Comparison of the sensitivity of the vaginal mucous membranes of the albino rabbit and laboratory rat to nonoxynoxynol-9

Kaminsky, M.; Szivos, Marylou M.; Brown, Kelly R.; Willigan, Donald A.

doi:10.1016/0278-6915(85)90161-9

Cited by 25 publications

(17 citation statements)

References 3 publications

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“…In the present study, we have evaluated the in vivo toxicities of the gel formulations after intravaginal application once daily for 14 days to rabbits. The rabbit is considered to be the most appropriate model with which to establish the tolerance of vaginal formulations because of the high sensitivity of its vaginal mucosa (9,22). We have previously reported that the gel alone prepared in acetate buffer is well tolerated by the vaginal mucosae of rabbits when it is applied once daily for 14 days (13).…”

Section: Discussionmentioning

confidence: 99%

Thermoreversible Gel Formulations Containing Sodium Lauryl Sulfate or n -Lauroylsarcosine as Potential Topical Microbicides against Sexually Transmitted Diseases

Roy

Gourde

Piret

et al. 2001

Antimicrob Agents Chemother

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The microbicidal efficacies of two anionic surfactants, sodium lauryl sulfate (SLS) and n-lauroylsarcosine (LS), were evaluated in cultured cells and in a murine model of herpes simplex type 2 (HSV-2) intravaginal infection. In vitro studies showed that SLS and LS were potent inhibitors of the infectivity of HSV-2 strain 333. The concentrations of SLS which inhibit viral infectivity by 50% (50% inhibitory dose) and 90% (90% inhibitory dose) were 32.67 and 46.53 M, respectively, whereas the corresponding values for LS were 141.76 and 225.30 M. In addition, intravaginal pretreatment of mice with thermoreversible gel formulations containing 2.5% SLS or 2.5% LS prior to the inoculation of HSV-2 strain 333 completely prevented the development of genital herpetic lesions and the lethality associated with infection. Of prime interest, no infectious virus could be detected in mouse vaginal mucosa. Both formulations still provided significant protection when viral challenge was delayed until 1 h after pretreatment. Finally, intravaginal application of gel formulations containing 2.5% SLS or 2.5% LS once daily for 14 days to rabbits did not induce significant irritations to the genital mucosa, as demonstrated from macroscopic and histopathologic examinations. These results suggest that thermoreversible gel formulations containing SLS or LS could represent potent and safe topical microbicides for the prevention of HSV-2 and possibly other sexually transmitted pathogens, including human immunodeficiency virus.

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Section: Discussionmentioning

confidence: 99%

Thermoreversible Gel Formulations Containing Sodium Lauryl Sulfate or n -Lauroylsarcosine as Potential Topical Microbicides against Sexually Transmitted Diseases

Roy

Gourde

Piret

et al. 2001

Antimicrob Agents Chemother

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“…Experiments to determine the sensitivity of the vaginal mucosa in albino rabbits and rats to N-9 exposure indicated that the levels of irritation after five consecutive daily doses of N-9 (2.5 to 25%) were concentration dependent in both animals (9). Similar studies evaluating the toxicity associated with N-9 application in rabbits and rats also demonstrated that changes in the continuity of the epithelial lining, edema of the submucosal layer, and inflammatory cell infiltrates were proportional to the concentration of N-9 administered (4).…”

mentioning

confidence: 99%

Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides

Catalone¹,

Kish-Catalone²,

Budgeon

et al. 2004

Antimicrob Agents Chemother

107

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Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, associated with N-9 exposure were characterized with the goal of validating a mouse model of microbicide toxicity. In vitro studies using submerged cell cultures indicated that human cervical epithelial cells were inherently more sensitive to N-9-mediated damage than human vaginal epithelial cells. These results correlated with in vivo findings obtained by using Swiss Webster mice in which intravaginal inoculation of 1% N-9 or Conceptrol gel (containing 4% N-9) resulted in selective and acute disruption of the cervical columnar epithelial cells 2 h postapplication accompanied by intense inflammatory infiltrates within the lamina propria. Although damage to the cervical epithelium was apparent out to 8 h postapplication, these tissues resembled control tissue by 24 h postapplication. In contrast, minimal damage and infiltration were associated with both short-and long-term exposure of the vaginal mucosa to either N-9 or Conceptrol. These analyses were extended to examine the relative toxicity of polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under evaluation as a candidate topical microbicide. In similar studies, in vivo exposure to 1% PEHMB caused minimal damage and inflammation of the genital mucosa, a finding consistent with the demonstration that PEHMB was >350-fold less cytotoxic than N-9 in vitro. Collectively, these studies highlight the murine model of toxicity as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides.

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“…Many animal species have been used as models to predict the in vivo mucosal toxicity. These include monkeys, dogs, guinea pigs, rabbits, rats, and mice (Eckstein et al, 1969;Chvapil et al, 1980;Gray et al, 1984;Kaminsky et al, 1985;Patton et al, 1999Patton et al, , 2004aPatton et al, , 2004bMilligan et al, 2002;Abdel-Rahman et al, 2004;Catalone et al, 2004). Except for nonhuman primates, these animal models do not mimic the vaginal inflammation that is seen clinically in humans due to their differences in genital tract physiology, anatomy, and histology.…”

Section: Introductionmentioning

confidence: 99%

“…The simple cuboidal or columnar epithelium is highly sensitive to mucosal irritants when compared to the stratified squamous epithelium of human vagina (D'Cruz et al, 2004b). A predetermined 4-point semiquantitative scoring system is used to assess changes in the continuity of the epithelial lining, edema of the submucosal layer, vascular congestion, and the inflammatory cell infiltrate of this layer after exposure to increasing doses of the test agent for 5 to 20 days (Eckstein et al, 1969;Chvapil et al, 1980;Kaminsky et al, 1985). Because of earlier reports on the correlation between rabbits and humans with respect to the irritation potential of vaginal formulations, the rabbit remains the only FDA recommended model for safety evaluation of vaginal products.…”

Section: Introductionmentioning

confidence: 99%

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

D’Cruz

Erbeck²,

Uckun

2005

Toxicol Pathol

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A porcine model was established to test the mucosal toxicity potential of a thiophene thiourea (PHI-443)-based anti-HIV microbicide and a vanadocene-based spermicide, vanadocene dithiocarbamate (VDDTC) in comparison to benzalkonium chloride (BZK). Nine domestic pigs (Duroc) in nonestrus stage received a single intravaginal application of 2% BZK, 2% PHI-443, or 0.1% VDDTC-containing gel. At various times after gel application, cell differentials and levels of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ , and TNF-α) in cervicovaginal lavage (CVL) fluid were monitored by flow cytometry and ELISA, respectively. Eight pigs were exposed intravaginally to a gel with and without BZK or VDDTC for 4 consecutive days and vaginal tissues were scored histologically for inflammation using a new scoring system. Only CVL fluid from pigs exposed to BZK showed a significant increase of IL-1β, IL-8, and also IL-18 production when compared to the controls, PHI-443 or VDDTC-treated groups. Maximum levels of BZK-induced IL-1β (100-fold), IL-8 (2,500-fold), IL-18 (80-fold), and IFN-γ (10-fold) were found at 24 hours. In the in vivo porcine vaginal irritation model, increased levels of vaginal IL-1β, IL-8, and IL-18 were associated with histological changes consistent with vaginal inflammation. These results demonstrate that key cervicovaginal inflammatory cytokines are useful in vivo biomarkers for predicting the mucosal toxicity potential of vaginal products in the physiologically relevant and sensitive porcine model.

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Comparison of the sensitivity of the vaginal mucous membranes of the albino rabbit and laboratory rat to nonoxynoxynol-9

Cited by 25 publications

References 3 publications

Thermoreversible Gel Formulations Containing Sodium Lauryl Sulfate or n -Lauroylsarcosine as Potential Topical Microbicides against Sexually Transmitted Diseases

Thermoreversible Gel Formulations Containing Sodium Lauryl Sulfate or n -Lauroylsarcosine as Potential Topical Microbicides against Sexually Transmitted Diseases

Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

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