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Mucosal Irritation Potential of Personal Lubricants Relates to Product Osmolality as Detected by the Slug Mucosal Irritation Assay
Abstract
The slug mucosal irritation assay has recently been used as a sensitive measure of mucus membrane tolerance for vaginal microbicide products and carriers. In the current study, it was determined whether musosal irritation potency of personal lubricants is related to varying product osmolalities.
Five commercial lubricants with an osmolality range were evaluated using the previously validated slug mucosal irritation assay. Specifically, Arion lusitanicus were treated with lubricants over 5 days to quantify mucus production and tissue damage, allowing assignment of each product into an irritation potency category (none, mild, moderate, or severe).
The irritation potency (assessed by the mucus production) of the lubricants showed a significant, quadratic relationship with the product osmolality (P = 0.001; R (2) = 0.99). Femglide, a hypo-osmotic lubricant (32 mOsm/kg), caused a negative mucus production. Pré, an iso-osmotic lubricant (316 mOsm/kg), caused no changes. Two moderately hyperosmotic lubricants, Replens and K-Y jelly (2143 and 2463 mOsm/kg), induced mild and moderate irritation, respectively. The highly hyperosmotic lubricant Astroglide (5848 mOsm/kg) resulted in severe irritation and tissue damage.
Commonly used personal lubricants show a full range of mucosal irritation potential, which is related to product osmolality.
... Regardless of the lubricant testing regulations, several studies have assessed lubricant safety since the late 1990s (7)(8)(9)(10)(11)(12)(13)(14) . These evaluations demonstrated epithelial damage and irritation, raising concerns regarding safety, and leading to the release of an advisory note in 2012 (15) . ...
... The authors found that rectal application of hyperosmolar lubricant led to greater epithelial injury than an iso-osmolar lubricant. In 2008, Adriaens and Remon tested several lubricants on slugs (12) . The lubricants were found to cause mild, moderate, and severe irritation corresponding to the osmolality of lubricant used. ...
... The lubricants were found to cause mild, moderate, and severe irritation corresponding to the osmolality of lubricant used. However, in contrast to Adriaens and Remon's study in slugs (12) , a study by Cunha et al. in cells showed no correlation between osmolality and cytotoxicity (19) . This study suggests the individual ingredients may be more important than the osmolality level itself. ...
... The HET-CAM assay is one of the alternatives presented by EURL-ECVAM 1 for the in vitro study of ocular irritancy (ICCVAM, 2007). Although various techniques for the characterization of vaginal formulations have been described on the literature (Garg et al., 2001(Garg et al., , 2010Adriaens and Remon, 2008;Cunha et al., 2014), most have been applied only to developing formulations with no correlation with in vivo results. The HET-CAM assay outcome consists on an Irritation Score (IS) that is a value calculated by different analysis methods (A and B), which is used to classify the irritancy potential of a test substance. ...
... The lubricants tested were: Fillergyn® gel (BSDpharma), Geliofil® Classic gel (Laboratoires Effik), GelSea® gel (LDPSA), Ginix® gel (ISUS), Ginix® Plus gel (ISUS), Hyalo Gyn® gel (Fidia Farmaceutici), K-Y® Jelly (Johnson & Johnson), Phyto Soya® gel (Arkopharma Laboratoires Pharmaceutiques), Velastisa® Intim VG moisturizer gel cream (ISDIN) and Vidermina® gel (Istituto Ganassini). Both Replens® (Laboratoires Majorelle) and Universal Placebo (Tien et al., 2005) were used as controls, since their toxicity profiles are largely described on the literature (Nachtigall, 1994;Bygdeman and Swahn, 1996;Tien et al., 2005;Valenta, 2005;Schwartz et al., 2007;Adriaens and Remon, 2008;Acartürk, 2009;Garg et al., 2010;Clark et al., 2011;Caramella et al., 2015). Universal Placebo was prepared by dissolving 2.7g of Hydroxyethyl-cellulose (2000cP) in 96.3g of water containing 0.85g of sodium chloride and 0.1g of sorbic acid. ...
... Furthermore, some other technological parameters have also been shown to be associated to the safety of vaginal products. Osmolality, in particular, it is considered a predictor for irritation (Adriaens and Remon, 2008). ...
... Both Replens ® (Laboratoires Majorelle) and Universal Placebo (Tien et al., 2005) were used as controls, since their low toxicity profiles are largely described on the literature (Nachtigall, 1994;Bygdeman and Swahn, 1996;Tien et al., 2005;Valenta, 2005;Schwartz et al., 2007;Adriaens and Remon, 2008;Acartürk, 2009;Garg et al., 2010;Clark et al., 2011;Caramella et al., 2015). Universal Placebo was prepared by dissolving 2.7 g hydroxyethylcellulose (2000cP) in 96.3 g water containing 0.85 g sodium chloride and 0.1 g sorbic acid. ...
... tentials for the eye and the vaginal epithelia are similar (ISO 10993-10, 2010). Although various non-animal techniques for the characterization of vaginal formulations have been described in the literature (Garg et al., 2001(Garg et al., , 2010Adriaens and Remon, 2008;Cunha et al., 2014), most have been applied only to developing formulations, without correlations with in vivo results having been performed. ...
... This data congruency might corroborate the need to perform several in vitro tests for a complete toxicity evaluation, since the combined results might be stronger predictors for in vivo toxicity (Samuel et al., 2016). Furthermore, osmolality has been shown to be associated with the safety of vaginal products (Adriaens and Remon, 2008). Our research group has previously reported osmolality results for the medicinal products and lubricants tested herein (Machado et al., 2017) and found that some that showed higher IS in the HET-CAM assay were also highly hyperosmolal, i.e., Lomexin ® (1446 ±20 mOsmol/kg), Colpothrophine ® (1723 ±20 mOsmol/kg), Geliofil ® (3582 ±11 mOsmol/kg), Vidermina ® (3707 ±16 mOsmol/kg), and K-Y ® Jelly (3631 ±13 mOsmol/kg) were highly hyperosmolal, all above the upper limit recommended by the WHO (1200 mOsmol/kg) (WHO, 2012;Machado et al., 2017). ...
The HET-CAM (Hen's Egg Test-Chorioallantoic Membrane) assay is an in vitro alternative to the in vivo Draize Rabbit Eye test that mimics vascular changes in the chorioallantoic membrane. This qualitative method assesses the irritancy potential of chemicals. The CAM responds to injury with an inflammatory process similar to that in the rabbit eye's conjunctival tissue. Regarding topical toxicity assessment of medical devices, ISO 10993-10 states that any skin or eye irritant material shall be directly labelled as a potential vaginal irritant without animal testing, suggesting that the irritation potential for the eye and the vaginal epithelia is similar. The aim of this work was to apply the HET-CAM assay to test the irritancy potential of vaginal formulations. Vaginal semisolid medicines and lubricants currently marketed were tested along with the Universal Placebo formulation that has been shown to be clinically safe. Nonoxynol-9 (N-9), a known vaginal irritant, was enrolled as positive control (concentrations ranging from 0.001 to 100% (v/v)). The assay was conducted according to the ICCVAM - Recommended test method (NIH Publication No. 10-7553 - 2010). Formulations were then classified according to irritation score (IS), using the analysis methods (A) and (B). The studied vaginal formulations showed low potential for irritation. N-9 was classified as a severe irritant at concentrations above 2%, which corroborates clinical data, envisaging a possible in vitro/in vivo correlation. IS (B) was considered a better classification output. Although still requiring further validation, the HET-CAM assay seems an ideal prospect for vaginal irritancy potential in vitro studies.
... Hyperosmolal lubricants containing spermicides such as nonoxynol-9 (N-9) induce exfoliation or shedding of the outer layers of the human colorectal epithelium and reduce its barrier properties [1][2][3]; both these toxic effects are thought likely to increase risk of acquiring and transmitting sexually transmitting infections such as HIV and Herpes Simplex Virus (HSV). Mucosal irritation has been shown to increase with increasing hyperosmolality of several commercially available vaginal lubricants using the slug mucosal irritation assay [4] and perhaps most importantly, to significantly increase vaginal transmission of genital herpes infections in the mouse/HSV model [5]. Lastly, use of some vaginal lubricants is associated with increased incidence of bacterial vaginosis (BV) [6][7][8][9][10]. ...
... The hypo-osmolal agents, including deionized water, showed no evident toxicity in the reconstructed EpiVaginal tissue model. This surprising result is consistent with earlier reports in the slug mucosal model [4] and in the mouse vaginal model [5] as well as the quite modest effects of tap water in the human colo-rectum [3]. ...
... The presence of glycerin as one of the ingredients might have also contributed to an increase in osmolality which resulted in the loss of apical layer in RepHresh exposed EpiVaginal tissues. The reduction in barrier function, as indicated here quantitatively by the reduction in TEER, was reported in the human colorectum [3] and the slug mucosal model [4] and later corroborated in the mouse vaginal and rectal models [5,24,25]. The shedding of the outer layers of the epithelium as a result of the toxic effects of hyperosmolal lubricants was also shown for the human colorectum [3] here we showed a similar toxic effect using human primary cell based organotypic vaginal epithelial tissue model. ...
Most of the widely used vaginal lubricants in the U.S. and Europe are strongly hyperosmolal, formulated with high concentrations of glycerol, propylene glycol, polyquaternary compounds or other ingredients that make these lubricants 4 to 30 times the osmolality of healthy vaginal fluid. Hyperosmolal formulations have been shown to cause marked toxicity to human colorectal epithelia in vivo, and significantly increase vaginal transmission of genital herpes infections in the mouse/HSV model. They also cause toxicity to explants of vaginal epithelia, to cultured vaginal epithelial cells, and increase susceptibility to HIV in target cells in cell cultures. Here, we report that the osmolality of healthy vaginal fluid is 370 ± 40 mOsm/Kg in women with Nugent scores 0–3, and that a well-characterized three-dimensional human vaginal epithelium tissue model demonstrated that vaginal lubricants with osmolality greater than 4 times that of vaginal fluid (>1500 mOsm/Kg) markedly reduce epithelial barrier properties and showed damage in tissue structure. Four out of four such lubricants caused disruption in the parabasal and basal layers of cells as observed by histological analysis and reduced barrier integrity as measured by trans-epithelial electrical resistance (TEER). No epithelial damage to these layers was observed for hypo- and iso-osmolal lubricants with osmolality of <400 mOsm/Kg. The results confirm extensive reports of safety concerns of hyperosmolal lubricants and suggest the usefulness of reconstructed in vitro vaginal tissue models for assessing safety of lubricants in the absence of direct clinical tests in humans.
... The HET-CAM assay is one of the alternatives presented by EURL-ECVAM 1 for the in vitro study of ocular irritancy (ICCVAM, 2007). Although various techniques for the characterization of vaginal formulations have been described on the literature (Garg et al., 2001(Garg et al., , 2010Adriaens and Remon, 2008;Cunha et al., 2014), most have been applied only to developing formulations with no correlation with in vivo results. The HET-CAM assay outcome consists on an Irritation Score (IS) that is a value calculated by different analysis methods (A and B), which is used to classify the irritancy potential of a test substance. ...
... The lubricants tested were: Fillergyn® gel (BSDpharma), Geliofil® Classic gel (Laboratoires Effik), GelSea® gel (LDPSA), Ginix® gel (ISUS), Ginix® Plus gel (ISUS), Hyalo Gyn® gel (Fidia Farmaceutici), K-Y® Jelly (Johnson & Johnson), Phyto Soya® gel (Arkopharma Laboratoires Pharmaceutiques), Velastisa® Intim VG moisturizer gel cream (ISDIN) and Vidermina® gel (Istituto Ganassini). Both Replens® (Laboratoires Majorelle) and Universal Placebo (Tien et al., 2005) were used as controls, since their toxicity profiles are largely described on the literature (Nachtigall, 1994;Bygdeman and Swahn, 1996;Tien et al., 2005;Valenta, 2005;Schwartz et al., 2007;Adriaens and Remon, 2008;Acartürk, 2009;Garg et al., 2010;Clark et al., 2011;Caramella et al., 2015). Universal Placebo was prepared by dissolving 2.7g of Hydroxyethyl-cellulose (2000cP) in 96.3g of water containing 0.85g of sodium chloride and 0.1g of sorbic acid. ...
... Furthermore, some other technological parameters have also been shown to be associated to the safety of vaginal products. Osmolality, in particular, it is considered a predictor for irritation (Adriaens and Remon, 2008). ...
... All products are intended for vaginal use except Colpotrophine®, which is recommended by the manufacturer for vulvar application. Universal placebo gel (Clark et al., 2011;Garg et al., 2010;Schwartz et al., 2007;Tien et al., 2005) and Replens® (Acartürk, 2009;Adriaens and Remon, 2008;Caramella et al., 2015;Valenta, 2005) were included, since they represent widely studied formulations. The comprehensive and attentive review on vaginal products classification showed us that there is misunderstanding between vaginal and intravaginal products. ...
... The osmolality was determined in triplicate using a freezing point osmometer (Osmomat 3000, Gonotec, Germany), as previously described (Adriaens and Remon, 2008;Cunha et al., 2014), on a 50 μg aliquot. The standardization was performed using three standards: distilled water (zero point), NaCl 300 mOsm/Kg and NaCl 850 mOsm/ Kg, commercially available from the equipment manufacturer. ...
... Osmolality has been highlighted, and specific recommendations have been proposed: values of 380 mOsmol/kg or lower are desirable (hypo and isosmolal), but values as high as 1200 mOsmol/kg have been considered acceptable on an interim basis (Use and procurement of additional lubricants for male and female condoms: WHO/UNFPA/FHI360 Advisory note, 2012). Available pre-clinical and clinical data support that hyperosmolal vaginal products may be related to safety issues (Adriaens and Remon, 2008), as well as detrimental effects on sperm motility, viability and chromatin quality (Agarwal et al., 2008;Kutteh et al., 1996). Vaginal products' safety goes beyond chemical toxicity to include physical parameters such as osmolality (Dezzutti et al., 2012). ...
Vaginal semisolid products are frequently used to treat vaginal infections and atrophy-related symptoms of menopause. Formulations composition and the methods for their characterization, especially those developed concerning the target epithelia, are key tools to predict in vivo results at early stages of product development. However, recent studies on this subject have been almost exclusively focused on anti-HIV preparations. The aim of this work consists on improving traditional characterization methods by using physiological parameters in order to construct predictive tools to characterize a new ideal vaginal semisolid formulation whatever target it may have. Ten vaginal antimicrobial and hormonal products already available in the market were studied (Gino-Canesten®, Sertopic®, Dermofix®, Gyno-pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®, Ovestin®, Blissel®, Colpotrophine®). Furthermore, Universal Placebo gel and Replens® were used for comparison. Products were characterized in terms of: pH and buffering capacity in a vaginal fluid simulant (VFS); osmolality - directly and upon dilution in VFS; textural parameters (firmness, adhesiveness and bioadhesion) using vaginal ex vivo porcine epithelium; and viscosity (including VFS dilution at 37°C and after administration on an ex vivo model). Interestingly, the majority of the tested commercial vaginal formulations did not present technological characteristics close to the ideal ones when tested under target biological conditions. The inclusion of such methodologic adaptations is expected to optimize cost-efficiency of new formulations development by predicting efficacy and safety profiles at early stages of product development.
... This frame depicts the relation between mucus production by slugs and osmolality of lubricant to which slugs were exposed. We generated the graph by using regression coefficients reported by Adriaens and Remon (42). For use in the classroom, instructors may simply use with attribution Figure 1 of Adriaens and Remon (42). ...
... We generated the graph by using regression coefficients reported by Adriaens and Remon (42). For use in the classroom, instructors may simply use with attribution Figure 1 of Adriaens and Remon (42). The key observation is that mucus production-a sign of irritation-increased as the osmolality of the lubricant to which slugs were exposed increased. ...
... In the present manuscript, we report on the subset of 50 eligible subjects who were selected to enroll first to the tolerance phase Microorganisms 2024, 12,1917 3 of 16 to measure vaginal pH, relative humidity, and microbiome profiles as exploratory endpoints. Subjects were randomized to one of five treatment groups (approximately 9-11 subjects per group), and stratified by three age groups (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44), and 45-65 years). Treatment groups consisted of five water-based personal lubricants (herein referred to as lubricants A to E) from two brands (Durex and KY; Reckitt, Slough, UK). ...
... The effects of personal lubricants on the vaginal microbiome remain poorly understood in vivo. Most of the published literature concerns the impact of these products on the vaginal epithelial barrier and mucosal inflammation, or ability to alleviate vaginal dryness, rather than vaginal microbiome integrity [8,[29][30][31]. Only one case-control clinical study has been published regarding self-collected vaginal swabs before and after self-reported lubricant use without controlling for lubricant type and amount used during condomless sexual intercourse [32]. ...
Vaginal mucosa undergoes physiological changes across the lifespan, such as increased pH and reduced natural lubrication which are known to impact vaginal commensal microorganisms, hence increasing the chances of vaginal infections. An improved understanding of vaginal microbiome composition in different age groups and the effect of social behaviors, such as the use of personal lubricants, could facilitate the development of new strategies to maintain good vaginal health. The objective of this study was to assess the effect of water-based lubricants on the human vaginal microbiome. Fifty females from three age groups (18–29, 30–44, and 45–65 years) with mild-to-moderate vaginal dryness were randomized to one of five lubricants (four of which were formulated to meet expert guidance on osmolality and pH). Subjects entered the study at tolerance or treatment phase (vaginal intercourse minimum once a week using assigned lubricant). Four vaginal swabs per participant were sampled during pre-(“baseline”), post-first (“2 h”, “24 h”) and post-last (“4 weeks”) lubricant application to assess bacterial and fungal diversity via amplicon sequencing. Vaginal pH and relative humidity were measured at baseline, 2 h, and 24 h post-lubricant application. Relative bacteriome abundance was statistically compared between timepoints for each lubricant group. Vaginal moisture, age, BMI, and pH were correlated with bacteriome relative abundance. Lactobacilli and Gardnerella sp. Were predominant across participants. Repeated lubricant application did not significantly alter the vaginal bacteriome during 4 weeks of product use (p > 0.05) when measured by relative abundance and alpha-diversity index. Bacteriome diversity and abundance differed significantly between age groups at baseline whereas lactobacilli relative abundance was negatively associated with age and vaginal pH.
... The latter observation provides an additional invaluable insight because many commercially-available water-based vaginal lubricants are characterized by high osmolarity with the idea that hyperosmolar products will attract water and facilitate lubrication through increased volume. Unfortunately, it has been shown that hyperosmolarity is associated with mucosal irritation (Adriaens and Remon 2008) and damage to the vaginal epithelial barrier (Ayehunie et al. 2018), the effect not observed with iso and hypo-osmolar vaginal lubricants. As increased osmolarity seems to unfavorably affect the lubricating properties of the water-based lubricant gel tested here the question arises whether the increased osmolarity of lubricating gels is associated with better lubrication in vivo. ...
... As increased osmolarity seems to unfavorably affect the lubricating properties of the water-based lubricant gel tested here the question arises whether the increased osmolarity of lubricating gels is associated with better lubrication in vivo. If this is not the case (as osmolarity attracts water, but also negatively affects the intrinsic lubricating potential) hyperosmolar lubricants should be reevaluated as they may convey no additional benefits while increasing epithelial damage (Adriaens and Remon 2008;Ayehunie et al. 2018) and the risk of sexually transmitted diseases (Fuchs et al. 2007). ...
Quantitative assessment of biotribological properties requires expensive specialized equipment. The aim was to: i) adapt an open-source load cell-based platform (PASTA) for biotribometric analysis; ii) study the effects of oxidation on the water-based lubricant using PASTA. Water-based lubricant was treated with 2,2'-azobis(2-amidinopropane) dihydrochloride and/or glutathione. The samples were analyzed with the ORP-146S redox microsensor and PASTA using a modified HX711 integrated circuit bord, NodeMCU ESP-32S, and an open-source Python script. PASTA can be adapted for affordable and reliable quantitative biotribometric assessment. Glutathione can prevent the loss of lubrication capacity of a water-based lubricant upon exposure to air.
... The latter observation provides an additional invaluable insight because many commercially-available water-based vaginal lubricants are characterized by high osmolarity with the idea that hyperosmolar products will attract water and facilitate lubrication through increased volume. Unfortunately, it has been shown that hyperosmolarity is associated with mucosal irritation [35] and damage to the vaginal epithelial barrier [36] , the effect not observed with iso and hypo-osmolar vaginal lubricants. As increased osmolarity seems to unfavorably affect the lubricating properties of the water-based lubricant gel tested here the question arises whether the increased osmolarity of lubricating gels is associated with better lubrication in vivo. ...
... As increased osmolarity seems to unfavorably affect the lubricating properties of the water-based lubricant gel tested here the question arises whether the increased osmolarity of lubricating gels is associated with better lubrication in vivo. If this is not the case (as osmolarity attracts water, but also negatively affects the intrinsic lubricating potential) hyperosmolar lubricants should be reevaluated as they may convey no additional benefits while increasing epithelial damage [35,36] and the risk of sexually transmitted diseases [37] . ...
Background
Understanding molecular and biochemical mechanisms affecting biotribological properties of tissues, biological fluids, and drugs may accelerate the invention of novel drug formulations and targets and facilitate the discovery of etiopathogenetic mechanisms. Unfortunately, biotribometric equipment is expensive and unaffordable. The first aim was to assess whether PASTA, an open-source platform based on a hacked kitchen scale, can be adapted for the analysis of biotribometric properties. The second aim was to demonstrate the use of PASTA by studying the effects of oxidation on the lubricating properties of the commercial water-based lubricant.
Methods
The PASTA platform was adapted using a custom-made tribometric adapter attached to the bottom of the hacked kitchen scale connected to a computer via the NodeMCU ESP-32S. A commercial water-based lubricant was oxidized with 2,2’-azobis(2-amidinopropane) dihydrochloride and/or protected against oxidation with glutathione. The samples were analyzed using a simple tribometric assay with the PASTA platform and the ORP-146S redox microsensor.
Results
A mastPASTA custom-made adapter enables the use of PASTA for reliable quantitative tribometric studies. Oxidation of the commercial water-based lubricant does not reduce its lubrication capacity, however, the addition of the antioxidant glutathione protects against the loss of its lubrication capacity upon exposure to air by a redox-unrelated mechanism.
Conclusion
PASTA can easily be adapted for studying tribological properties. The effects of the addition of antioxidants to water-based vaginal lubricants should be explored as a possible way to enhance durability and efficacy and increase their health benefits.
... Many commercially available lubricants have osmolalities above the World Health Organization (WHO) recommended limit of 1200 mOsm/kg [15,16]. Multiple studies have shown that hypertonic lubricants may be toxic to mucosal epithelial cells, inducing significant epithelial cell shedding in in-vitro and animal models as well as in humans [6,7,17,18]. For example, one study showed that application of a lubricant with an elevated osmolality caused shedding of large sheets of epithelial cells from rectal tissue [7]. ...
... Certainly, in this cohort, there is no clear pattern to suggest a markedly pro-inflammatory vaginal microenvironment induced by lubricant use. Some previous studies (primarily from in vitro models) had raised concerns regarding the ability of lubricants (especially hyperosmolar lubricants) to lead to mucosal irritation and epithelial cell damage [6,7,9,17,40]. If true, this presumably would lead to a pro-inflammatory vaginal cytokine profile with potential implications for women's reproductive health, including elevated risk of acquisition of STIs and HIV. ...
Background
Limited data suggest that personal lubricants may damage the vaginal mucosal epithelium, alter the vaginal microbiota, and increase inflammation. We compared vaginal cytokine profiles and microbiota before and after vaginal lubricant use and condomless vaginal sex.
Methods
Reproductive-age women were recruited to a 10-week observational cohort study and were asked to self-collect vaginal samples and behavioral diaries daily. This nested case–control analysis utilized samples collected before and after self-reported condomless sexual activity with lubricants (22 case participants) and without lubricants (22 control participants). Controls were matched to cases on race/ethnicity. Microbiota composition was characterized by sequencing amplicons of the 16S rRNA gene V3–V4 regions. Cytokine concentrations were quantified using a magnetic bead 41-plex panel assay and read using a Bio-Plex 200 array reader. Wilcoxon signed-rank tests were used to assess baseline differences in vaginal cytokines between cases and controls as well as differences pre- and post-exposure. Linear mixed effects models were used to examine differences in relative post-to-pre change in each individual cytokine between matched cases and controls. Similar analyses were conducted for the microbiota data.
Results
Mean age was 29.8 years (SD 6.8), and 63.6% were African American. There were few statistically significant changes in cytokines or microbiota before and after exposure in cases or controls. In mixed-effects modeling, the mean relative post-to-pre change of cytokines was higher in cases vs. controls for macrophage derived chemokine (MDC) (p = 0.03). The microbiota data revealed no significant changes when measured by similarity scores, diversity indexes and descriptive community state types (CST) transition analyses. However, post sexual activity, the mean relative abundance of L. crispatus decreased for those who used lubricants (particularly those who were L. iners -dominated prior to exposure) .
Conclusions
Although there were overall few differences in the vaginal microbiota and cytokine profiles of lubricant users and controls before and after condomless vaginal sex, there was a trend toward decreases in relative abundance of L. crispatus following use of lubricant. Future larger studies that take into account osmolarity and composition of lubricants may provide additional insights.
... Osmolality was determined in triplicate using a freezing point osmometer (Micro-Osmometer, Model 3300, Advanced Instruments, Norwood, MA, USA), as previously described [26,27], on a 20 µL aliquot. Standardization was performed using three standards: distilled water (zero point), 50 mOsm/Kg, and 850 mOsm/Kg. ...
Background/Objectives: Cytolytic vaginosis or, classically, Doderlein’s cytolysis is characterized by significant growth of species of the Lactobacillus genus, which leads to high amounts of lactic acid in the vaginal environment. Lactobacillus crispatus has been proposed as a key pathogen in this clinical condition. The symptomatology of cytolytic vaginosis is commonly confused with that of vulvovaginal candidosis, leading to inadequate and ineffective azole therapies. Nevertheless, historically, the use of sodium bicarbonate intimate baths was an effective way to reduce the symptoms of cytolytic vaginosis. Methods: In this study, four HPMC gel prototypes were developed, containing sodium bicarbonate concentrations ranging from 4% to 7% (w/w). These gels were evaluated for their physicochemical properties, antimicrobial activity, interference with lactobacilli adhering to cells, and cellular and tissue biocompatibility. Results: The gels presented pH values of around 9.0, and osmolality between 706 mOsm/kg (F4) and 1065 mOsm/kg (F7). The viscosity upon heating to physiologic temperature and dilution with simulated vaginal fluid was highly affected by the concentration of sodium bicarbonate. Gels with higher sodium bicarbonate concentrations (F6 and F7) were not shown to be stable in these conditions. All formulations exhibited effective antimicrobial activity against seven L. crispatus strains, with MIC values ranging from 6.25% to 25% (v/v) in terms of dilution. Additionally, the 4% (w/w) gel significantly interfered with the adhesion of L. crispatus to epithelial cells in competition and exclusion assays, reducing adhesion by more than 90% in relation to the control. Cytotoxicity tests on the Hec-1A, HeLa, and VK2/E6E7 cell lines indicated that the F4 and F5 gels demonstrated lower cytotoxicity levels compared to those with higher concentrations. Furthermore, ex vivo assays using porcine vaginal tissue confirmed that the 4% gel was non-toxic at a 25% (v/v) dilution. Conclusions: Based on these results, the 4% (w/w) sodium bicarbonate gel (F4) emerges as a promising therapeutic option for cytolytic vaginosis, offering effective bacterial interference, favourable physicochemical properties, and biocompatibility suitable for vaginal application.
... These values of osmolality are higher than those obtained for the original formula of Universal Placebo and can be related to the presence of glycols. In this case, there is propylene glycol, which is known to increase this parameter and is absent from the original formulation [42]. In fact, the WHO recommends that glycerin, another glycol used in the pharmaceutical industry, and propylene glycol should not exceed 9.9% (w/w) and 8.3% (w/w), respectively [41]. ...
Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers , like nanogels, for topical use. An effective alternative to conventional therapies is the nanopar-ticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC50 starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ's effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the per-meation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells.
... 27 In addition, emerging data suggest that lubricants may adversely affect the vaginal epithelium, lamina propria, and the vaginal microbiota. [27][28][29][30][31] Hormonal replacement therapy (HRT) may be considered for climacteric symptoms in the absence of contraindications, whereas local estrogens are primarily indicated to alleviate symptoms and reverse atrophic changes in cases where VVA represents the sole menopausal complaint. 12,32,33 Although local estrogen therapies are effective and safe at very low doses, 32,34,35 medication adherence is quite variable (52%-74%), 36 mainly due to safety concerns, inconvenience, and inadequate symptom relief from treatment. ...
Background
Vulvovaginal atrophy (VVA) includes a wide range of conditions affecting the reproductive and urinary systems, often requiring careful evaluation and management for optimal health.
Aims
This study aims to evaluate the symptom management effects of a real time temperature‐monitored non‐ablative RF device for the treatment of postmenopausal Chinese women with VVA symptoms.
Methods
This pilot study involved 24 postmenopausal Chinese women with one or more VVA symptoms, who wished to remain sexually active. VHIS, VAS, and FSFI were used to track and evaluate various aspects of the patient's condition. Analyses were conducted at the end of the study to verify the statistical significance of the treatment's results.
Results
All patients reported substantial, statistically significant, improvements on every VVA symptom tracked. Approximately 80% of the patients reported total symptom reversal at 12‐week post‐treatment follow‐up.
Conclusion
This pilot study demonstrated that non‐ablative, monopolar RF technology equipped with real time temperature monitoring is feasible and safe in the treatment of postmenopausal women with VVA symptoms, and efficacious at up to 12 weeks post‐treatment.
... However, some transfeminine individuals report challenges with dilating, 8 and lubricant use may be associated with vaginal symptoms, as it has been shown to influence natal vaginal tissue health in cisgender women. [12][13][14] While douching is associated with inflammation and negative health outcomes for the natal vagina, 15,16 some healthcare providers recommend douching for neovaginal care. Some recommend douching daily, while others recommend douching only after dilation or penetrative sex; many recommend douching with water, while others recommend alternative douching solutions such as soap, saline, vinegar, or iodine solutions. ...
Background
Vaginoplasty is a gender-affirming surgery that is medically necessary for some transfeminine individuals. Little research exists describing vaginal health after the initial recovery from surgery, and evidence-based guidelines for vaginal care practices are unavailable.
Aim
The study sought to describe self-reported gynecological concerns and vaginal care practices among transfeminine persons who have undergone vaginoplasty.
Methods
A total of 60 transfeminine participants 18+ years of age, living in Canada, and who had undergone vaginoplasty at least 1 year prior were recruited through social media, community groups, healthcare provider referrals, and study recontact. Participants completed a cross-sectional, online questionnaire detailing demographics, gynecological concerns, and genital practices and exposures. Hierarchical clustering was used to group participants based on behavioral practices and exposures. Associations between clusters and gynecological concerns were assessed.
Outcomes
Outcomes included self-reported gynecological concerns within the past year, recent vulvar or vaginal symptoms (past 30 days), and behavioral practices/exposures, including douching with varied products and dilating.
Results
Participants reported a variety of concerns in the past year, including urinary tract infection (13%) and internal hair regrowth (23%). More than half (57%) had experienced at least 1 recent vaginal symptom, most commonly malodor (27%) and vaginal bleeding (21%). Of participants, 48% were dilating weekly and 52% reported douching in the past 30 days. Four distinct clusters of vaginal practices/exposures were identified: limited exposures; dilating, no douching; dilating and douching; and diverse exposures. No significant associations between cluster membership and gynecological concerns were identified, though cluster membership was significantly associated with surgical center (P = .03). Open-text write-ins provided descriptions of symptoms and symptom management strategies.
Clinical Implications
The results provide insight for clinicians on common patient-reported gynecological concerns and current vaginal care practices and exposures, including symptom management strategies.
Strengths and Limitations
This was the first study to investigate vaginal health and genital practices/exposures among a community sample of transfeminine individuals. As participants self-enrolled for a detailed survey and swab collection, individuals experiencing concerns were likely overrepresented.
Conclusion
Transfeminine individuals reported a range of gynecological concerns outside of the surgical healing period. Genital practices/exposures varied across clusters, but no clear associations between clusters and symptoms were identified; instead, practice/exposure clusters were dependent on where the individual underwent vaginoplasty. There is a need for evidence to inform diagnostics, treatments, and vaginal care guidelines to support vaginal health.
... Slugs are placed on a tested substance. If the formulation causes irritation, the slug produces mucus as a protective mechanism [107]. Based on the total amount of the produced mucus, and in relation to the positive and negative controls, it is possible to assess the irritation potential of the formulation and predict the discomfort the formulation may cause to the patient [37]. ...
Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer's disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.
... The osmotic concentration (measured as osmolality) of cervicovaginal fluid from women with Lactobacillus-dominated vaginal microbiota (Nugent 0-3) is ∼370 +/-40 mOsmol/kg of fluid (31). However, the vast majority of vaginal lubricants and moisturizers are hyperosmolal (31,38,39) and are associated with mucosal irritation (40), decreased epithelial cell viability and barrier integrity in vitro (31,39,41), and cause rectal epithelial damage and denudation in vivo (42). For these reasons, the World Health Organization (WHO) recommends the osmolality of vaginal lubricants should ideally not exceed 380 mOsm/Kg, although given the limited availability of products meeting this criterion, an interim upper limit of 1,200 mOsm/Kg is recommended (43). ...
The vaginal microbiome influences a wide range of health outcomes in women, where a microbiome dominated by Lactobacillus spp. is considered optimal and associated with reduced risk of pre-term birth and acquisition of sexually transmitted infections including HIV. Conversely, replacement of lactobacilli by non-optimal bacteria leads to the development of bacterial vaginosis, which is associated with increased risk of these outcomes. Lactobacilli produce the metabolite lactic acid (LA) which is a potent antibacterial and antiviral agent. The potential therapeutic benefits of LA have prompted the development of numerous over-the-counter LA-containing gels for use in the vagina, although a comprehensive analysis of the impact of these formulations on the cervicovaginal epithelium and pro-inflammatory cytokine/chemokine responses, has not been assessed. Here, we evaluated the properties of 11 over-the-counter gels, including 9 containing LA, marketed for use in the vagina. Ten of the 11 gels had an osmolality greater than vaginal fluid from women with Lactobacillus-dominated microbiota (370 ± 40 mOsmol/kg in women with Nugent score 0–3), with six gels that were hyperosmolal >2,000 mOsmol/kg. Using a reconstructed primary cell model of the vaginal epithelium, we found hyperosmolal gels had a detrimental impact on epithelial barrier integrity, resulting in substantial cellular toxicity (<10% viability as compared to untreated cells) and reduced epithelial barrier integrity [≈30% of untreated cells, assessed by transepithelial electrical resistance (TEER)]. Treatment of vaginal tissues with most of the gels elicited the production of pro-inflammatory factors including IL-1α (8 of 11) and IL-1β (10 of 11) which are associated with heightened risk of HIV acquisition in vivo. The majority of the OTC gels elicited moderate tissue damage as determined by histology. The detrimental effects of these gels on the human vaginal epithelium in vitro may predict compromised epithelial barrier integrity and genital inflammation in vivo, which has implications for sexual and reproductive health. This study highlights the importance of evaluating the impact of intravaginal products on the integrity and inflammatory status of the mucosal epithelium to avoid unfavorable off target effects.
... The application of more toxic compounds to the mucosa likely mediates HIV risk via direct epithelial disruption, and this is likely the reason for the increased HIV risk associated with the application of the spermicide nonxynol-9 (N9) [99], which induces epithelial damage to both the vaginal and rectal mucosa [100,101], although the penile impact of this spermicide has not been defined. The vaginal application of sexual lubricants with high osmolality can also damage the epithelium [102,103], although a link between HIV acquisition and specific lubricants has not been described to our knowledge, and again, there have been no penile studies. ...
Globally, most Human Immunodeficiency Virus type 1 (HIV) transmission occurs through vaginal–penile sex (heterosexual transmission). The local immune environment at the site of HIV exposure is an important determinant of whether exposure during sex will lead to productive infection, and the vaginal and penile immune milieus are each critically shaped by the local microbiome. However, there are key differences in the microbial drivers of inflammation and immune quiescence at these tissue sites. In both, a high abundance of anaerobic taxa (e.g., Prevotella) is associated with an increased local density of HIV target cells and an increased risk of acquiring HIV through sex. However, the taxa that have been associated to date with increased risk in the vagina and penis are not identical. Just as importantly, the microbiota associated with comparatively less inflammation and HIV risk—i.e., the optimal microbiota—are very different at the two sites. In the vagina, Lactobacillus spp. are immunoregulatory and may protect against HIV acquisition, whereas on the penis, “skin type” flora such as Corynebacterium are associated with reduced inflammation. Compared to its vaginal counterpart, much less is known about the dynamics of the penile microbiome, the ability of clinical interventions to alter the penile microbiome, or the impact of natural/induced microbiome alterations on penile immunology and HIV risk.
... Whereas the hyperosmotic lubricants in study all contained glycerin (i.e., glycerol) and all induced some mucosal irritation in the slug mucosal irritation assay. 18 After dilution in VFS, all formulations were affected, considerably decreasing their osmolality and with statistical differences (two-way ANOVA, p < 0.001) between the two measurements, with osmolality values in accordance with the maximum limit recommended by WHO. This attenuation in osmolality was already expected, since VFS is a hypotonic solution (185 mOsm/Kg) and the formulations have higher osmolalities, causing a progressive decrease in osmolalities compared to measurement without adding VFS. ...
Background
The human papillomavirus (HPV) is responsible for over 90% of all cervical cancer cases. The use of vaginal gels is often indicated for local vaginal drug delivery. Previous studies have shown that Thymus vulgaris essential oil (TEO) exhibits anticancer properties besides antifungal and antibacterial properties. Its activity derives from a specific increase in free radicals and oxidative stress caused in cancer cells. Furthermore, mitoxantrone (MTX), an anthracenedione and C8, an acridine orange derivative, were shown to inhibit the growth of the cervical cancer cell line HeLa.
Results
The results showed that TEO + C8 is the most promising formulation in terms of viscosity and osmolality properties in vaginal fluid simulant (VFS). The combined action of TEO with the compound's MTX and C8 resulted in HeLa cell viability reduction compared with the effect obtained with the individual formulations containing each one of the compounds.
Conclusions
The formulation TEO + C8 holds promise in terms of cost-benefit and topical application of the active compound for the HeLa cells.
... Some lubricants have shown toxicity to epithelial cells in vitro [25][26][27], in a three-dimensional vaginal epithelium tissue-model [27][28][29] and in mice [30]. In most cases, the level of toxicity correlates with the hyperosmolality of the lubricant [31,32] (i.e., the higher concentration of solutes in the lubricant compared with the tissues to which it is applied), as well as the presence of bacteriostatic preservatives (e.g. chlorhexidine, methylparaben and propylparaben). ...
The outer layers of the vaginal epithelium (VE) are important because they accumulate glycogen which, under optimal conditions, Lactobacillus spp. consume to grow and acidify the vaginal microenvironment with lactic acid. We hypothesized that exposure to lubricant, for example in the conduct of a transvaginal ultrasound (TVUS), may contribute to the shedding of mature epithelial cells, exposing immature cells. Cervicovaginal fluid (CVF) was sampled at four time points by menstrual cup (Softdisc™) from 50 women referred for TVUS, during which a controlled volume of lubricant was applied to the TVUS wand. Samples were collected (1) immediately before TVUS and (2) 6–12 hours, (3) within one week, and (4) two weeks after TVUS. Clinical vaginal lubricants are similar to commercial lubricants, and often have a high osmolality or pH, and contain bactericides such as methylparaben and propylparaben. The number and maturity of epithelial cells in each CVF sample were measured by quantitative and differential fluorimetry (maturity index, MI). Comparisons of cell-counts and maturity were made by paired Wilcoxon signed-rank tests. Among women with a high pre-TVUS MI (> 3), there was a decrease in median cell-count and mean MI in the sample collected 6–12 hours after TVUS (p<0.001, n = 26 and p < 0.001, n = 26, respectively). For these women, cell-count and MI remained lower in the sample collected within the subsequent week (p<0.001, n = 29 and p<0.01, n = 29, respectively), and MI remained lower in the sample collected within two weeks of TVUS (p<0.01, n = 25), compared to the pre-TVUS sample. Among participants with a low pre-TVUS MI (< 3), cell-count was higher in the sample collected within two weeks of TVUS compared to the pre-TVUS sample (p = 0.03, n = 15), but no significant changes in MI were observed. Results were similar when restricted to reproductive-age women. This preliminary data indicates hypertonic vaginal lubricants may increase vaginal epithelial cell shedding.
... Furthermore, the snail model overcomes some of in vitro cell culture assays limitations; due to the lack of a protective barrier formed by mucus, in vitro cell lines are more sensitive to chemicals than the in vivo mucosa. Another significant advantage is assessing tissue damage, which can be evaluated by microscopic examination and the release of several markers, including proteins and enzymes [35][36][37]. ...
Preventive measures have proven to be the most effective strategy to counteract the spread
of the SARS-CoV-2 virus. Among these, disinfection is strongly suggested by international health organizations’ official guidelines. As a consequence, the increase of disinfectants handling is going to expose people to the risk of eyes, mouth, nose, and mucous membranes accidental irritation.
To assess mucosal irritation, previous studies employed the snail Arion lusitanicus as the mucosal model in Slug Mucosal Irritation (SMI) assay. The obtained results confirmed snails as a suitable experimental model for their anatomical characteristics superimposable to the human mucosae and the different easily observed readouts. Another terrestrial gastropod, Limacus flavus, also known
as “ Yellow slug “, due to its larger size and greater longevity, has already been proposed as an SMI assay alternative model. In this study, for the first time, in addition to the standard parameters recorded in the SMI test, the production of yellow pigment in response to irritants, unique to the snail L. flavus, was evaluated. Our results showed that this species would be a promising model for mucosal irritation studies. The study conducted testing among all those chemical solutions most commonly recommended against the SARS-CoV-2 virus.
... The osmolality was determined in triplicate using a freezing point osmometer (Osmomat 3000, Gonotec, Germany) on a 50 mg aliquote, as previously described (Machado et al., 2017;Adriaens and Remon, 2008;Cunha et al., 2014). ...
Vulvovaginal candidosis (VVC), caused mainly by the yeast Candida albicans, is the second most prevalent vaginal infection. It has been found to have a large impact on women's quality of life, self-esteem and routines. The prevalence of recurrent vulvovaginal candidosis (RVVC) remains high so the development of alternative treatments is needed. The main objective of this study was to develop and characterize sodium bicarbonate gels to treat VVC. We described key formulation characteristics and analyzed their influence on in vitro performance evaluations. The potential to inhibit Candida albicans’s growth, the pH, osmolality, viscosity and rheological performance in contact with vaginal fluid simulant and the bioadhesion's profile (using a vaginal ex vivo porcine model) were studied for all formulations. Among the formulations, formulation C (5% sodium bicarbonate, 1% carbomer and 94% water) was the most effective in inhibiting the C. albicans’ growth. This gel presented the same potential (the same MIC 2.5%) to inhibit other etiological agents of VVC (C. glabrata, C. krusei, C. tropicalis and C. parapsilosis) for all species tested. Additionally, sensorial characteristics of gel C were in accord with users’ preferences. This gel exhibited physicochemical characteristics acceptable for short term treatments, suggesting good overall performance for the treatment of VVC. Furthermore, Gel C was biocompatible with the HeLa cell line (MTT assay) and was classified as a non-severe irritant in the HET-CAM assay (irritation score 4 ± 1). Overall, gel C was deemed the best performing of the set tested, and suitable for further development.
... A hypo-osmolar lubricant caused negative mucus production, while a highly hyperosmotic lubricant resulted in severe irritation and tissue damage. An iso-osmolar lubricant caused no changes [7]. Dezzutti et al. showed that hyper-osmolar lubricants were associated with cellular toxicity and vaginal epithelial damage while showing no anti-viral activity [8]. ...
Purpose: Vaginal lubricants are widely used by women to resolve intercourse difficulties or as performance enhancers. However, little information is available regarding the safety of over-the-counter (OTC) lubricants. Therefore, in this study, a set of commercial lubricant products available on the Korean online market were selected and evaluated in vitro for their safety relevant to their osmolality. Materials and Methods: Five commercially available gel-based OTC lubricant products were included in this study. Osmolality was determined using a vapor pressure 5520 osmometer. Cell viability was measured by MTT assay and Western blotting. Human vaginal tissue integrity was measured by immunohistochemistry. Results: Four OTC lubricant showed hyper-osmolality, while one OTC lubricant was within the minimum WHO-recommended standards. The findings showed that four hyperosmolal OTC vaginal lubricants showed cellular damage to the cultured vaginal cell line and human vaginal explant. One iso-osmolal OTC vaginal lubricant showed less cellular damage to both cultured vaginal cell lines and human vaginal explants. Conclusion: Present study showed that the osmolality of OTC vaginal lubricant is a major factor affecting epithelial cell survival and tissue integrity. The effect of each ingredient contained in OTC lubricants was not considered. Thus, additional research is needed to evaluate formulae to enable production of safer OTC vaginal lubricants.
... Commercially available lubricants (lidocaine-free) caused a wide range of mucosal irritations based on their osmolality in a slug model designed to examine mucus membrane tolerance. 52 Methylparaben, a preservative commonly added in lidocaine jelly, was also shown to cause pain sensation in mouse sensory neurons. 53 In a rabbit model, lidocaine injection promoted muscular contraction and rigidity in masticatory muscles through calcium ATPase inhibition, 54 which may have contributed to the increased POST through pharyngeal myalgia. ...
Purpose
Postoperative sore throat (POST) is a relatively common morbidity. Topical lidocaine lubricants have been proposed to prevent POST; however, their effectiveness remains uncertain. This meta-analysis aimed to evaluate the prophylactic effect of lidocaine lubrications against POST, cough, and hoarseness in adult patients after surgery.
Methods
Randomized-controlled trials from PubMed, Embase, the Cochrane Library, and the ClinicalTrials.gov registry that were published from inception until 26 March 2018 were included that compared the effectiveness of lidocaine lubricants with that of controls in preventing the incidence of overall POST and moderate to severe POST (POSTMS) at the first and 24th postoperative hour (POST-1h, POST-24h, POSTMS-1h, and POSTMS-24h). Postoperative cough and hoarseness at the 24th postoperative hour were also studied. Bias assessment and subgroup, sensitivity, and trial sequential analyses were also performed.
Results
Fourteen randomized-controlled trials (n = 2146) were selected. The incidences of POST-1h and POST-24h were 41.1 % and 22.6 % for the lidocaine group, and 41.9% and 23.5% for the control group, respectively. No effect was found on any of the outcome measurements. The overall risk ratios were 1.11 (95% confidence interval [CI], 0.82 to 1.51) and 1.06 (95% CI, 0.37 to 3.02) for the incidence of POST-1h and POSTMS-1h, respectively; 0.99 (95% CI, 0.83 to 1.17) and 0.49 (95% CI, 0.16 to 1.50) for POST-24h and POSTMS-24h, respectively; and, 1.09 (95% CI, 0.71 to 1.66) and 0.91 (95% CI, 0.66 to1.24) for postoperative cough (PC)-24h and postoperative hoarseness (PH)-24h, respectively.
Conclusion
Lidocaine lubricants applied on the tips of endotracheal tube are not effective against the morbidities of POST, PC, and PH.
Trial registration
PROSPERO (CRD42017073259); registered 26 October, 2017.
... Semen 320 [24] Mid-cycle cervical mucus 250-422 [25] Vaginal secretions 260-290 [26] Osmolality expressed in milliosmoles. condition using pre-warmed 2-cell Leja chamber and 4 μL of the sample giving depth of 20 μm. ...
Vaginal lubricants are commonly used by couples trying-to-conceive. However, most vaginal lubricants are sperm toxic and therefore should not be used by couples trying-to-conceive. Despite this, lubricant sperm toxicity is insufficiently reported and guidance for healthcare professionals (HCPs) is absent. In this study, lubricant-related practices of fertility-based HCPs in Scotland were sampled via an online survey. Lubricants identified as being utilised in the fertility setting were subsequently incubated with prepared sperm samples to establish effects on sperm motility. HCP recommendations (n = 32) on lubricant use were varied although knowledge related to sperm toxicity was generally poor. HCPs infrequently asked about lubricant use and were unaware of guidance in this area. Aquagel, the only prescribed lubricant identified in this study, reduced sperm progressive motility to 49% of control after 10 minutes, even at concentrations as low as 5%. Vitality testing suggested the deterioration in progressive motility with Aquagel was not as a result of cell death. Conversely, Pré Vaginal Lubricant, a ‘sperm-safe’ lubricant, did not significantly affect any markers of sperm function assessed. Development of clinical guidance in this area is recommended to ensure HCPs deliver informed advice as lubricant use in couples trying-to-conceive may inadvertently contribute to delay in conception.
... In the scientific literature N9, at a concentration of 3-4%, is recognized as a vaginal irritant. It is even recommended as a positive control for laboratories evaluating vaginal irritation (Dhondt et al., 2004;Rastogi et al., 2016;Adriaens and Remon, 2008;Cosmetic Ingredient Revie, 2018). ...
Personal lubricants and lubricants used in condoms contain a number of ingredients which are also present in cosmetic products. These have to comply to the medical device regulation (745/2017) which should provide the same level of consumer protection, if not more, as foreseen in the legal framework of cosmetics (1223/2009). In the current study we developed an analytical method capable of identifying and quantifying 15 ingredients, commonly found in lubricants and cosmetics. Based upon their most important toxicological endpoint, the substances involved were grouped in three toxicological classes provoking either irritation, contact allergic dermatitis or systemic toxicity. The method was applied on 30 condoms and 54 personal lubricants present on the EU market. Their safety was assessed using the same reasoning as commonly applied for cosmetic ingredients. Higher mucosae susceptibility, the main exposed area for lubricants, was taken into account in this assessment.
The results show that the majority of the products studied are safe. Nevertheless, for some products the safety could not be confirmed. The results also highlight the fact that there is no consensus for a number of ingredients, used as well in cosmetics as in medical devices. Alignment between both legislations would improve the safety of these products and further raise the general level of consumer protection.
... While lubricants are typically made with ingredients from the "generally recognized as safe" list and do not contain pharmacologically active ingredients, there is a wide range of variability in the composition and chemical properties of personal lubricants [4]. In particular, water-based lubricants with hyperosmolar properties have been shown to induce epithelial tissue damage and cytotoxicity when applied in a single dose to rectal explants and epithelial cell cultures, or applied intermittently to the rectum of rhesus macaques in vivo [4][5][6][7][8][9]. Inflammation caused by tissue damage alters expression of drug metabolizing enzymes and transporters that can affect the absorption, distribution and clearance of antiretroviral (ARV) drugs [10]. ...
Introduction
Oral pre‐exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is highly effective in preventing HIV infection among men who have sex with men (MSM). The effects of consistent personal lubricant use in the rectum on tissue PrEP drug concentrations and the rectal microbiota are unknown. We investigated rectal PrEP drug concentrations and the microbiota in MSM before and after repeated rectal application of a hyperosmolar lubricant.
Methods
We randomized 60 HIV‐negative MSM to apply 4 mL of hyperosmolar rectal lubricant daily (n = 20), take daily oral TDF/FTC (n = 19), or both (n = 21) for seven days. Blood, rectal biopsies and rectal secretions were collected via rigid sigmoidoscopy before and on day 8 after product use. Tenofovir (TFV) and FTC as well as their intracellular metabolites tenofovir‐diphosphate (TFV‐DP), FTC‐triphosphate (FTC‐TP) were measured by HPLC‐mass spectrometry. Rectal mucosal microbiota was sequenced with 16S rRNA sequencing using Illumina MiSeq.
Results
Seven days of lubricant application was not associated with differences in PrEP drug concentrations in rectal tissue or secretions. Lubricant use was associated with a decrease in the relative abundance of the Bacteroides genus (p = 0.01) and a non‐significant increase in the Prevotella genus (p = 0.09) in the rectum. PrEP drug concentrations in rectal tissue and secretions were not associated with microbiota composition or diversity either before or after lubricant use.
Conclusions
Repeated rectal application of a hyperosmolar lubricant does not affect mucosal PrEP drug concentrations but is associated with changes in the rectal microbiome.
... Moreover, it also tends to cause mucosal irritation (p=0.001), resulting in further aggravation of long-term symptoms [12]. The efficacy and safety of other drugs in the treatment of VVA remain largely undefined. ...
Objective
To evaluate the clinical therapeutic efficacy and safety of modified Erzhi granules (MEG) in patients with menopause-related vulvovaginal atrophy (VVA).
Methods
This randomized, double-blind, placebo-controlled study comprised two groups, including the treatment and control groups. Patients receive MEG and placebo for 12 weeks, respectively. Vaginal health score (VHS), vaginitis score, vaginal maturation index (VMI), female sexual function index (FSFI), and modified Kupperman Index (modified KI) were used as efficacy endpoints and assessed at baseline, 4, 8, and 12 weeks during administration, and 4 weeks after drug withdrawal. At baseline and 12 weeks, serum estradiol (E2), follicle stimulating hormone (FSH), pelvic ultrasound, breast ultrasound, and other safety parameters were measured, recording adverse events.
Results
At 12 weeks, VHS, percentage of superficial cells in the vaginal epithelium and FSFI were significantly increased, while vaginitis score, percentage of basal cells in the vaginal epithelium, and modified KI were significantly decreased in comparison with baseline and control group (all P<0.05); these differences persisted for up to 4 weeks after drug withdrawal. The placebo group showed no significant change during treatment compared with baseline values (p>0.05). Serum E2 and FSH levels, endometrial thickness, and breast thickness in all patients were within the normal ranges before and after treatment, with no serious adverse reactions observed.
Conclusion
MEG significantly alleviates menopause-related vulvovaginal atrophy, with no overt adverse effects on the endometrium, breast, hepatic, and renal functions.
... The FDA and EMA traditionally list lubricants as medical devices and exclude these products from extensive pre-clinical and clinical testing as otherwise required for drug products. Recent in vitro and in vivo studies on animals suggest that water-based lubricants are not safe and induce mucosal irritation due to product hyperosmolarity 12 that can lead to toxic effects and eventually lead to increase in the acquisition and transmission of sexually transmitted pathogens such as HIV 12 . These results highlight the potential of many top selling brands of sexual lubricants to cause epithelial injury due to their hyperosmolarity. ...
Vaginal lubricants are used to solve intercourse difficulties or as sexual enhancers, but recent reports raise questions about their safety in terms of fertility. In this study, twenty semen samples were tested against commercially available vaginal lubricants for progressive spermatozoa motility and vitality with varying exposure time intervals. Results showed that the vaginal lubricant which least affected progressive spermatozoa motility was the oil-based vaginal lubricant, which kept the mean percentage of progressive spermatozoa motility within the minimum normal range of 32%, following 60 minutes of exposure. The silicone-based vaginal lubricant produced similar results to the oil-based vaginal lubricant, however the progressive spermatozoa motility dropped below the minimum normal range within 60 minutes of exposure. The fertility lubricant did not produce mean progressive motilities that were within the normal minimum range at any of the three time intervals, producing poor results overall. The vaginal lubricant which produced the poorest results was the water-based, which immobilized all of the spermatozoa within 5 minutes of exposure and killed on average 95.23% within 60 minutes. Although further assessment is required, these results highlight potential fertility issues related to the formulation of commercially available vaginal lubricants. © 2017, Women's Health and Action Research Centre. All rights reserved.
... The FDA and EMA traditionally list lubricants as medical devices and exclude these products from extensive pre-clinical and clinical testing as otherwise required for drug products. Recent in vitro and in vivo studies on animals suggest that water-based lubricants are not safe and induce mucosal irritation due to product hyperosmolarity 12 that can lead to toxic effects and eventually lead to increase in the acquisition and transmission of sexually transmitted pathogens such as HIV 12 . These results highlight the potential of many top selling brands of sexual lubricants to cause epithelial injury due to their hyperosmolarity. ...
Vaginal lubricants are used to solve intercourse difficulties or as sexual enhancers, but recent reports raise questions about their safety in terms of fertility. In this study, twenty semen samples were tested against commercially available vaginal lubricants for progressive spermatozoa motility and vitality with varying exposure time intervals. Results showed that the vaginal lubricant which least affected progressive spermatozoa motility was the oil-based vaginal lubricant, which kept the mean percentage of progressive spermatozoa motility within the minimum normal range of 32%, following 60 minutes of exposure. The siliconebased vaginal lubricant produced similar results to the oil-based vaginal lubricant, however the progressive spermatozoa motility dropped below the minimum normal range within 60 minutes of exposure. The fertility lubricant did not produce mean progressive motilities that were within the normal minimum range at any of the three time intervals, producing poor results overall. The vaginal lubricant which produced the poorest results was the water-based, which immobilized all of the spermatozoa within 5 minutes of exposure and killed on average 95.23% within 60 minutes. Although further assessment is required, these results highlight potential fertility issues related to the formulation of commercially available vaginal lubricants.
(Afr J Reprod Health 2017; 21[3]: 96-101).
... This is especially prominent with the use of aerosolized lidocaine and is attributed to the additives present in the product [13,17]. It can also be due to the osmolarity of the jelly since mucosal irritation can depend on the osmolarity of the lubricant [18]. But some other studies have shown a better result with the use of lidocaine [19]. ...
Background and objectives
Post-operative airway symptoms can be troublesome to patients following an uneventful general anesthesia with endotracheal intubation. In this study, we compared the effectiveness of lubricating an endotracheal tube with betamethasone gel or lidocaine jelly with using an unlubricated tube in reducing the incidence and severity of postoperative sore throat, hoarseness and cough.
Methods
This was a prospective, randomized, single-blind comparative study carried out among 120 ASA I and II patients aged 18–65 years undergoing elective surgery under general anesthesia with endotracheal intubation. Patients were randomly divided into three groups of 40 patients each. Endotracheal tube used for patients in group C was unlubricated, while that for group B and group L were lubricated up to 15 cm mark with 2.5 ml of 0.05% betamethasone gel or 2% lidocaine jelly respectively. Incidence and severity of postoperative sore throat, hoarseness and cough were observed at 1, 6 and 24 h following extubation.
Results
At 24 h following extubation, group B had the lowest incidence of postoperative sore throat among the three groups (group B: 12.5% vs group L: 37.5% vs group C: 25%; p = 0.036). Severity of postoperative sore throat at 24 h was less with betamethasone (score 0: 87.5%, 1: 10%) compared with lidocaine (score 0: 62.5%, 1: 37.5%) and control (score 0:75%, 1: 20%) (p = 0.006). Observations at other times and of other variables were comparable.
Conclusion
Wide spread application of 0.05% betamethasone gel to lubricate the endotracheal tube significantly reduces the incidence and severity of sore throat at 24 h of extubation but not of hoarseness or cough.
... Multiple in vitro studies that investigated the safety of over-the-counter vaginal lubricants found most products to be hyperosmotic, a property that can potentially damage the integrity of the epithelium (Adriaens & Remon, 2008;Begay et al., 2011;Cunha et al., 2014;Dezzutti et al., 2012;Fashemi et al., 2013). Apoptosis of epithelial cells can occur when intracellular fluid becomes depleted due to the high concentration of extracellular lubricant. ...
The profound impact of the human microbiome on health makes it imperative that nurses understand the basic structures and functions of the various microbial communities. In studying the human microbiome, advances in DNA and RNA sequencing technology offer benefits over traditional culturebased methods. Such technology has permitted more thorough investigations of microbial communities, particularly those of the gastrointestinal (GI) and female reproductive tracts. Although individual variations exist, each site exhibits distinct compositions. The diverse GI microbiota aid in digestion, mood regulation, and vitamin synthesis. While many factors affect the composition and functions of the GI microbiota, diet likely exerts the strongest influence. Vaginal microbiota tend to be less diverse, and mainly serve to protect women from infection. The composition of the vaginal microbiota is influenced by sexual activity, hygienic practices, medications, smoking, and other factors. Our increasing knowledge about the structures and functions of the GI and vaginal microbiota allows nurses to provide targeted, evidence-based education and care for various populations.
... Vaginal lubricants are used to prevent dryness and dyspareunia during sexual activity [17,18]. Although water-based vaginal lubricants are commonly recommended, many contain preservatives that may aggravate sensitive vaginal mucosa [19,20]. Petroleum-based lubricants are not recommended because they may increase the risk of vaginal infection [16]. ...
... The normal osmolality of female vaginal secretions is 260-290 mOsm/kg and that of human semen is 250-380 mOsm/ kg. There have been several in vitro studies, and one human in vivo study, indicating that exposure to high osmolality lubricants may cause vaginal and anal epithelial compromise or damage [28][29][30][31]. Epithelial damage can cause increased irritation, worsening of GSM symptomatology and, in some cases, may theoretically increase the risk of transmission of sexually transmitted diseases. ...
Genitourinary syndrome of menopause (GSM) is a group of symptoms that encompasses vulvovaginal atrophy (VVA), and affects more than half of all postmenopausal females. There are many etiologies that may cause GSM-like symptoms including declining hormone levels, post partum lactation, medications, and certain medical illnesses. GSM is often under-recognized by both the woman and her health care professional. VVA can cause a constellation of signs and symptoms including irritation, pain burning, and itchiness. Although systemic and local hormonal treatment is often recommended, many women may decline their use or opt for a more conservative approach. Numerous women are opting for over-the-counter products for their dryness solutions, including moisturizers, lubricants, and vulvar washes to help manage these symptoms. There is a lot of consumer confusion concerning these products, and with a plethora of varieties on the market, it is easy for the woman to get confused concerning type of products and the additives and chemical that maybe found within them. This review article summarizes the common characteristics of vaginal moisturizers, lubricants, washes, and dispels some of the misperceptions concerning common chemical/additives found in these products. It is important for the reader to note that trade names of several over-the-counter products are mentioned throughout the manuscript and this should not be interpreted as a specific product endorsement.
Personal lubricants intended for local or systemic delivery via the vaginal route can induce vaginal irritation, damage the vaginal epithelial barrier which can enhance microbial entry, induce inflammation, and alter the microbiome of the vaginal ecosystem. Therefore, manufacturers of personal lubricants and medical devices are required to show biocompatibility and safety assessment data to support regulatory decision-making within a specified context of use. Furthermore, due to ethical concerns and the introduction of the 7th amendment of the European Council Directive which bans animal testing for cosmetic ingredients and products coupled with the Food and Drug Administration modernization Act 2.0 guidelines, there is a wave of drive to develop alternative test methods to predict human responses to chemical or formulation exposure. In this framework, there is a potential to use three-dimensional organotypic human vaginal-ectocervical tissue models as a screening tool to predict the vaginal irritation potential of personal lubricants and medicaments. To be physiologically relevant, the in vitro tissue models need to be reconstructed using primary epithelial cells of the specific organ or tissue and produce organ-like structure and functionality that recapitulate the in vivo–like responses. Through the years, progress has been made and vaginal tissue models are manufactured under controlled conditions with a specified performance criterion, which leads to a high level of reproducibility and reliability. The utility of vaginal tissue models has been accelerated in the last 20 years with an expanded portfolio of applications ranging from toxicity, inflammation, infection to drug safety, and efficacy studies. This article provides an overview of the state of the art of diversified applications of reconstructed vaginal tissue models and highlights their utility as a tool to predict vaginal irritation potential of feminine care products.
Gelatin is a water-soluble natural polyampholyte with poor mucoadhesive properties. It has traditionally been used as a major ingredient in many pharmaceuticals, including soft and hard capsules, suppositories, tissue engineering, and regenerative medicine. The mucoadhesive properties of gelatin can be improved by modifying it through conjugation with specific adhesive unsaturated groups. In this study, gelatin was modified by reacting with crotonic, itaconic, and methacrylic anhydrides in varying molar ratios to yield crotonoylated-, itaconoylated-, and methacryloylated gelatins (abbreviated as Gel-CA, Gel-IA, and Gel-MA, respectively). The successful synthesis was confirmed using ¹H NMR, FTIR spectroscopies, and colorimetric TNBSA assay. The effect of chemical modification on the isoelectric point was studied through viscosity and electrophoretic mobility measurements. The evolution of the storage (G′) and loss (G′′) moduli was employed to determine thermoreversible gelation points of modified and unmodified gelatins. The safety of modified gelatin derivatives was assessed with an in vivo slug mucosal irritation test (SMIT) and an in vitro MTT assay utilizing human pulmonary fibroblasts cell line. Two different model dosage forms, such as physical gels and spray-dried microparticles, were prepared and their mucoadhesive properties were evaluated using a flow-through technique with fluorescent detection and a tensile test with ex vivo porcine vaginal tissues and sheep nasal mucosa. Gelatins modified with unsaturated groups exhibited superior mucoadhesive properties compared to native gelatin. The enhanced ability of gelatin modified with these unsaturated functional groups is due to the formation of covalent bonds with cysteine-rich subdomains present in the mucin via thiol–ene click Michael-type addition reactions occurring under physiologically relevant conditions.
Bacterial vaginosis (BV) is a common cause of vaginitis worldwide and is associated with serious reproductive health outcomes, including increased risk of preterm birth, sexually transmitted infections, and pelvic inflammatory disease. The current and only FDA-approved treatment regimens for BV are antibiotics, such as metronidazole and clindamycin. Antibiotics provide a short-term cure for bacterial vaginosis; however, fail to provide a consistent long-term cure for many women. Fifty to eighty percent of women experience a BV recurrence within a year of completing antibiotic treatment. This may be because after antibiotic treatment, beneficial strains of Lactobacillus , such as L. crispatus, do not recolonize the vagina. In the absence of an effective long-term cure, patients, providers, and researchers are exploring different approaches to treatment and prevention, resulting in a rapid evolution of perspectives on BV pathogenesis and approaches to management. Current areas of investigation for BV management include probiotics, vaginal microbiome transplantation, pH modulation, and biofilm disruption. Behavioral modifications that may help include smoking cessation, condom use and hormonal contraception. Additional strategies considered by many people include dietary modification, non-medical vaginally applied products, choice of lubricant, and treatments from medical practices outside of allopathic medicine. This review aims to provide a comprehensive and up to date outline of the landscape of ongoing and potential treatment and prevention strategies for BV.
Importance and objectives:
Evaluation and treatment of dyspareunia remains a significant unmet need despite the availability of safe and effective treatments. The objectives of this review are to consider evaluation techniques, the medical causes, and treatment options for dyspareunia in postmenopausal women.
Methods:
This narrative review used PubMed to search for English-language articles related to postmenopausal dyspareunia. Search terms included, but were not limited to, dyspareunia, genitourinary syndrome of menopause, sexual dysfunction, postmenopausal dyspareunia, posthysterectomy dyspareunia, and postcancer dyspareunia.
Findings:
Many postmenopausal women with dyspareunia do not discuss their symptoms with their physicians. Healthcare clinicians should broach the topic of dyspareunia with their patients using oral or written questionnaires. In addition to a thorough medical history and physical examination, various tools can be used as further assessments, including vaginal pH, vaginal dilators, imaging, vulvar biopsy, vulvoscopy and photography, the cotton swab test, sexually transmitted infection screening, and vaginitis testing. Although dyspareunia in postmenopausal women is often due to the genitourinary syndrome of menopause, other conditions can also cause dyspareunia, including hypertonic pelvic floor, hysterectomy, cancer treatment, lichen conditions, vulvar cancer, vestibulodynia, and pelvic organ prolapse. Some of the treatments discussed include lubricants, moisturizers, vaginal estrogen, ospemifene, dehydroepiandrosterone, local testosterone therapy, cannabidiol, and fractional CO2 laser treatments. In some cases, dyspareunia may need to be specifically addressed by pelvic floor physical or sex therapists.
Conclusions:
Dyspareunia is a common issue in postmenopausal women, which remains largely untreated. Women with dyspareunia require a thorough history, targeted physical examination, and coordination of multiple disciplines including medical clinicians, pelvic floor physical therapists, and sex therapists.
Vestibulodynia (VBD), an idiopathic pain disorder characterized by erythema and pain of the vulvar vestibule (the inner aspect of the labia minora and vaginal opening), is the most common cause of sexual pain for women of reproductive age. Women also feel discomfort with contact with clothing and tampon use. As most women with this disorder only have pain with provocation of the tissue, topical anesthetics applied to the vestibule are the current first line treatment for temporary pain relief. Treatment options are limited due to anatomical constraints of the vestibular region, poor drug retention time, imprecise dosing, leakage, and overall product messiness. In this study we report a novel approach to treatment of VBD using thin film designed to fit the vulvar vestibule and deliver lidocaine locally. Two use cases for VBD treatment were identified 1) rapid drug release (<5 min), for use prior to intercourse and 2) long-acting release (≥120 min) for prolonged use and relief throughout the day. Cellulose-based mucoadhesive thin films were fabricated using a solvent casting method. Three polymers including hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethycellulose (HMPC), were selected owing to their biocompatibility and ideal properties for film casting. Films casted with HEC, HPC, and HPMC exhibited mucoadhesive properties relative to a control, with the highest mucoadhesive force recorded for films casted with HPC. Effect of media volume, pH, presence of mucin and presence of drug on film dissolution rates were investigated. Dissolution rates were independent of media volume, media pH or drug presence, whereas faster dissolution rates were obtained for all films in presence of mucin. In vitro lidocaine release kinetics were influenced by polymer type, percent drug loading and film casting thickness. Lidocaine release was based on a diffusion mechanism rather than through film dissolution and faster release (∼5 min) was observed for HEC films compared HPC films (∼120 min). Higher drug loading and film thickness resulted in slower and more prolonged release kinetics of lidocaine. All films were biocompatible and exhibited good mechanical properties. Two film formulations (9% w/w HPC with 12% w/w LHC, 5% w/w HEC with 6% w/w LHC) were optimized to meet the two use case scenarios for VBD treatment and moved into in vivo testing. In vivo testing demonstrated the safety of the films in BALB/c mice, and the pharmacokinetic analysis demonstrated the delivery of lidocaine primarily to the vaginal tissue. We demonstrate the ability to develop a mucoadhesive, biodissolvable thin film and fine-tune drug release kinetics to optimize local delivery of lidocaine to the vulva.
Vaginal dryness is common during and after menopause due to declining estrogen. It is one of the symptoms of vulvovaginal atrophy (VVA), which is part of the genitourinary syndrome of menopause. This can be distressing for women and cause pain, discomfort, and dyspareunia. Vaginal dryness affects over 50% of postmenopausal women but is under-reported and thus under-treated due to barriers to seeking help. Estrogen replacement can resolve symptoms, but may be contraindicated or not desired by all women. Over-the-counter vaginal moisturizers and lubricants can ease the symptoms of VVA. However, their chemical composition varies enormously and some are known to cause detrimental effects due to unphysiological pH, osmolality, and additives. The primary purpose of this review is to assess both their efficacy and safety. Women should be directed toward products that are as 'body-similar' as possible to vaginal secretions in terms of pH and osmolality. Products with potentially harmful ingredients should be avoided. Lubricants can be trialed for sexual activity and moisturizers for symptom control, even if topical or systemic menopause hormone therapy is being used.
Introduction:
Postoperative sore throat (POST) is a common complication after tracheal intubation. Various studies have examined the efficacy of interventions using lidocaine to prevent POST. Here, we present a meta-analysis assessing their efficacy.
Evidence acquisition:
We systematically searched the PubMed, Embase, and Cochrane databases to identify randomized controlled trials (RCTs) assessing the efficacy of lidocaine interventions in the prevention of POST. Data synthesis was obtained by using relative risks (RRs) with 95% confidence intervals (CIs) for the incidences of POST, cough, and hoarseness after different interventions.
Evidence synthesis:
Twenty-seven RCTs involving 3049 patients were analyzed, including 14 on the use of intracuff lidocaine, 8 on the use of a lidocaine jelly, 8 on the use of a lidocaine spray, and 4 on the use of intravenous lidocaine. Intracuff lidocaine and intravenous lidocaine showed significant efficacy compared with controls in preventing POST at 1 h and 24 h, whereas lidocaine jelly and lidocaine spray did not. Intracuff lidocaine, lidocaine spray, and intravenous lidocaine decreased the incidence of cough, but only the intracuff lidocaine decreased the incidence of hoarseness.
Conclusions:
This meta-analysis indicated that intracuff lidocaine and intravenous lidocaine are effective in preventing POST. In addition, intracuff lidocaine was associated with reducing the risk of both cough and hoarseness.
Preclinical safety assessment of vaginal products includes cytotoxicity assays upon cell lines. Furthermore, tissue explants have been considered for application on ex vivo models. In this study, traditional and renewed methods were studied for toxicity assessment of vaginal semisolids upon products currently used in clinical practice as antimicrobials (Gino-Canesten®, Sertopic®, Dermofix®, Gyno-Pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®), containing estrogens (Ovestin®, Blissel®, Colpotrophine®), and reference formulations (Replens®, Universal Placebo). Two in vitro cytotoxicity tests were performed: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake upon uterine (HEC-1A), cervical (HeLa) and vaginal (VK2 E6/E7) cells, according to ISO/EN 10993-5 (in vitro evaluation of medical devices). Similarly, a strategy to determine tissue viability on ex vivo porcine vaginal model (through MTT reduction assay and histological analysis) was developed and optimized. The vaginal cell line VK2 E6/E7 conducted to the most accurate calculation of half-maximal toxic concentration among all cells on the MTT assay. However, it was shown not be sensitive to the neutral red uptake assay. Tissues from the porcine model were collected with approx. 15% variability in thickness and variation coefficients lower than 25% when testing negative and positive controls were achieved. These models can improve cost-efficiency in early steps of product development.
Background:
The main aim of this work was to develop stable (>2 years) doxycycline formulation, at clinically relevant concentrations and using clinically relevant formulation. Doxycycline has a MMP- inhibitory effects that is important for the treatment of various oral mucosal conditions. Therefore, protecting doxycycline from degradation in aqueous formulation requires halting or prevention of oxidation and epimerisation of the active compound.
Methods:
Stabilizing excipients were intuitively put together to enhance the stability as a cumulative effort. A total of 30 hydrogels were compared with different types and concentrations of stability enhancing excipients, pH, storage temperatures (4, 25 and 40°C) and mucoadhesive polymers. The duration of the study was from day 1 and up to 58 months. The gelation temperature was adjusted below the actual body temperature. The complexation efficiency between the doxycycline and HPβCD was studied using the DSC, FTIR and XRPD.
Results:
The majority of formulations at 4°C were highly stable by the end of 58 months and their stabilities were improved at all 3 temperatures.
Conclusion:
In conclusion, it is possible to prevent doxycycline from both oxidation and epimerization in an aqueous formulation, for up to 5 years.
Objective:
The vaginal microbiota helps protect the female genital tract from disease. We sought to describe the composition of the vaginal microbiota in premenopausal, perimenopausal, and postmenopausal women and to explore the association between the microbiota and vulvovaginal atrophy (VVA).
Methods:
Eighty-seven women (aged 35-60 y) were classified as premenopausal (n = 30), perimenopausal (n = 29), or postmenopausal (n = 28) according to Stages of Reproductive Aging Workshop guidelines. Midvaginal bacterial community composition was characterized by 16S ribosomal RNA gene analysis.
Results:
Bacterial communities clustered into six community state types (CSTs), of which four were dominated by Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, or Lactobacillus jensenii, and two (CST IV-A and CST IV-B) had low relative abundance of Lactobacillus. CST IV-A was characterized by Streptococcus and Prevotella, whereas CST IV-B was characterized by Atopobium. There were significant associations between menopause stage and CST (P = 0.004) and between VVA and CST (P = 0.002). Perimenopausal women were more likely to be classified as CST IV-A or L. gasseri CST, whereas postmenopausal women were often classified as CST IV-A. CSTs dominated by L. crispatus and L. iners were more prevalent in premenopausal women. Nineteen participants had signs of mild or moderate VVA. Compared with women with no VVA, the vaginal microbiota of women with mild or moderate atrophy had 25-fold greater odds of being classified as CST IV-A versus L. crispatus CST (adjusted odds ratio, 25.89; 95% credible interval, 2.98-406.79).
Conclusions:
A distinct bacterial community state (CST IV-A) with a low relative abundance of Lactobacillus is associated with VVA. Future studies recruiting a larger number of women are needed to replicate the findings. This study provides an impetus for future longitudinal studies designed to manage, modulate, and restore vaginal microbiota homeostasis, which would provide stronger evidence for a causal relationship with VVA and ultimately improve the treatment and prevention of atrophic vaginitis in menopause.
Introduction:
This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM).
Methods:
This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire.
Results:
In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n = 60) or LAT/TIM (n = 55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4-6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group.
Conclusion:
TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores.
Trial registration:
UMIN Clinical Trials Registry Identifier, UMIN000023862.
Funding:
Santen Pharmaceutical Co., Ltd., Osaka, Japan.
What is a female sexual orgasm? What biological, psychological, or social functions does it serve?
Male and female genital anatomy evolve from the same embryonic tissue. Is it possible that men and women have the same potential for orgasmic response? Have forces external to a woman’s biology influenced her potential enjoyment of this bodily function or is female orgasm a by-product of that early sameness, and variable because it has no or very little functional or evolutionary benefit?
Female sexual response models and the classification of female sexual dysfunctions continue as works-in-progress which direct research and treatments.
The ultimate therapeutic aim is to allow each woman to have the best possible sex life and orgasm that she wants. The current treatments for female orgasmic dysfunction are on the whole successful. However, we need to be supportive of the pharmaceutical industry finding medications that can be used appropriately and responsibly to benefit women with changes that cannot be resolved with current strategies.
Orgasms are a very important quality of life issue for many women.
For persons at risk of HIV infection who practice receptive anal intercourse (RAI), topical rectal microbicides represent a promising option for coitally-dependent protection. The study compared colorectal distribution and user sensory experiences of two different volumes of rectal gel for suitability as rectal microbicide. Eight HIV negative men with a history of recent RAI were enrolled into a two-period, sequence randomized, dosing study comparing 3.5 mL and 10 mL of radiolabeled (1 mCi 99mTc-DTPA) universal placebo hydroxyethyl cellulose (HEC) gel. Each participant received two doses in the research unit, one of each volume, separated by a washout period of at least 2 weeks. Each research unit dose was followed by a self-administered take-home dose in the context of preparing for RAI. Safety and gastrointestinal distribution were assessed after the research unit doses; safety, perceptibility, and acceptability were assessed after take-home doses. There were no adverse effects of Grade 2 or higher and all resolved spontaneously. Both volumes were well tolerated and received high acceptability scores. Perceptibility scores showed meaningful effect size differences ranging from Cohen's d=.5 to d=1.2. The 3.5 mL and 10 mL gel volumes distributed similarly (p>0.2) within the rectosigmoid ranging from 0.69 cm to 18.84 cm and 1.21 cm to 19.01 cm from the anorectal junction, respectively. Both volumes covered the typical gastrointestinal distribution of ejaculate following simulated intercourse based on other studies. Either of these gel volumes could reasonably be pursued for the next phase of development of rectal microbicides.
The objectives of this study are to compare the two definitions of female sexual dysfunction, namely dysfunction per se (A category) and personal distress caused by dysfunction (B category), and to gauge their associations with some sociodemographic aspects and level of sexual well-being. The subjects were a nationally representative sample of sexually active Swedish women (n: 1056) aged 18-65 y, who participated in a combined structured interview/questionnaire investigation. The functions analysed were: self-reported sexual desire, interest, lubrication, orgasm, genital pain and vaginism, which were subclassified for the A and B categories into no, mild (sporadically occurring) and manifest dysfunction. Sexual well-being was reported along a six-grade scale ranging from very satisfied to very dissatisfied. The sociodemographic items registered were: education, occupation, financial situation, social group, immigrant status, location of domicile and church-going. Aggregated mild and manifest dysfunction per se of sexual interest, orgasm and vaginal lubrication were reported by about 60-90%. More than one-third had dyspareunia, but few reported vaginism. Mild dysfunctions were clearly more common than manifest dysfunctions. Not fully 45% of those with manifest low interest and orgasm perceived these dysfunctions as manifestly distressing, while in 60-70% lubricational insufficiency of dyspareunia led to manifest distress. Age and the included sociodemographic variables had marginal or no influence on sexual functions. A four-factor sexual function pattern was identified, closely linking A and B categories in a pairwise manner. Three factors, labelled sexual desire, orgasm and genital function were powerful classifiers (discriminant analysis) of level of sexual well-being. Hence, it is a matter of taste whether to use the A or the B category. Together, they can explain the gross level of satisfaction with sexual life to an adequate extent.
Nonoxynol-9 (N-9) is virucidal in vitro, and is therefore a candidate microbicide for preventing sexual transmission of HIV. However, the activity of N-9 is nonspecific, suggesting that virucidal levels may produce adverse effects including epithelial disruption, inflammation of the genital mucosa, or both. A randomized placebo controlled trial of daily use of 100 mg of N-9 took place for 1 week in 40 female volunteers. Outcome measures included symptoms, colposcopic and histologic changes in the genital tract, and impact on vaginal flora. Genital irritation was reported by 10 of the N-9 and 5 of the placebo group. Colposcopy showed erythema in 9 of the N-9 group and 2 of the placebo group. Histologic inflammation was found in 7 of the N-9 group and 2 of the placebo group. Inflammatory changes were characterized by patchy infiltration of the lamina propria predominantly with CD8+ lymphocytes and macrophages, in the absence of epithelial disruption. A transient reduction in numbers of lactobacilli was observed in 9 of the 15 women using N-9, and 6 of 18 women using placebo. N-9 used for 7 days in a standard spermicidal dose was associated with increased irritation, colposcopic and histologic evidence of inflammation and was more frequently associated with reduction in numbers of lactobacilli during gel use. The clinical significance of the recruitment of cells susceptible to HIV infection to the genital mucosa is unknown but raises concerns about the suitability of N-9 as a microbicide when given in this dose.
To determine the safety of a vaginal microbicide, COL-1492, containing 52.5 mg nonoxynol-9, applied once daily for 14 days among healthy volunteers.
A randomized, double-blind controlled trial with three arms, COL-1492 gel versus placebo gel versus no-treatment controls, was conducted. Outcomes of interest were reported genital symptoms, incidence of gynaecological signs, and incidence of genital lesions revealed by colposcopy. Participants were enrolled in four centres (Belgium, The Netherlands, and two in Thailand).
A total of 534 women participated in the study: 179 used COL-1492, 178 used placebo, and 177 were no-treatment controls. Study visits were scheduled 1 week prior to enrollment (day -7), day 0 (enrollment), day 8 and day 14. The most frequently reported genital symptom was vaginal discharge in both the COL-1492 and placebo groups. This appeared to be related to leakage of the product out of the vagina. The incidence of lesions associated with epithelial disruption (ulcers and abrasions) was very low (< 2%) and there was no statistically significant difference between the three groups. Of the lesions observed by colposcopy that did not involve epithelial disruption, petechial haemorrhage was the most frequently detected, with an incidence of 20.1, 9.0 and 7.3% in the COL-1492, placebo and control groups, respectively. COL-1492 users had a higher incidence of erythema (8.4 versus 2% in the other groups).
COL-1492 showed minimal toxicity when applied once daily. A Phase III trial to assess the product's effectiveness in HIV prevention is currently ongoing.
Traditional vaginal lubricants have been shown to adversely affect sperm motility. Astroglide, a new vaginal lubricant, and K-Y Jelly were tested at varying concentrations to assess their suitability for infertility patients requiring a lubricant. The vaginal lubricants tested impaired sperm motility in a concentration-dependent but not time-dependent manner. We conclude that all traditional vaginal lubricants should be avoided in patients desiring conception. Future studies should attempt to mimic in vivo conditions and focus on concentration-dependent effects.
A new formulation of intranasal flunisolide containing less propylene glycol was compared with the original formulation for efficacy and acceptability in more than 200 patients with symptoms of perennial allergic rhinitis. In this multicenter, randomized, double-blind, parallel group study, symptomatic patients were treated with either the new or the original formulation of 0.025% solution of intranasal flunisolide for 4 weeks to provide 200 micrograms flunisolide daily. Both formulations were highly effective in decreasing symptom scores as evident from patient diary reports before and after treatment (P less than .001). Similarly, nasal airflow was improved with each treatment as measured by anterior rhinomanometry (P less than .0002) and the number of patients with nasal eosinophilia decreased (P less than .01). Finally, fewer patients using the new formulation reported nasal burning or stinging and the acceptability rating of the new formulation was higher.
To determine the prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome in a clinical population of reproductive-age women.
A ten-page questionnaire was administered to a consecutive sample of women age 18-45 years who were approached in the waiting areas of two obstetrics and gynecology practices and three family medicine practices in central North Carolina. Of 701 women approached to fill out the questionnaire, 581 (83%) returned completed forms suitable for analysis.
The reported prevalence of dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome was 90, 46, 39, and 12%, respectively. Low income was found to be a risk factor for dysmenorrhea and dyspareunia, and African-American race was found to be a risk factor for pelvic pain. Pelvic pain was also more common among women 26-30 years old. Otherwise, dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome were not associated with age, parity, marital status, race, income, or education.
Dysmenorrhea, dyspareunia, pelvic pain, and irritable bowel syndrome are common complaints among women of reproductive age and are not consistently associated with demographic risk factors. Therefore, inquiry about these pelvic pain complaints should be a routine part of health care for women.
To determine the effects of natural vegetable oils and vaginal lubricants on sperm motion and viability.
Four widely used vaginal lubricants (K-Y Jelly, Astroglide, Replens, and Touch) and two vegetable oil products that have been used as vaginal lubricants were purchased through local vendors. Sperm was obtained by masturbation without lubrication from normal, healthy donors. Lubricants were mixed with sperm from individual donors and the effects on sperm motility were determined at 1, 15, 30, and 60 minutes.
Southwestern Fertility Associates of The University of Texas Southwestern Medical Center at Dallas.
Sperm motility was evaluated by manual motility counts and by computer-assisted semen analysis. Sperm viability was evaluated with Hoechst 33258 dye. The effects of the various lubricants were compared with those of a spermicidal agent, Gynol II (negative control) and Ham's F-10 (positive control).
Commercial lubricants inhibited sperm motility by 60-100% after 60 minutes of incubation. Sperm exposed to Replens or Astroglide were nonmotile and nonviable after incubation for 60 minutes, similar to the control, nonoxynol-9 containing product Gynol II. Canola oil had no detrimental effects and was indistinguishable from Ham's F-10 in terms of sperm viability and motility.
For couples with infertility, the use of vaginal lubricants during intercourse is not recommended. In cases where a lubricant is required, careful selection can maximize sperm motility and viability.
Thiocarboxanilide UC-781 is a highly potent and selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, which also has virucidal properties. Recent studies have shown that UC-781 would seem an ideal candidate for application as a vaginal virucide.
To investigate the antiviral potency and stability of UC-781 in a lipophilic gel formulation.
UC-781 was formulated in replens gel at different concentrations and administered intravaginally to rabbits at 5% in replens gel for 10 days. UC-781 was also exposed to temperatures of 4, 37 and 50 degrees C, and to low pH (6.0, 4.3, 2.0 and 1.2). A number of microorganisms were exposed in culture to serial dilutions of UC-781.
The drug was stable under low pH conditions and did not lose its antiviral potency upon 4 h exposure to pH 3.5 (the estimated vaginal pH). UC-781 can be easily formulated into a lipophilic gel (replens; up to 5%) and proved fully stable at 50 degrees C for 30 days. There was no effect on the growth of microorganisms (i.e., Candida and Lactobacillus strains) that are present in the vaginal flora. Neither systemic side-effects, nor local inflammation or damage of the vaginal mucosa or epithelium were observed in rabbits to which 5% UC-781 in replens gel had been administered. UC-781, formulated as 0.5, 0.2 and 0.05% replens gel, and UC-38, alpha-APA and zidovudine, formulated as 0.5 or 0.2% replens gel, were effective in protecting CEM cells in the very beginning against productive HIV-1 replication. This points to an efficient diffusion of the drugs from the lipophilic gel to the hydrophilic culture medium. However, subsequent subcultivations at a dilution rate of 1:10 every 3-4 days resulted in a rapid breakthrough of virus with all drugs except UC-781 in its 0.5 and 0.2% gel formulation. These cultures were fully protected against HIV-1 and remained completely cleared from virus for at least 10 subcultivations.
The virus that emerged under 0.05% UC-781 remained highly sensitive to the NNRTI, including UC-781, in cell culture, suggesting a lack of resistance development under our experimental conditions.
A fluid medium was developed to simulate the fluid produced in the human vagina. The composition of the medium was based on an extensive review of the literature on constituents of human vaginal secretions. In choosing the ingredients for this medium, the goal was to emphasize properties that influence interactions of vaginal fluid with topical contraceptive, prophylactic, or therapeutic products. Among these properties, pH and osmolarity play a dominant role in physicochemical processes that govern drug release and distribution.
PIP
This article investigates a vaginal fluid simulant intended to model the fluid properties originating in the vagina--specifically the vaginal transudite found in healthy, nonpregnant premenopausal women. Methods of volume measurement of vaginal fluid fell into two categories: those that measured the quantity of vaginal fluid present at any one time and those that measured production over an extended interval. A volume of 0.75 ml vaginal fluid simulant was used. The proposed simulant was designed to incorporate information about chemical composition determined by previous researchers; this information emphasized pH modeling and the osmolarity of the material. Consequently, the specific "recipe" for 1 liter of this simulant given as compound and weight (g) was as follows: NaCl, 3.51; KOH, 1.40; Ca(OH)2, 0.222; borine serum albumin, 0.018; lactic acid, 2.00; acetic acid, 1.00; glycerol, 0.16; urea, 0.4; glucose, 5.0. The simulant was designed to have the same physical and chemical properties as those known to influence intravaginal gel efficacy. Further efforts by other researchers are needed if improved simulants are to be developed.
The objective of this study was to develop a simple alternative test using naked snails (slugs) for screening the irritating potency of chemicals on mucosal surfaces.
The effect of various absorption enhancers and two beta-blocking agents on the mucosal tissue was determined from the total protein and lactate dehydrogenase released from the foot mucosa after treatment. Additionally, mucus production and reduction in body weight of the slugs caused by the treatment were measured.
According to the effects on the mucosal epithelium of the slugs the following rank order of increasing toxicity was established: PBS, HP-beta-CD (5%), beta-CD (1.8%) and oxprenolol hydrochloride (1%) < DDPC (1%) < STDHF (1%) < BAC (1%), SDC (1%) and propranolol hydrochloride (1%). The results of the present study are in agreement with other studies using the same compounds on other models.
The results of this study indicated the mucosa of slugs can serve as a primary screening tool for the evaluation of chemicals on mucosal surfaces. By simply measuring mucus production and weight loss reliable toxicity information can be obtained. This demonstrates rapid screening tests can be carried out using simple toxicity endpoints.
Propylene glycol (PG) (1-2 propanediol; CAS No 57-55-6) is a low toxicity compound widely used as a food additive, in pharmaceutical preparations, in cosmetics, and in the workplace-for example, water based paints, de-icing fluids, and cooling liquids. Exposure to PG mist may occur from smoke generators in discotheques, theatres, and aviation emergency training. Propylene glycol may cause contact allergy, but there is sparse information on health effects from occupational exposure to PG.
Non-asthmatic volunteers (n=27) were exposed in an aircraft simulator to PG mist over 1 minute, during realistic training conditions. Geometric mean concentration of PG was 309 mg/m3 (range 176-851 mg/m3), with the highest concentrations in the afternoon. The medical investigation was performed both before and after the exposure (within 15 minutes). It included an estimate of tear film stability break up time, nasal patency by acoustic rhinometry, dynamic spirometry, and a doctor's administered questionnaire on symptoms.
After exposure to PG mist for 1 minute tear film stability decreased, ocular and throat symptoms increased, forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) was slightly reduced, and self rated severity of dyspnoea was slightly increased. No effect was found for nasal patency, vital capacity (VC), FVC, nasal symptoms, dermal symptoms, smell of solvent, or any systemic symptoms. Those exposed to the higher concentrations in the afternoon had a more pronounced increase of throat symptoms, and a more pronounced decrease of tear film stability. In four subjects who reported development of irritative cough during exposure to PG, FEV1 was decreased by 5%, but FEV1 was unchanged among those who did not develop a cough. Those who developed a cough also had an increased perception of mild dyspnoea.
Short exposure to PG mist from artificial smoke generators may cause acute ocular and upper airway irritation in non-asthmatic subjects. A few may also react with cough and slight airway obstruction.
We conducted a comprehensive systematic literature review of five sexual problems in order to estimate their population prevalence and to investigate issues arising from the reviewing of epidemiological literature. Two independent reviewers scrutinized abstracts, extracted data, and assessed methodological quality. Twenty-eight relevant studies were identified. Prevalence figures varied considerably, and meta-analysis was not possible because of heterogeneity in study quality and design. Prevalence depends on case definition, characteristics of the study population, and time frame of the prevalence estimates, therefore, design, implementation, and reporting of epidemiological studies needs standardization before systematic reviews and meta-analyses can be carried out.
Nonoxynol-9 (rINN, nonoxinol-9) is an over-the-counter spermicide that has in-vitro anti-HIV-1 activity. Results of studies of its effectiveness in prevention of HIV-1 infection in women have been inconclusive. We aimed to assess effectiveness of this vaginal gel.
We did a randomised, placebo-controlled, triple-blinded, phase 2/3 trial with COL-1492, a nonoxynol-9 vaginal gel, in 892 female sex workers in four countries: Benin, Côte d'Ivoire, South Africa, and Thailand. 449 women were randomly allocated nonoxynol-9 and 443 placebo. Primary endpoint was incident HIV-1 infection. Secondary endpoints included Neisseria gonorrhoeae and Chlamydia trachomatis infections. Analysis was by intention to treat.
765 women were included in the primary analysis. HIV-1 frequency in nonoxynol-9 users was 59 (16%) of 376 compared with 45 (12%) [corrected] of 389 in placebo users (402.5 vs 435.0 woman-years; hazard ratio adjusted for centre 1.5; 95% CI 1.0-2.2; p=0.047). 239 (32%) women reported use of a mean of more than 3.5 applicators per working day, and in these women, risk of HIV-1 infection in nonoxynol-9 users was almost twice that in placebo users (hazard ratio 1.8; 95% CI 1.0-3.2). 516 (68%) women used the gel less frequently than 3.5 times a day, and in these, risk did not differ between the two treatments. No significant effect of nonoxynol-9 on N gonorrhoeae (1.2; 0.9-1.6) or C trachomatis (1.2; 0.8-1.6) infections was reported.
This study did not show a protective effect of COL-1492 on HIV-1 transmission in high-risk women. Multiple use of nonoxynol-9 could cause toxic effects enhancing HIV-1 infection. This drug can no longer be deemed a potential HIV-1-prevention method. Assessment of other microbicides should continue.
Spermicides containing nonoxynol-9 (N-9) may increase HIV transmission. In women, intravaginal N-9 is found in the uterus shortly after its insertion. Exposure of the female upper reproductive tract to N-9 may alter epithelial integrity, thereby increasing HIV transmission risk. Our goal was to characterize the histological effects of N-9 on uterine epithelium in an animal model. Female mice were exposed to intravaginal or intrauterine Advantage-S (N-9), Replens, K-Y(R) jelly or water. After various exposure times, mice were sacrificed and stained uterine tissue sections were analyzed by a pathologist blinded to treatment.Intravaginal and intrauterine N-9 administration resulted in disruption of uterine epithelium compared to Replens, K-Y jelly or water. N-9 caused rapid (within 10 min), focal, uterine epithelial sloughing and complete epithelial loss within 24 h. Epithelial regeneration began 48 h after exposure N-9 and was completely restored within 72 h; the new epithelial layer, however, was composed of cuboidal cells instead of normally present columnar cells. In addition, hemorrhage and necrosis were present are all time points examined. Our results demonstrate for the first time that N-9 has a deleterious effect on uterine epithelium. Although these results were observed in a mouse model, similar disruption of the upper reproductive tract epithelium in women by N-9 may facilitate HIV infection and serve as an unrecognized portal of human HIV transmission.
Frequent use of some vaginal formulations can induce mucosal irritation. Therefore, it is important to evaluate their vaginal tolerance.
The goal of this study was to optimize the mucosal irritation test using slugs for the evaluation of the local tolerance of vaginal gels and investigate the relevance of the test.
The irritation potential of the gels was assessed by the amount of mucus produced during a repeated 30-minute contact period. Membrane damage was estimated from the release of proteins and enzymes. After optimization of the procedure, the local tolerance of several vaginal gels was evaluated.
Hydroxyethyl cellulose gel induced no irritation, because the mucus production and the protein release were low and no enzyme release was detected. Replens and K-Y jelly resulted in an increased mucus production; however, no increased protein and no enzyme release were detected. The nonoxynol-9-containing gels Protectaid, Advantage S, and Conceptrol caused a higher mucus production and an increased protein release and/or enzyme release, indicating severe irritation.
The mucosal irritation test using slugs can be used for local tolerance testing of vaginal formulations.
The current study was conducted to determine the relative safety of sexual lubricants for rectal use.
Our goal was to identify a sexual lubricant that would not damage the rectal epithelium.
We describe a mouse assay to determine the degree to which lubricants cause rectal sloughing. We also tested lubricants for cytotoxicity and their effect on Herpes simplex virus (HSV-2) infection after rectal challenge.
Of the products tested, Delube and KY-Plus are most likely to damage the rectal epithelium, whereas Viamor, Vagisil, and Astroglide would cause some degree of rectal damage. PBS, Carraguard, and methylcellulose were not toxic in any of the assays.
We have developed a quantitative method to assay the degree of sloughing of the rectal epithelium. Using this and other techniques, we are able to predict the degree to which lubricants could be safe for rectal use.
The objective of this study was to limit the test procedure time of the Slug Mucosal Irritation test to one day and to determine whether it is a relevant and reliable method to predict the eye irritation potential of chemicals. The irritation potential of several eye reference chemicals can be estimated by the amount of mucus produced when tested at a 1% concentration (60 min). Since some in vivo irritating chemicals did not influence this endpoint the effect of increasing concentrations on membrane damage was investigated. This study revealed that when tested at a 3.5% concentration (60 min) the underestimated chemicals induced an increased protein and/or enzyme release. A two-step classification prediction model was developed that classified the chemicals first by the amount of mucus produced (1%, 60 min). Chemicals that did not affect this endpoint were classified based on the membrane damage induced by a second treatment (3.5%, 60 min). The results were compared with the corresponding EU classification (NI, R36 and R41) and 71% of the chemicals were correctly classified with a specificity and sensitivity of 75% and 94%, respectively. Repeated testing of the chemicals revealed a good intra-laboratory reproducibility. The test seems to be a promising method for screening the eye irritating potential of chemicals.
Alternative methods to the Draize eye irritation test, such as the hen's egg test-chorioallantoic membrane (HET-CAM) or the bovine corneal opacity and permeability (BCOP) tests, are currently used to evaluate the irritant potential of cosmetic or consumer products. Although, for strong irritants, the results of these tests correlate well with those of the Draize test, they appear to be less suited to identify mild irritants. In order to improve the sensitivity of alternative eye irritation tests, we developed a novel method that uses a human corneal epithelial cell line (CEPI), and the endpoints of cytotoxicity and IL-8 release. Twelve make-up removers were assessed by the HET-CAM, BCOP and CEPI tests, as well as in a clinical in-use test under ophthalmological control after their application to the external eye lid. In addition, we investigated the impact of osmolality and raw material composition on in vitro and clinical results and compared the in vitro results with those of clinical studies. Overall, although HET-CAM results were unrelated to eye discomfort and adverse clinical signs, they correlated mainly with the presence and concentration of surfactants in the test articles. BCOP scores were unrelated to clinical signs, but related mainly to glycol and sodium lactate content and concentration in the test articles. Cytotoxicity in CEPI mainly correlated with presence and concentrations of surfactants, and IL-8 release to clinical signs and/or glycol and sodium lactate concentrations. Overall, IL-8 release appeared to be the most sensitive and reliable endpoint to predict human eye tolerance to mildly irritant products. Although our results suggest that the IL-8 assay appears to be a promising screen for borderline-irritant formulations, further experiments are required to confirm and validate these preliminary results.
ACIDFORM gel is being studied as a vaginal contraceptive and microbicide. This study was conducted to make certain that males will not be subjected to an unacceptable risk of penile irritation as a result of exposure to the product in future studies.
This was a randomized, double-masked, single-center Phase I study in circumcised and uncircumcised men to assess penile irritation, safety and acceptability of seven consecutive doses of ACIDFORM gel compared with K-Y Jelly Personal Lubricant. Each participant was instructed to apply 2 mL of the study product to his penis at bedtime, to wash it off 6-10 h later and to record any symptoms on a diary card. At the follow-up visit, a genital examination was performed and participants were asked about adverse events (AEs) and completed an acceptability questionnaire.
Of the 36 men enrolled, 2 out of 24 (8.3%) ACIDFORM gel users and 5 out of 12 (41.7%) K-Y Jelly users reported genital symptoms. Genital examination findings were observed in 2 out of 24 (8.3%) ACIDFORM gel users and in 1 out of 12 (8.3%) K-Y Jelly users. All product-related AEs were considered mild except for two in the K-Y Jelly group. Both products were acceptable.
ACIDFORM gel applied to the penis for seven consecutive days appears to be at least as safe and well-tolerated as the marketed lubricant K-Y Jelly among healthy low-risk men.
A fluid medium was developed to simulate the salient physical and chemical properties of human semen. The composition of the medium was based upon an extensive review of the literature on constituents of human semen. In choosing the ingredients for this medium, the goal was to emphasize properties that influence interactions of human semen with topical contraceptive, prophylactic, or therapeutic products. Among these properties, pH and buffering capacity, osmolarity, ionic strength, and rheological properties play dominant roles in the physico-chemical processes that govern drug release kinetics and delivery vehicle distribution.
The purpose of this study was to evaluate the local tolerance of vaginal gels (three gels containing dapivirine, the placebo gel, and Conceptrol) with the Slug Mucosal Irritation test and to compare the results with those of the rabbit vaginal irritation test. The irritation potential on the slug mucosa was assessed by the mucus production caused by a repeated treatment for 5 successive days. Additionally, membrane damage was estimated by the protein and enzyme release. By means of a classification prediction model the formulations were classified into four irritation classes. The effect of a 10-day intravaginal application of the gels on the rabbit vaginal and cervical mucosa was evaluated by means of macroscopic and microscopic examination. The placebo and dapivirine gels induced no irritation of the slug mucosa (low mucus production and protein release, no enzyme release) and no vaginal or cervical irritation in rabbits. Conceptrol caused severe irritation of the slug mucosa (increased mucus production, protein release, and enzyme release) and irritation of the rabbit vagina and cervix. The results obtained with the Slug Mucosal Irritation test were comparable to those of the rabbit vaginal irritation test.
The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.
An expanded Phase I trial was performed to assess the safety and acceptability of 6% cellulose sulfate gel (CS) in comparison with K-Y Jelly.
Sexually abstinent (cohort I) and sexually active (cohort II) women in India, Nigeria and Uganda applied 3.5 ml of either 6% CS gel or K-Y Jelly for seven consecutive days. Safety was assessed by symptoms and signs (including colposcopy) of genital irritation, review of adverse events, and by changes in vaginal health as assessed by microscopy.
One hundred and eighty women (90 on CS and 90 on K-Y Jelly) were enrolled. Baseline characteristics of women in both gel groups were similar. In cohort I, six (14%) women on CS and 12 (27%) on K-Y Jelly reported genital symptoms, two (in K-Y Jelly group) of whom withdrew from the study. New colposcopy findings or findings showing deterioration were detected in four (9%) women on CS and nine (21%) women on K-Y Jelly in cohort I. Two women on CS and three on K-Y Jelly in cohort II reported genital symptoms. Five women (11%) in each gel group in cohort II had new colposcopy findings or findings showing deterioration. The differences between the gel groups were not statistically significant. The majority of women had no problem with their assigned product.
A vaginal application of 6% cellulose sulfate twice daily for seven consecutive days is as safe and well tolerated as a similar regimen of K-Y Jelly. Further development of 6% CS for prevention of HIV and pregnancy is recommended.
A three-dimensional organotypic vaginal-ectocervical (VEC) tissue model has been developed to test the irritation of topically applied spermicides, microbicides, and vaginal-care products. The in vitro tissue model was reconstructed using normal VEC epithelial cells and is well stratified, containing differentiated basal, suprabasal, intermediate, and superficial cell layers similar to in vivo tissue. The intermediate and superficial cell layers contain glycogen, and the expression of cytokeratins 13 and 14 in the tissue also parallels that of native tissue. The MTT viability assay and histological assessment were used to test inter-lot and intra-lot reproducibility. The MTT average intra-lot coefficient of variation (CV) was less than 10% and the time required to reduce tissue viability by 50% (ET-50) following application of 1% Triton X-100 averaged 1.25+/-0.24h (n=23) upon completion of the 11-day culture period and 1.30 h+/- 0.19 for the same tissues stored overnight at 4 degrees C on agarose gels. The utility of the VEC model for irritation studies was examined by testing commercially available products using the MTT assay and histological assessment. The average ET-50 values ranged between 1.8 and 2.7h for feminine washes, 3.9-6.7 h for spermicides, 6.8-18 h for anti-itch creams, and >18 h for douches, lubricants, and anti-fungal creams. Studies of cytokines released from VEC cultures following product application showed that elevated concentrations of IL-1alpha and IL-1beta were associated with toxicity of test materials. In conclusion, the VEC tissue model is a highly reproducible, non-animal means to assess the irritation of contraceptives, microbicides, and vaginal-care products.
Topical microbicides against the human immunodeficiency virus (HIV) 1 that are nonirritating to the female genital epithelium are urgently needed to slow the heterosexual spread of HIV infection. Products that are also effective contraceptives provide additional benefits. Cellulose sulfate (CS) is a noncytotoxic antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV.
We performed a multicenter, Phase I, placebo-controlled, randomized study to evaluate the genital toxicity of CS. Two cohorts of healthy women used 3.5 ml of 6% CS gel or 3.5 ml of K-Y Jelly, vaginally, bid, for 14 days. The first cohort was sexually abstinent, and the second cohort was sexually active.
CS was associated with only a slightly higher odds ratio (OR) of symptoms of minor urogenital irritation compared to the inactive lubricant K-Y Jelly (OR=2.02, 95% confidence interval=0.90-4.53). In addition, there were minor shifts in some genital flora, but there was no evidence of greater inflammation as evidenced by few colposcopic findings, decreased influx of polymorphonuclear cells and minimal changes in proinflammatory cytokines. Moreover, both products appeared acceptable to most women. Product leakage was identified as more of a problem in sexually abstinent women, but less so in women using the product for sexual intercourse, as would be the case in actual practice.
CS was safe for twice-daily use for 14 days. CS is appropriate for future studies in effectiveness trials.
To evaluate the effect of vaginal lubricants Pre-Seed, FemGlide, Astroglide, and Replens on human sperm motility and chromatin integrity.
Prospective, comparative, in vitro study.
Andrology laboratory at tertiary care hospital.
Thirteen normozoospermic donors.
Semen samples from 13 subjects were incubated in human tubal fluid media (HTF) controls and 10% (vol/vol) of Pre-Seed, FemGlide, Astroglide, and Replens lubricants. After 30 minutes, progressive sperm motility was assessed by light microscopy. Semen samples of 12 patients were placed in positive control (HTF), negative control (10% K-Y Jelly lubricant), and 10% vol/vol Pre-Seed and FemGlide lubricants. After 4 hours culture, spermatozoa were analyzed for percent DNA fragmentation index with use of the acridine orange-based sperm chromatin structure assay.
Sperm motility and percent DNA fragmentation index.
Percent motility did not differ significantly between HTF controls and Pre-Seed, whereas FemGlide, Replens, and Astroglide lubricants demonstrated a significant decrease in motility. There was no significant difference in percent DNA fragmentation index between the HTF controls and Pre-Seed, but a significant decline in sperm chromatin quality occurred with FemGlide and K-Y Jelly.
Pre-Seed does not cause a significant decrease in progressive sperm motility or chromatin integrity in contrast to other lubricants used by couples.
The Vulvodynia Survival Guide
- Mate
Evaluation of Astroglide, a new vaginal lubricant – Effects of length of exposure and concentration on sperm motility.
- Frishman