Comparison of Vaginal Tolerance Tests of Spermicidal Preparations in Rabbits and Monkeys

Eckstein, Peter P.; Jackson, Mike; Millman, Nina; Sobrero, Aquiles J.

doi:10.1530/jrf.0.0200085

Cited by 152 publications

(98 citation statements)

References 2 publications

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“…The vagina (cervical end, middle, and vulvar end), cervix (left and right), uterine horns (left and right), uterus (left and right), ovaries (left and right), and urinary bladder were excised for macroscopic and histologic examinations. The degree of irritation was determined as described previously (9). The four basic criteria used for macroscopic evaluations were vascularization, edema, ulceration, and necrosis.…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

“…The total scoring system was as follows: 1 to 4, minimal; 5 to 8, mild; 9 to 12, moderate; and 13 to 16, marked. A total score of between 0 and 8 is considered acceptable, a total score of 9 or 10 is marginal, and a total score of over 11 is unacceptable (9).…”

Section: Methodsmentioning

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 FDA requires the rabbit vaginal irritation model for preclinical safety testing, as it is the gold-standard model to predict vaginal irritation (29). Rabbits have a simple cuboidal or columnar epithelium that is highly sensitive to mucosal irritants.…”

Section: Vaginal Irritation Safety Testing Of Placebo Gel Formulationmentioning

confidence: 99%

Formulation Development and Evaluation of Innovative Two-Polymer (SR-2P) Bioadhesive Vaginal Gel

2014

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The main objective of this investigation was to study the feasibility of developing a vaginal bioadhesive microbicide using a SRI's proprietary two-polymer gel platform (SR-2P). Several formulations were prepared with different combinations of temperature-sensitive polymer (Pluronic® F-127) and mucoadhesive polymer (Noveon® AA-1), producing gels of different characteristics. Prototype polymeric gels were evaluated for pH, osmolality, buffering capacity, and viscosity under simulated vaginal semen dilutions, and bioadhesivity using ex vivo mini pig vaginal tissues and texture analyzer. The pH of the polymeric gel formulations ranged from 5.1 to 6.4; the osmolality varied from 13 to 173 mOsm. Absolute viscosity ranged from 513 to 3,780 cPs, and was significantly reduced (1.5-to 3-fold) upon incubation with simulated vaginal and semen fluid mixture. Among the tested gels (indicated in the middle row as a molar ratio of a mixture of Noveon vs. Pluronic), only SR-2P retained gel structure upon dilution with simulated fluids and mild simulated coital stress. The pH of the SR-2P gel was maintained at about 4.6 in simulated vaginal fluid and also showed high peak force of adhesion in mini pig vaginal tissue. Furthermore, SR-2P gel caused no or only minimal irritation in a mouse vaginal irritation model. The results of this preliminary study demonstrated the potential application of SR-2P gel as a vaginal microbicide vehicle for delivery of anti-HIV agents.

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“…The rabbit is preferred by regulatory authorities because of its sensitivity to vaginal irritants and because of the wealth of experience with this model in safety evaluations of spermicides (6). However, histological differences between the rabbit and human vaginal epithelia likely mean that this species is overly sensitive (7).…”

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confidence: 99%

The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

Holt

Cameron²,

Dias³

et al. 2015

Antimicrob Agents Chemother

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dWhen developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. With an estimated 2.3 million new human immunodeficiency virus type 1 (HIV-1) infections in 2012 (1) and a total number of people living with HIV estimated at 35.3 million in the same year, the need for effective prevention strategies remains critical. Although barrier prevention strategies, such as male and female condoms, are effective, and behavioral programs teaching the benefits of monogamy and abstinence have shown some success (2-4), they have not significantly impacted the epidemic. One area of key concern is sub-Saharan Africa, where 57% of HIV-infected people are women (1). In order to provide prevention strategies to women in this high-risk population, locally (vaginally or rectally) applied products containing potent antiretroviral drugs are being developed by many different groups. These microbicides represent one of the most promising prophylactic strategies currently being developed in terms of being simple to self-administer, relatively easy to produce, and by virtue of the lower drug levels required compared to those with systemic approaches, the potential to be within reach of the health system and nongovernmental organization (NGO) budgets in the developing world. A key advantage to the topical microbicide approach is also that the same targeted active ingredient...

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Comparison of Vaginal Tolerance Tests of Spermicidal Preparations in Rabbits and Monkeys

Cited by 152 publications

References 2 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

Formulation Development and Evaluation of Innovative Two-Polymer (SR-2P) Bioadhesive Vaginal Gel

The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

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