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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.
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.
PMCID: PMC3161103  PMID: 21309617
2.  In Vitro and Ex Vivo Testing of Tenofovir Shows It Is Effective As an HIV-1 Microbicide 
PLoS ONE  2010;5(2):e9310.
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.
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.
PMCID: PMC2824823  PMID: 20174579
3.  Effect of Vaginal Lubricants on Natural Fertility 
Obstetrics and gynecology  2012;120(1):44-51.
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.
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.
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.
Lubricants are commonly used by couples during procreative intercourse. Lubricant use during procreative intercourse does not appear to reduce the probability of conceiving.
PMCID: PMC3427535  PMID: 22914390
4.  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.
PMCID: PMC2751015  PMID: 11741271
Tableting; Trypsin; Preparation; Compression; Dissolution
5.  Reformulated tenofovir gel for use as a dual compartment microbicide 
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.
Reduced glycerine (RG)-tenofovir gel was compared with the original tenofovir gel for physiochemical characteristics, product safety and anti-HIV-1 activity.
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.
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.
PMCID: PMC3417689  PMID: 22581908
HIV prevention; rectal microbicide; formulation; preclinical testing; safety
6.  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.
PMCID: PMC3708353  PMID: 23841994
lubricants; condoms; HIV prevention; Africa
7.  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.
PMCID: PMC2855760  PMID: 19636696
Sexual pleasure; HIV/STI prevention; vaginal Microbicide; pregnancy prevention
8.  Increasing safer sexual behavior among Lao kathoy through an integrated social marketing approach 
BMC Public Health  2011;11:872.
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.
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.
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.
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.
PMCID: PMC3257214  PMID: 22087632
9.  Preventing Friction Induced Chondrocyte Apoptosis: A Comparison of Human Synovial Fluid and Hylan G-F 20 
The Journal of rheumatology  2012;39(7):1473-1480.
Symptomatic osteoarthritis (OA) is a common painful disease with limited treatment options. A rising number of OA patients have been treated with intraarticular injections of hyaluronic acid, including the high molecular weight hylan G-F 20, which is injected following arthrocentesis. This study investigated the effectiveness of hylan G-F 20 to lower coefficient of friction (COF) and prevent chondrocyte apoptosis in vitro.
A disc-on-disc bovine cartilage bearing was used to measure the static and kinetic COF when lubricated with hylan G-F 20, human synovial fluid (HSF) and phosphate buffered saline (PBS). Following friction testing, we stained paraffin embedded sections of these cartilage bearings for activated caspase-3, a marker of apoptosis.
Bearings lubricated with hylan G-F 20 had kinetic COF values that were similar to bearings lubricated with PBS, but significantly higher than those lubricated with HSF. There were no significant differences in static COF values in bearings lubricated with hylan G-F 20 as compared to PBS or HSF. However, bearings lubricated with HSF had a significantly lower static COF values compared to bearings lubricated with PBS. The mean percentage of caspase-3 positive chondrocytes in the superficial and upper intermediate zones of bearings lubricated with hylan G-F 20 were significantly higher when compared to bearings lubricated with HSF or unloaded controls, but significantly lower than those lubricated with PBS.
These findings indicate that joint lubrication may prevent chondrocyte apoptosis by lowering the COF. Furthermore, removal of synovial fluid prior to hylan G-F 20 injection may be detrimental to cartilage health.
PMCID: PMC3605976  PMID: 22660808
articular cartilage; chondrocyte; apoptosis; synovial fluid; hylan
10.  Use of Saliva as a Lubricant in Anal Sexual Practices Among Homosexual Men 
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.
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.
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.
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.
PMCID: PMC3975591  PMID: 19131893
homosexual; saliva; lubricant; anal intercourse
11.  Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomised controlled trial 
Lancet  2007;370(9583):251-261.
Female-controlled methods of HIV prevention are urgently needed. We assessed the effect of provision of latex diaphragm, lubricant gel, and condoms (intervention), compared with condoms alone (control) on HIV seroincidence in women in South Africa and Zimbabwe.
We did an open-label, randomised controlled trial in HIV-negative, sexually active women recruited from clinics and community-based organisations, who were followed up quarterly for 12–24 months (median 21 months). All participants received an HIV prevention package consisting of pre-test and post-test counselling about HIV and sexually transmitted infections, testing, treatment of curable sexually transmitted infections, and intensive risk-reduction counselling. The primary outcome was incident HIV infection. This study is registered with, number NCT00121459.
Overall HIV incidence was 4.0% per 100 woman-years: 4.1% in the intervention group (n=2472) and 3.9% in the control group (n=2476), corresponding to a relative hazard of 1.05 (95% CI 0.84–1.32, intention-to-treat analysis). The proportion of women using condoms was significantly lower in the intervention than in the control group (54% vs 85% of visits, p<0.0001). The proportions of participants who reported adverse events (60% [1523] vs 61% [1529]) and serious adverse events (5% [130] vs 4% [101]) were similar between the two groups.
We observed no added protective benefit against HIV infection when the diaphragm and lubricant gel were provided in addition to condoms and a comprehensive HIV prevention package. Our observation that lower condom use in women provided with diaphragms did not result in increased infection merits further research. Although the intervention seemed safe, our findings do not support addition of the diaphragm to current HIV prevention strategies.
PMCID: PMC2442038  PMID: 17631387
12.  The slippery slope: Lubricant Use and Rectal Sexually Transmitted Infections: a newly identified risk 
Sexually transmitted diseases  2012;39(1):59-64.
Use of lubricant products is extremely common during receptive anal intercourse (RAI) yet has not been assessed as a risk for acquisition of sexually transmitted infections (STIs).
From 2006–2008 a rectal health and behavior study was conducted in Baltimore and Los Angeles as part of the UCLA Microbicide Development Program (NIAID IPCP# #0606414). Participants completed questionnaires and rectal swabs were tested for Neisseria gonorrhoeae and Chlamydia trachomatis with the Aptima Combo 2 assay and blood was tested for syphilis (for RPR and TPHA with titer) and HIV. Of those reporting lubricant use and RAI, STI results were available for 380 participants. Univariate and multivariate regressions assessed associations of lubricant use in the past month during RAI with prevalent STIs.
Consistent lubricant use during RAI in the past month was reported by 36% (137/380) of participants. Consistent past month lubricant users had a higher prevalence of STI than inconsistent users (9.5% vs. 2.9%; p=0.006). In a multivariable logistic regression model testing positive for STI was associated with consistent use of lubricant during RAI in the past month (adjusted Odds Ratio (AOR) 2.98 (95%CI 1.09, 8.15) after controlling for age, gender, study location, HIV status, and numbers of RAI partners in the past month.
Findings suggest some lubricant products may increase vulnerability to STIs. Because of wide use of lubricants and their potential as carrier vehicles for microbicides, further research is essential to clarify if lubricant use poses a public health risk.
PMCID: PMC3244680  PMID: 22183849
rectal sexually transmitted infections; lubricants; rectal health
13.  Acceptability and Use of Sexual Barrier Products and Lubricants among HIV-Seropositive Zambian Men 
AIDS Patient Care and STDs  2008;22(12):1015-1020.
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.
PMCID: PMC2929379  PMID: 19072108
14.  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.
PMCID: PMC2862605  PMID: 19908966
15.  A study on risk factors associated with inconsistent condom and lubricant use among men who have sex with men in central Karnataka, India 
The Australasian Medical Journal  2011;4(10):469-473.
Among the sexual minority groups, the Men who have Sex with Men (MSM) community is a large and scattered network. Sexual activity among MSM is frequent and often unplanned. STI and HIV are major medical problems faced by this vulnerable group. Stigma and discrimination towards this group result in poor access to preventive services that encourage condom and lubricant usage.
A cross-sectional, community-based study of 309 MSM was carried out in the Davangere district between December 2008 and February 2010. Participants were identified in three stages: cruising venue identification and mapping; determining eligibility and willingness to participate; and recruitment to the study. Consecutive sampling was used to recruit the participants with the help of a snowball technique, obtaining informed and written consent.
Of the participants 79.61% and 88.03% reported inconsistent use of condom and lubricant during the three months prior to the interview, respectively. In multivariate analysis, middle socioeconomic class, sex in a public place and increased frequency of sex were significantly associated with inconsistent condom use. Whereas, practising both types of anal sex (receptive and insertive), not using a condom during the last sexual encounter and increased frequency of sex were significantly associated with inconsistent lubricant use.
Many social and behavioural factors are involved in the inconsistent use of condom and lubricant among MSM. Preventive programmes must identify these factors in order to target consistent condom and lubricant use among the MSM community.
PMCID: PMC3562872  PMID: 23386862
Inconsistent condom use; Men who have Sex with Men; Human Immunodeficiency Virus; Sexual risk behaviour
16.  The consequences of yield stress on deployment of a non-Newtonian anti-HIV microbicide gel 
Journal of non-Newtonian fluid mechanics  2011;166(19-20):1116-1122.
A recent study in South Africa has confirmed, for the first time, that a vaginal gel formulation of the antiretroviral drug Tenofovir, when applied topically, significantly inhibits sexual HIV transmission to women [10]. However the gel for this drug, and anti-HIV microbicide gels in general, have not been designed using full understanding of how gel spreading and retention in the vagina govern successful drug delivery. Elastohydrodynamic lubrication theory can be applied to model such spreading of microbicide gels, which are inherently non-Newtonian [13,15]. A yield stress is emerging as one of the important properties of microbicide gel vehicle deployment, as this may improve retention within the vaginal canal. On the other hand, a yield stress may decrease the initial extent of the coating flow. Here, we first explain a certain yield stress paradox observed generally in many lubrication flows. Four conditions are determined, via scaling analysis, which mitigate the inconsistency in the use of lubrication theory to analyze the specific problem of elastic wall squeezing flow of yield stress fluid. Parameters characterizing these conditions are obtained experimentally for a test gel. Using them, it is shown that the lubrication approximation may be applied to the elastic wall-squeezing problem for this gel.
PMCID: PMC3342340  PMID: 22563138
Yield stress; Carreau fluid; Lubrication flow; Anti-HIV microbicide; Squeezing flow; Biviscosity model
17.  The Diaphragm and Lubricant Gel for Prevention of Cervical Sexually Transmitted Infections: Results of a Randomized Controlled Trial 
PLoS ONE  2008;3(10):e3488.
We evaluated the effectiveness of the Ortho All-Flex Diaphragm, lubricant gel (Replens®) and condoms compared to condoms alone on the incidence of chlamydial and gonococcal infections in an open-label randomized controlled trial among women at risk of HIV/STI infections.
We randomized 5045 sexually-active women at three sites in Southern Africa. Participants who tested positive for curable STIs were treated prior to enrollment as per local guidelines. Women were followed quarterly and tested for Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (GC) infection by nucleic-acid amplification testing (Roche Amplicor®) using first-catch urine specimens. STIs detected at follow-up visits were treated. We compared the incidence of first infection after randomization between study arms in both intent-to-treat (ITT) and per-protocol populations.
Baseline demographic, behavioral and clinical characteristics were balanced across study arms. Nearly 80% of participants were under 35 years of age. Median follow-up time was 21 months and the retention rate was over 93%. There were 471 first chlamydia infections, 247 in the intervention arm and 224 in the control arm with an overall incidence of 6.2/100 woman-years (wy) (relative hazard (RH) 1.11, 95% Confidence Interval (CI): 0.93–1.33; p = 0.25) and 192 first gonococcal infections, 95 in the intervention arm and 97 in the control arm with an overall incidence of 2.4/100wy (RH 0.98, 95%CI: 0.74–1.30; p = 0.90). Per protocol results indicated that when diaphragm adherence was defined as “always use” since the last visit, there was a significant reduction in the incidence of GC infection among women randomized to the intervention arm (RH 0.61, 95%CI: 0.41–0.91, P = 0.02).
There was no difference by study arm in the rate of acquisition of CT or GC. However, our per-protocol results suggest that consistent use of the diaphragm may reduce acquisition of GC.
Trial Registration NCT00121459 [NCT00121459]
PMCID: PMC2567030  PMID: 18941533
18.  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.
PMCID: PMC4190534  PMID: 25247884
vaginal drug delivery; microbicides; buffer capacity; osmolality; cytotoxicity
19.  Alkyl Polyglucosides as Components of Water Based Lubricants 
Water can be used as an ecological lubricant base if it is possible to select additives which can beneficially modify its tribological and corrosion properties. Additionally, those additives should not be harmful to human health and the natural environment. These conditions limit or even eliminate the possibility for the application of the additives used in traditional oil bases as they are insoluble in water and often toxic. Alkyl polyglucosides (APGs) have been suggested as additives improving lubricating properties of water. They are biodegradable and do not have to be recycled. They exhibit surface activity. They produce micelles at low concentration and lyotropic liquid crystals at high concentration. Two types of alkyl polyglucosides differing in alkyl chain lengths and degrees of polymerization were used in this investigation. Tribological tests were carried out using a ball-on-disc T-11 tester. The balls were made of steel, whereas the discs were made of steel, aluminium oxide, zirconium oxide, polyamide and poly(methyl methacrylate). The description of the device and the methods has been given in the literature (Szczerek and Tuszyński in TriboTest 8:273–284, 2002). The addition of APGs improves the lubricating properties of water. The relative decrease in motion resistance and wear depends both on the type of friction couple and on the kind of alkyl polyglucoside used. The tribological test results obtained were correlated with the activity of APGs measured as wettability of friction couples by their solutions.
PMCID: PMC3629283  PMID: 23606804
Friction coefficient; Wear; Lubricants; Surfactants
20.  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.
PMCID: PMC3556347  PMID: 23082796
21.  Progenitor cell therapy for traumatic brain injury: effect of serum osmolarity on cell viability and cytokine production 
Regenerative medicine  2010;5(1):65.
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.
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.
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.
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.
PMCID: PMC2823122  PMID: 20017695
cytokines; inflammation; mesenchymal stem cells; osmolarity
22.  Effects of feminine hygiene products on the vaginal mucosal biome 
Microbial Ecology in Health and Disease  2013;24:10.3402/mehd.v24i0.19703.
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.
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.
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.
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.
PMCID: PMC3758931  PMID: 24009546
Lactobacillus; L. crispatus; cytokines; Interleukin-8; Nonoxynol-9; vaginal microbiota; vaginal epithelial colonization; mucosal immunity
23.  N-Acetylcarnosine sustained drug delivery eye drops to control the signs of ageless vision: Glare sensitivity, cataract amelioration and quality of vision currently available treatment for the challenging 50,000-patient population 
Innovative Vision Products, Inc. (IVP)’s scientists developed the lubricant eye drops (Can-C™) designed as 1% N-acetylcarnosine (NAC) prodrug of l-carnosine containing a mucoadhesive cellulose-based compound combined with corneal absorption promoters in a sustained drug delivery system. Only the natural l-isomeric form of NAC raw material was specifically synthesized at the cGMP facility and employed for the manufacturing of Can-C™ eye drops.
Objective and study design:
In the present clinical study the authors assessed vision before and after 9 month term of topical ocular administration of NAC lubricant eye drops or placebo in 75 symptomatic patients with age-related uncomplicated cataracts in one or both eyes, with acuity in one eye of 20/40 or worse (best-corrected distance), and no previous cataract surgery in either eye and no other ocular abnormality and 72 noncataract subjects ranged in age from 54 to 78 years.
Subjects in these subsample groups have reported complaints of glare and wanted to administer eye drops to get quick eye relief and quality of vision for their daily activities including driving and computer works. Following 9 months of treatment with NAC lubricant eye drops, most patients’ glare scores were improved or returned to normal in disability glare tests with Halometer DG. Improvement in disability glare was accompanied with independent improvement in acuity. Furthermore, patients with the poorest pretreatment vision were as likely to regain certain better visual function after 9 months of treatment with N-acetylcarnosine lubricant eye drops as those with the worth pretreatment vision.
Patients or other participants:
The authors made a reference to electronic records of the product sales to patients who have been made the repurchase of the Can-C™ eye drops since December 2001.
Based on this analysis of recorded adjustments to inventory, various parameters were analyzed during the continued repurchase behavior program, including testimonials from buyers. With these figures, researchers judged on the patients’ compliance rate to self-administer NAC eye-drops.
Main outcome measure and results:
The ophthalmic drug showed potential for the non-surgical treatment of age-related cataracts for participants after controlling for age, gender and daily activities and on a combined basis of repurchases behavior reports in more than 50,000 various cohort survivors, has been demonstrated to have a high efficacy and good tolerability for prevention and treatment of visual impairment determined for the older population with relative stable pattern of causes for blindness and visual impairment. The mechanisms of prevention and reversal of cataracts with NAC ophthalmic drug are considered which include prevention by the intraocular released carnosine of free-radical-induced inactivation of proprietary lens antioxidant enzymes (superoxide dismutase); prevention of carbohydrate and metal-catalyzed autooxidation of ascorbic acid-induced cross-linking glycation reactions to the lens proteins; transglycation properties of carnosine, allowing it to compete for the glycating agent, protecting proteins (lens crystallins) against modification; universal antioxidant and scavenging activity towards lipid hydroperoxides, aldehydes and oxygen radicals; activation with l-carnosine ingredient of proteasome activity in the lens; chaperone-like disaggregating to lens crystallins activity of NAC and of its bioactivated principal carnosine. Blindness incidence increased with advancing age, such as cataract and glaucoma, which are by far the commonest causes of blindness in our sample and in all age groups, glaucomatous neurodegeneration can be treated with developed NAC autoinduction prodrug eye drops equipped with corneal absorption promoters. The common blinding affections presenting in developed countries such as, senile macular degeneration, hereditary chorioretinal dystrophies, diabetic retinopathy are poorly represented in our current summary of vital-statistics and will be reported inherent in next N-acetylcarnosine ophthalmic drug studies.
The authors present evidence, about why only a certain kind of NAC is safe, and why only certain formulas designed by IVP for drug discovery are efficacious in the prevention and treatment of senile cataract for long-term use. Overall cumulated studies demonstrate that the designed by IVP new vision-saving drug NAC eye drops help the aging eye to recover by improving its clarity, glare sensitivity, color perception and overall vision.
PMCID: PMC2685223  PMID: 19503764
age-related ophthalmic diseases; cataract; disability-glare; halos; Halometer; visual-acuity; N-acetylcarnosine lubricant eye drops; repurchase behavior analysis; 50,000-patients’ compliance to self-administer eye drops
24.  Effect of various analgesics and lubricants on isolation of Chlamydia trachomatis and Neisseria gonorrhoeae. 
Journal of Clinical Microbiology  1982;15(3):522-524.
Five preparations used as analgesics or lubricants in surgical, obstetrical, gynecological, and investigative procedures were tested for their effect on the isolation of Chlamydia trachomatis. Three lignocaine preparations and a lubricating jelly containing 2% phenol were inhibitory to chlamydiae. In contrast, K-Y lubricating jelly was relatively nontoxic to chlamydiae. Since K-Y jelly also had only slight toxic activity against gonococci, it is recommended for the lubrication of instruments which need to be used for the efficient isolation of these microorganisms.
PMCID: PMC272129  PMID: 6804489
25.  Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells 
Molecular Vision  2010;16:1791-1800.
Increasing evidence suggests that tear hyperosmolarity is a central mechanism causing ocular surface inflammation and damage in dry eye disease. Mapracorat (BOL-303242-X) is a novel glucocorticoid receptor agonist currently under clinical evaluation for use in the treatment of dry eye disease. This study assessed the anti-inflammatory effects of mapracorat in an in vitro osmotic stress model which mimics some of the pathophysiological changes seen in dry eye.
Human corneal epithelial cells were cultured in normal osmolar media (317 mOsM) or 440 mOsM hyperosmolar media for 24 h. Luminex technology was used to determine the effect of mapracorat on hyperosmolar-induced cytokine release. Effects of mapracorat on mitogen-activated protein kinase (MAPK) phosphorylation were determined by cell based ELISA. Effects of mapracorat on nuclear factor kappa B (NFκB) and activator protein-1 (AP-1) transcriptional activity were assessed by reporter gene assay. Dexamethasone was used as a control.
Hyperosmolar conditions induced release of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) from cultured human corneal epithelial cells, and altered the phosphorylation state of p38 and c-Jun N-terminal kinase (JNK) and transcriptional activity of NFκB and AP-1. Incubation of cells with mapracorat inhibited hyperosmolar-induced cytokine release with comparable activity and potency as dexamethasone. This inhibition was reversed by the glucocorticoid receptor antagonist mifepristone (RU-486). Increased phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat. Mapracorat also significantly decreased the hyperosmolar-induced increase in NFκB and AP-1 transcriptional activity.
Mapracorat acts as a potent anti-inflammatory agent in corneal epithelial cells challenged with osmotic stress, with comparable activity to the traditional steroid dexamethasone. These in vitro data suggest that mapracorat may be efficacious in the treatment of dry eye disease.
PMCID: PMC2932489  PMID: 20824100

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