Elsevier

Contraception

Volume 66, Issue 5, November 2002, Pages 369-375
Contraception

Original research article
Safety of single daily use for one week of C31G HEC gel in women

https://doi.org/10.1016/S0010-7824(02)00433-XGet rights and content

Abstract

Genital irritation and user acceptability was compared after seven nightly bedtime exposures to 1.2% C31G hydroxyethyl cellulose (HEC), 2% nonoxynol-9 (N-9) (Gynol II) or HEC vehicle alone. Sixty healthy women over 18 years old at low risk for sexually transmitted disease with normal menses were randomly assigned to one of three groups. Entrance and exit pelvic exams documented vaginal pH and Gram stain. Genital irritation was assessed by patient diaries, a telephone call 24 to 48 h after first use, colposcopy done the day after last product use, and an acceptability questionnaire at exit. Eighty percent of the women using C31G HEC experienced symptoms of vaginal burning or heat compared to 25% of the N-9 users and 5% of the vehicle users. Colposcopic findings were similar for the active treatments of C31G HEC and N-9: 50% vs. 60% developed new lesions, 25% vs. 20% had lesions that disrupted epithelial integrity, and 50% vs. 45% had minor lesions, respectively. Findings with the HEC vehicle were half as frequent. Twelve percent of women had epithelial disruption that was assessed by the colposcopist as applicator-related. Gram stains were half as likely to show bacterial vaginosis after N-9 use (6 → 3) and one fourth as likely after vehicle or C31G HEC use (4 → 1). When asked if they would use the product if it were an effective contraceptive, 55% of the vehicle users, 35% of the N-9 users, and 25% of the C31G HEC users agreed. Product acceptability of C31G HEC was limited by the sensation of heat or burning. The C31G HEC product had a similar safety profile to N-9 in this comparative trial.

Introduction

Due to the increasing occurrence of heterosexual transmission of human immunodeficiency virus (HIV) infection worldwide, attention has focused on means to reduce this problem. Female-controlled vaginal products are being developed to provide protection against both pregnancy and sexually transmitted infections. The finding that frequent use of the detergent barrier spermicide nonoxynol-9 may increase the risk of HIV transmission [1] has accelerated the interest in identifying other compounds that could prevent the heterosexual transmission of HIV. An estimated 21 million US women would be interested in using a vaginal microbicide if it were available [2].

An investigational spermicide with microbicidal properties, C31G hydroxyethyl cellulose (HEC) or Savvy (Biosyn, Philadelphia, PA, USA), composed of two surface-active compounds, a myristamine oxide and a cetyl betaine in equimolar concentrations, offers a potential alternative to nonoxynol-9. C31G has shown in vitro activity against a large number of gram-positive and gram-negative bacterial strains that is wider than nonoynol-9 (N-9) [3]. It has antifungal properties as well, at in vitro minimum inhibitory concentrations of 0.0015% [4]. It is a potent virucidal agent with activity against HIV and herpes simplex virus (HSV) [5]. Viral inactivation of both cell-free and cell-associated HIV (SupT1 cells) has been reported in vitro for C31G [6]. Preexposure of chlamydial elementary bodies to 0.1% C31G reduces the in vitro infectivity over 95% compared to a 17% reduction in infectivity by 0.1% N-9 [7]. Also, C31G has demonstrated in vitro spermicidal activity equal to N-9 with the ability to penetrate cervical mucus [8].

These properties suggest that C31G may be a promising alternative to nonoxynol-9 both as a spermicide and as a microbicide/virucide. Oral exposure to C31G in humans is safe. TheraSol, a marketed antimicrobial mouthwash1, has C31G as an active ingredient [9]. C31G is safe in animal models. In female mice, 95% of an oral dose of 0.21 g/kg was absorbed by 8 h. Urinary excretion was the main mechanism of drug elimination [10]. Topical application of 0.3 mL of C31G for 4 h before removal resulted in 3% systemic absorption and 3% retention of product in the skin of rabbits [10]. In rats and dogs, over 80% of the intravenous dose was eliminated in urine with the balance in feces. Oral administration resulted in greater fecal excretion (48% rat, 31% dog). Vaginal administration in animals was confounded by oral ingestion of the product during grooming. Half the dose was absorbed with an excretion pattern matching that of oral ingestion. Ten-day rabbit vaginal irritation studies of 2% to 20% C31G showed irritation equivalent to similar concentrations of N-9. Six-month rat toxicology studies of up to 150 mg/kg/day and 9-month beagle exposure to a maximum of 18 mg daily showed no systemic toxicity. A study of cultured vaginal epithelium (keratinocytes) by Krebs et al. [11] showed C31G to be one fifth as toxic as N-9 over a 48-h continuous exposure to 0.00025%, but showed increased toxicity compared to N-9 when vaginal cells were exposed for 2 h a day for 3 days. Seventy-five percent cell toxicity was seen at a concentration of 0.6 × 10−3 C31G compared to 2.2 × 10−3 N9.

The current study was designed to evaluate vaginal epithelial changes using a colposcope after seven daily consecutive exposures to 1.2% C31G formulated with hydroxyethyl cellulose (HEC) compared to either 2% N-9 (Gynol II) as a positive control or HEC vehicle as a negative control product.

Section snippets

Materials and methods

The study objectives were twofold:

  • To assess symptoms using participant diary and interviews, and seek evidence of genital irritation by colposcopy of C31G HEC compared to a marketed N-9 product and the vehicle alone after seven daily product uses.

  • To assess user acceptability of C31G HEC compared to the marketed N-9 product by participant questionnaire.

Selected demographics of study participants

Sixty women were randomized to the three treatments (see Table 1). The participants were similar in age (32 ± 7 years) with mean parity of 1.4 ± 1.4. The incidence of smoking was slightly higher in the C31G HEC group.

The enrollees in the N-9 group were less likely to have had more than one delivery, yet were more likely to use sterilization as their contraceptive method. All of the participants completed the study and none were lost to follow-up.

Gynecologic examination findings

No epithelial lesions were found on naked-eye

Discussion

Both of the active products caused epithelial disruption in this study. Of note, half the women with such lesions experienced difficulty with the applicator itself. One woman using the negative control product (vehicle) exited due to bleeding after product use. The design of the applicator should be carefully considered to avoid areas that can scrape or damage epithelium. The instruction to place the product “as high in the vagina as possible” should be modified since it implies that the woman

Summary

This Phase I double-blind randomized study of C31G HEC suggests that physical epithelial changes after 7 consecutive days of product use were similar to changes seen with a marketed 2% N-9 product (Gynol II). The subjective symptoms of genital burning or heat, however, were much greater with the C31G HEC product, which limits its usefulness as currently formulated. The applicator and instructions used in this study were responsible for half the deep epithelial injuries and should be

Notes

  • 1.

    Oratec: Therasol and Other Antimicrobial Agent, http://www.oratec.net/home.irrig.html.

  • 2.

    Health Decisions, 6350 Quadrangle Drive, Suite 300, Chapel Hill, NC 27517, 919-967-1111, www.healthdec.com.

  • 3.

    Heinke Technology Incorporated, 5120 NW 38th Street, Lincoln, NE 68524, 402-470-2600, www.htiplastic.com.

Acknowledgements

This study was funded by NIH Contract No. N01-HD-8-3286, administered through the Master Agreement Order # 2 (Master Agreement Announcement NICHD-CD-95-02) for the NIH Clinical Network for Contraceptive Research. The authors wish to acknowledge H. Trent MacKay, M.D., M.P.H., Special Assistant for Obstetrics and Gynecology, Contraception and Reproductive Health Branch and Health Decisions, for study oversight. Susan A. Ballagh, M.D., David F. Archer, M.D., and Jay M. Baker, M.D., were partially

References (18)

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