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Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.

Pedersen C, Slepenkin A, Andersson SB, Fagerberg JH, Bergström CA, Peterson EM - PLoS ONE (2014)

Bottom Line: Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel.Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection.The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.

ABSTRACT
The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

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Related in: MedlinePlus

Comparison of the three treatment groups as to protection against a vaginal challenge with C. trachomatis.The overall mice culture positive over a month period in each treatment group after a vaginal inoculation with 500 IFU of C. trachomatis is shown. The positive control group was sham treated whereas the other two groups received the vaginal gel formulated with and without INP0341. The P values, as determined by the Fischer’s exact test, are shown comparing groups to one another. A P value <0.05 was considered statistically significant. The experiment was repeated with two sets of mice and the graph reflects the combined results of the two experiments.
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pone-0110918-g005: Comparison of the three treatment groups as to protection against a vaginal challenge with C. trachomatis.The overall mice culture positive over a month period in each treatment group after a vaginal inoculation with 500 IFU of C. trachomatis is shown. The positive control group was sham treated whereas the other two groups received the vaginal gel formulated with and without INP0341. The P values, as determined by the Fischer’s exact test, are shown comparing groups to one another. A P value <0.05 was considered statistically significant. The experiment was repeated with two sets of mice and the graph reflects the combined results of the two experiments.

Mentions: The formulated gel with and without 1 mM INP0341 showed a protective effect in mice when administered intravaginally, with the former showing a greater effect, against a vaginal challenge with C. trachomatis, serovar D (Figure 5). All (10/10) of the mice in the positive control group were infected as shown by positive vaginal cultures within the four weeks after inoculation. In contrast, 65% (13/20) of the mice treated with the gel without INP0341 were infected (P = 0.064) whereas only 32% (8/25) of mice treated with the gel formulation with INP0341 were infected as determined by a positive vaginal culture (P<0.001). The difference between the group of mice treated with the gel not containing INP0341 when compared to mice treated with the formulated INP0341 was significant, in terms of the total number of infected mice over the 4 week observation period (P = 0.038).


Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.

Pedersen C, Slepenkin A, Andersson SB, Fagerberg JH, Bergström CA, Peterson EM - PLoS ONE (2014)

Comparison of the three treatment groups as to protection against a vaginal challenge with C. trachomatis.The overall mice culture positive over a month period in each treatment group after a vaginal inoculation with 500 IFU of C. trachomatis is shown. The positive control group was sham treated whereas the other two groups received the vaginal gel formulated with and without INP0341. The P values, as determined by the Fischer’s exact test, are shown comparing groups to one another. A P value <0.05 was considered statistically significant. The experiment was repeated with two sets of mice and the graph reflects the combined results of the two experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214720&req=5

pone-0110918-g005: Comparison of the three treatment groups as to protection against a vaginal challenge with C. trachomatis.The overall mice culture positive over a month period in each treatment group after a vaginal inoculation with 500 IFU of C. trachomatis is shown. The positive control group was sham treated whereas the other two groups received the vaginal gel formulated with and without INP0341. The P values, as determined by the Fischer’s exact test, are shown comparing groups to one another. A P value <0.05 was considered statistically significant. The experiment was repeated with two sets of mice and the graph reflects the combined results of the two experiments.
Mentions: The formulated gel with and without 1 mM INP0341 showed a protective effect in mice when administered intravaginally, with the former showing a greater effect, against a vaginal challenge with C. trachomatis, serovar D (Figure 5). All (10/10) of the mice in the positive control group were infected as shown by positive vaginal cultures within the four weeks after inoculation. In contrast, 65% (13/20) of the mice treated with the gel without INP0341 were infected (P = 0.064) whereas only 32% (8/25) of mice treated with the gel formulation with INP0341 were infected as determined by a positive vaginal culture (P<0.001). The difference between the group of mice treated with the gel not containing INP0341 when compared to mice treated with the formulated INP0341 was significant, in terms of the total number of infected mice over the 4 week observation period (P = 0.038).

Bottom Line: Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel.Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection.The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.

ABSTRACT
The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

Show MeSH
Related in: MedlinePlus