidative Stress Markers Induced by Hyperosmolarity in Primary Human Corneal Epithelial Cells 
PLoS ONE  2015;10(5):e0126561.
Oxidative stress has been known to be involved in pathogenesis of dry eye disease. However, few studies have comprehensively investigated the relationship between hyperosmolarity and oxidative damage in human ocular surface. This study was to explore whether and how hyperosmolarity induces oxidative stress markers in primary human corneal epithelial cells (HCECs). Primary HCECs were established from donor limbal explants. The hyperosmolarity model was made in HCECs cultured in isosmolar (312 mOsM) or hyperosmotic (350, 400, 450 mOsM) media. Production of reactive oxygen species (ROS), oxidative damage markers, oxygenases and anti-oxidative enzymes were analyzed by DCFDA kit, RT-qPCR, immunofluorescent and immunohistochemical staining and Western blotting. Compared to isosmolar medium, ROS production significantly increased at time- and osmolarity-dependent manner in HCECs exposed to media with increasing osmolarities (350–450 mOsM). Hyperosmolarity significantly induced oxidative damage markers in cell membrane with increased toxic products of lipid peroxidation, 4–hydroxynonenal (4-HNE) and malondialdehyde (MDA), and in nuclear and mitochondria DNA with increased aconitase-2 and 8-OHdG. Hyperosmotic stress also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), but reduced the levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), and glutathione peroxidase-1 (GPX1). In conclusion, our comprehensive findings demonstrate that hyperosmolarity induces oxidative stress in HCECs by stimulating ROS production and disrupting the balance of oxygenases and antioxidant enzymes, which in turn cause cell damage with increased oxidative markers in membrane lipid peroxidation and mitochondrial DNA damage.
doi:10.1371/journal.pone.0126561
PMCID: PMC4449087  PMID: 26024535
20.  Use of Saliva as a Lubricant in Anal Sexual Practices Among Homosexual Men 
Objectives
Compared with other sexually active adults, men who have sex with men (MSM) are more frequently infected with several pathogens including cytomegalovirus, hepatitis B virus, and Kaposi sarcoma-associated herpesvirus. Because one common element between these organisms is their presence in saliva, we evaluated saliva exposure among MSM in a heretofore relatively unrecognized route—via use of saliva as a lubricant in anal sex.
Methods
MSM in a San Francisco population–based cohort were interviewed regarding use of saliva by the insertive partner as a lubricant in various anal sexual practices.
Results
Among 283 MSM, 87% used saliva as a lubricant in insertive or receptive penile–anal intercourse or fingering/fisting at some point during their lifetime; 31%–47% did so, depending upon the act, in the prior 6 months. Saliva use as a lubricant was more common among younger men and among HIV-infected men when with HIV-infected partners. Even among MSM following safe sex guidelines by avoiding unprotected penile–anal intercourse, 26% had anal exposure to saliva via use as a lubricant.
Conclusions
Among MSM, use of saliva as a lubricant is a common, but not ubiquitous, practice in anal sex. The findings provide the rationale for formal investigation of whether saliva use in this way contributes to transmission of saliva-borne pathogens in MSM.
doi:10.1097/QAI.0b013e31819388a9
PMCID: PMC3975591  PMID: 19131893
homosexual; saliva; lubricant; anal intercourse
21.  Acceptability and Use of Sexual Barrier Products and Lubricants among HIV-Seropositive Zambian Men 
AIDS Patient Care and STDs  2008;22(12):1015-1020.
Abstract
This study assessed the acceptability and preference for sexual barrier and lubricant products among men in Zambia following trial and long-term use. It also examined the role of men's preferences as facilitators or impediments to product use for HIV transmission reduction within the Zambian context. HIV-seropositive and - serodiscordant couples were recruited from HIV voluntary counseling and testing centers in Lusaka between 2003 and 2006; 66% of those approached agreed to participate. HIV seropositive male participants participated in a product exposure group intervention (n = 155). Participants were provided with male and female condoms and vaginal lubricants (Astroglide® [BioFilm, Inc., Vista, CA] & KY® gels [Johnson & Johnson, Langhorne, PA], Lubrin® suppositories [Kendwood Therapuetics, Fairfield, NJ]) over three sessions; assessments were conducted at baseline, monthly over 6 months and at 12 months. At baseline, the majority of men reported no previous exposure to lubricant products or female condoms and high (79%) levels of consistent male condom use in the last 7 days. Female condom use increased during the intervention, and male condom use increased at 6 months and was maintained over 12 months. The basis for decisions regarding lubricant use following product exposure was most influenced by a preference for communicating with partners; participant preference for lubricant products was distributed between all three products. Results illustrate the importance of development of a variety of products for prevention of HIV transmission and of inclusion of male partners in interventions to increase sexual barrier product use to facilitate barrier acceptability and use in Zambia.
doi:10.1089/apc.2007.0212
PMCID: PMC2929379  PMID: 19072108
22.  Characterization of Commercially Available Vaginal Lubricants: A Safety Perspective 
Pharmaceutics  2014;6(3):530-542.
Vaginal lubricants are widely used by women to help solve intercourse difficulties or as enhancers, but recent reports raise questions about their safety. Twelve commercially available gel products were tested for pH value, pH buffering capacity, osmolality and cytotoxicity relevant to vaginal delivery. Obtained data were analyzed in light of the recent Advisory Note by the World Health Organization (WHO) for personal lubricants to be concomitantly used with condoms. Results showed that most products do not comply with pH and osmolality recommended standards, thus posing a potential hazard. Four products presented values of osmolality around three-times higher than the maximum acceptable limit of 1200 mOsm/kg. In vitro cell testing further identified substantial cytotoxicity even at 1:100 dilutions for three products, contrasting with no significant effect of up to at least a 1:5 dilution of a Universal Placebo gel. However, no direct correlation between these last results and pH or osmolality was found, thus suggesting that the individual toxicity of specific formulation components plays an important role in the outcome of a particular product. Although further assessment is required, these results highlight potential safety issues related to the formulation of commercially available vaginal lubricants.
doi:10.3390/pharmaceutics6030530
PMCID: PMC4190534  PMID: 25247884
vaginal drug delivery; microbicides; buffer capacity; osmolality; cytotoxicity
23.  Progenitor cell therapy for traumatic brain injury: effect of serum osmolarity on cell viability and cytokine production 
Regenerative medicine  2010;5(1):65.
Introduction
The potential translation of mesenchymal stem cell (MSC) therapy into a multimodal protocol for traumatic brain injury requires evaluation of viability and cytokine production in a hyperosmolar environment. Optimization of MSC therapy requires delivery to the target area without significant loss of cellular function or viability. No model evaluating the potential efficacy of MSC therapy at varying osmolarities currently exists.
Methods
Rat MSCs were characterized with flow cytometric immunophenotyping. MSCs (passage 3) were placed in culture with multipotent adult progenitor cell media at varying osmolarities (250, 270, 290, 310, 330, 350 and 370 mOsm) potentially found with hypertonic saline infusion. After culture for 24 h, cellular viability was measured using flow cytometry (n = 6). Next, brain tissue supernatant was harvested from both normal rat brains and injured brains 6 h after cortical injury. Subsequently, MSCs were placed in culture with multipotent adult progenitor cell media ± 20% normal brain or injured brain supernatant (at the aforementioned osmolarities) and allowed to remain in culture for 24 h (n = 11). At this point, media supernatant cytokine levels were measured using a multiplex cytokine assay system.
Results
MSCs showed no clinically significant difference in viability at 24 h. MSCs cultured with 20% injured brain supernatant showed an decrease in proinflammatory cytokine production (IL-1α and IL-1β) with increasing osmolarity. No difference in anti-inflammatory cytokine production (IL-4 and IL-10) was observed.
Conclusion
Progenitor cell therapy for traumatic brain injury may require survival and activity in a hyperosmolar environment. Culture of MSCs in such conditions shows no clinically significant effect on cell viability. In addition, MSC efficacy could potentially be enhanced via a decrease in proinflammatory cytokine production. Overall, a multimodal traumatic brain injury treatment protocol based upon MSC infusion and hypertonic saline therapy would not negatively affect progenitor cell efficacy and could be considered for multicenter clinical trials.
doi:10.2217/rme.09.73
PMCID: PMC2823122  PMID: 20017695
cytokines; inflammation; mesenchymal stem cells; osmolarity
24.  Characterization of UC781-Tenofovir Combination Gel Products for HIV-1 Infection Prevention in an Ex Vivo Ectocervical Model 
HIV continues to be a problem worldwide. Topical vaginal microbicides represent one option being evaluated to stop the spread of HIV. With drug candidates that have a specific action against HIV now being studied, it is important that, when appropriate and based on the mechanism of action, the drug permeates the tissue so that it can be delivered to specific targets which reside there. Novel formulations of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) and the nonnucleoside reverse transcriptase inhibitor UC781 have been developed and evaluated here. Gels with three distinct rheological properties were prepared. The three gels released both UC781 and TFV under in vitro conditions at concentrations equal to or above the reported 50% effective concentrations (EC50s). The drug concentrations in ectocervical tissues were well in excess of the reported EC50s. The gels maintain ectocervical viability and prevent infection of ectocervical explants after a HIV-1 challenge. This study successfully demonstrates the feasibility of using this novel combination of antiretroviral agents in an aqueous gel as an HIV infection preventative.
doi:10.1128/AAC.06284-11
PMCID: PMC3370776  PMID: 22430977
25.  Effect of topical vaginal products on the detection of prostate-specific antigen, a biomarker of semen exposure, using ABAcards☆,☆☆ 
Contraception  2012;88(3):382-386.
Background
Prostate-specific antigen (PSA) is a biomarker of recent semen exposure. There is currently only limited information on whether topical vaginal products affect PSA assays. We investigated this question using various dilutions of several vaginal products (lubricants and spermicides) and the Abacus ABAcard for PSA detection.
Study Design
Pooled semen controls and various dilutions of nonoxynol-9 (N9), carboxymethyl cellulose (CMC), Replens, Gynol 2, K-Y jelly, Astroglide, Surgilube, combined with pooled semen dilutions, were tested for PSA using the Abacus ABAcard.
Results
N9 (2% with saline) and CMC did not appear to affect the results of testing with the ABAcard, but not all semen dilutions were tested. The other products (including Replens and Gynol, which is 2% N9 with propylene glycol, K-Y, Astroglide and Surgilube) at some of the dilutions tested either affected or gave invalid results with PSA testing using the ABAcard. Both Gynol 2 and K-Y at 1:10 dilution gave false-positive results.
Conclusions
Some vaginal products affect PSA results obtained by using the semiquantitative ABAcard. In vivo confirmation is necessary to further optimize PSA detection when topical vaginal products are present.
doi:10.1016/j.contraception.2012.10.034
PMCID: PMC4547343  PMID: 23218862
Vaginal products; PSA; Semen; Biomarker; ABAcard; Lubricants; Spermicide

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