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Effects of intrinsic variables on release of sodium dodecyl sulfate from a female controlled drug delivery system.

The release profile of sodium dodecyl sulfate (SDS), a potent microbicide, from a female controlled drug delivery system (FcDDS) made of Carbopol 934P and hydroxypropyl methylcellulose (HPMC) was evaluated using a newly developed in vitro Simulant Vaginal System (SVS). The major parameters involved in the release profiles of SDS were categorized as: (1) formulation variables (total loading weight of intravaginal delivery systems, SDS loading doses in intravaginal delivery systems); (2) intrinsic variables (vaginal fluid secretion rate, vaginal fluid pH); and (3) extrinsic variables (inserting position). In most conditions, about 70% of the loading dose of SDS was released from FcDDS within 6h of application. The release profile showed that concentrations needed for complete human papilloma virus (HPV) inactivation could be obtained within 10 min after the application. It was demonstrated that intrinsic variables (i.e., the rate and pH of vaginal fluid) played an integral role in determining the release profile of SDS, while loading dose of SDS in FcDDS did not significantly affect the percentage of the total amount of SDS released. It can be concluded that FcDDS can be exploited as a controlled delivery device for prevention against sexually transmitted diseases.

Acrylic Resins↗

How oestrogen or progesterone might change a woman's susceptibility to HIV-1 infection.

Worldwide, 18.5 million women are infected with the human immunodeficiency virus (HIV-1). At least 80% of these HIV infections have occurred as a result of sexual intercourse with an infected male partner. This review focuses on how HIV-1 enters the human female reproductive tract, and how oestrogen or progesterone, by altering the cervicovaginal epithelium, might change a woman's susceptibility to HIV infection. Experiments on hysterectomised Rhesus monkeys suggest that the vagina, rather than the cervix or uterus, is the main site of viral entry. If ovariectomised monkeys are given systemic oestrogen treatment, this makes them completely resistant to infection by intravaginally administered simian immunodeficiency virus (SIV), whereas progesterone-treated animals, like the untreated controls, are extremely susceptible. Some studies have also shown that women on systemic long-acting gestagen-only contraceptives have a thinner vaginal epithelium and hence might be more susceptible to HIV infection; this is certainly true of post-menopausal women. The beneficial effects of oestrogen are thought to be due to increased thickness and cornification of the cervicovaginal epithelium, which prevents the virus from coming into contact with the target Langerhans cells (LCs). Topical vaginal oestrogen treatment is widely used as a safe and effective way of thickening and keratinising the vaginal epithelium in post-menopausal women. Perhaps this could be an exciting new way of protecting women from HIV infection.

Administration, Intravaginal↗

Studies on gynaecological hydrophilic lactic acid preparations, Part 7: use of chitosan as lactic acid carrier in intravaginal tablets (globuli vaginales).

Intravaginal tablets based on hydrophilic methylcellulose and containing lactic acid complexed with chitosan undergo deformation under standard conditions. The high flow--limit of the gel originating from the tablets as well as its dynamic viscosity should ensure the durability of this dosage form on the vaginal mucosa. By selecting either ratios of lactic acid to chitosan of 1:1 or 2:1 it is possible to obtain tablets that disintegrate into a gel form at pH 3.8-4.4, i.e. the pH remains within the physiological range. Increasing the amount of lactic acid in the complex in relation to polymer to a 4:1 ratio results in gels with a lower pH while giving an acid reserve that can neutralize the excess of alkali present in severe vaginal infections.

Adhesives↗

A randomized trial of misoprostol versus extra-amniotic sodium chloride infusion with oxytocin for induction of labor.

OBJECTIVE: Our purpose was to compare the efficacy and safety of misoprostol and extra-amniotic sodium chloride infusion with oxytocin for induction of labor. STUDY DESIGN: This randomized trial compared two methods of labor induction in women requiring cervical ripening. One hundred twenty-three women undergoing labor induction with a Bishop score < or =5 were randomly selected to receive either misoprostol, 50 microg intravaginally every 4 hours, or extra-amniotic sodium chloride infusion. The primary outcome variable was the time interval from induction to vaginal delivery. RESULTS: Sixty-one women received extra-amniotic sodium chloride infusion and 62 women received misoprostol. The mean time interval from the start of induction to vaginal delivery was 15.0 +/- 5.0 hours and 16.5 +/- 7.2 hours for the extra-amniotic infusion and misoprostol groups, respectively (P, not significant). The cesarean delivery rate was not significantly different between the 2 groups (32.8% for the extra-amniotic infusion group; 19.4% for the misoprostol group). Maternal and neonatal outcomes were similar between the 2 groups. CONCLUSIONS: Both methods of induction are equally efficacious and result in similar maternal and neonatal outcomes.

Administration, Intravaginal↗

A new therapy for pelvic endometriosis and uterine adenomyosis: local effect of vaginal and intrauterine danazol application.

In order to investigate the effect of the local direct action of danazol upon endometriosis, intravaginal and intrauterine application were tried. A vaginal danazol ring containing 2 g to 3.5 g danazol not only reduced both dysmenorrhea and the extent of pelvic endometriosis in all 35 infertile women, but also resulted in conception in 13 out of 35 infertile women while the vaginal ring was in place. Uterine adenomyosis usually fails to respond to oral danazol therapy, but an intrauterine device containing 175 mg of danazol was effective in reducing the size of the uterus and in inducing pregnancy in 66.6% cases. It is noteworthy that this vaginal or intrauterine danazol therapy did not inhibit ovulation, but still effected atrophy of endometriosis and aided in the establishment of pregnancy. These results clearly demonstrate that the main mode of action of danazol is its direct action on endometriotic cells.

Administration, Intravaginal↗

Progesterone receptors in vaginal tissue of post-menopausal women.

Progesterone receptors were measured in both cytosolic and nuclear fractions in vaginal tissue samples obtained from a total of 17 post-menopausal women. Ten of the women were given oestriol (E3) intravaginally 6-24 h before surgery, while the remaining 7 received no treatment. Cytosolic receptors were not detected in any of the 7 tissue samples from the untreated women, but nuclear receptors were present in two cases. In the 10 women treated with E3, it was possible to measure cytosolic receptors in 5 tissue samples and nuclear receptors in 7 samples. The mean receptor concentrations in the cytosolic and nuclear fractions were similar (45-65 fmol/mg protein) and the apparent dissociation constant of the receptors in all the samples was 1-2 nmol/1. These data would seem to indicate that oestrogen treatment results in the synthesis of new receptors, although not in all tissues, which compounds the scepticism regarding the validity of the classical two-step model for steroid hormone action.

Administration, Intravaginal↗

Studies on gynaecological hydrophilic lactic acid preparations, part 6: use of Eudragit E-100 as lactic acid carrier in intravaginal tablets.

Hydrophilic intravaginal tablets based on methylcellulose and containing lactic acid component with Eudragit E-100 undergo swelling in standard conditions. A high flow-limit of the gel that originates from the tablets as well as its dynamic viscosity should allow for the durable dosage form in the vagina. By choosing a 1:1 ratio of lactic acid to Eudragit E-100, it is possible to obtain tablets disintegrating into a gelform at physiological range of 3.8-4.4. An increase in the amount of lactic acid in the complex in relation to the polymer up to 2:1 and 3:1 ratios results in gels with a lower pH. These gels possess an acid reserve that might be ableto neutralise the excess of alkali present in severe vaginal infections.

Administration, Intravaginal↗

Oestrus synchronization in dairy heifers using a progesterone releasing intravaginal device.

This paper describes a pilot trial carried out, to investigate the use of progesterone releasing intravaginal device(PRID) in controlled breeding in heifers under South African conditions. PRID's containing progesterone and oestradiol benzoate were employed for oestrus synchronization and reproductive management in ten 18-month-old, well-managed, heifers in a commercial Transvaal highveld dairy herd. PRID's were inserted into the vagina of each animal and removed after 12 days. Oestrus observation was done continuously and on the first observed oestrus the heifers were artificially inseminated once. Oestrus detection continued normally for returns to oestrus. Pregnancy was confirmed by rectal palpation eight weeks after breeding if no return to oestrus had occurred. The incidence of clinical oestrus within 3 days after removal of the PRID's (defined as the oestrus response) was 90%. The conception or pregnancy rate following the first artificial insemination was 77.8%.

Administration, Intravaginal↗

Studies on gynaecological hydrophilic lactic acid preparations. Part 5: The use of Eudragit E-100 as lactic acid carrier in intravaginal tablets.

Intravaginal tablets based on hydrophilic methylcellulose and containing lactic acid complexed with Eudragit E-100 undergo deformation under standard conditions. The high flow--limit of gel originating from the tablets as well as its dynamic viscosity should enable durability of this dosage form on the vaginal mucosa. By selecting either 1 : 1 or 2 : 1 ratios of lactic acid to Eudragit E-100 it is possible to obtain tablets that disintegrate into a gelform at pH 3.8-4.4, i.e. the pH remains within the physiological range. Increasing the amount of lactic acid in the complex in relation to the polymer to a 4:1 ratio results in gels with a lower pH while possessing an acid reserve that can neutralize the excess of alkali present in severe vaginal infections.

Administration, Intravaginal↗

Duration of vaginal retention and potential duration of antiviral activity for five nonoxynol-9 containing intravaginal contraceptives.

OBJECTIVE: The purpose of this study was to determine the vaginal retention of five nonoxynol-9 intravaginal contraceptives. METHOD: An open-label crossover study in 10 premenopausal volunteers was performed at an outpatient clinical research center. The outcomes are described utilizing the median and range. RESULT: At 8 h post-instillation, the median amounts of nonoxynol-9 present in the vagina were: Delfon 7.68 mg, Conceptrol 5.18 mg, Advantage 24 1.95 mg, VCF 1.74 mg, and Semicid 1.51 mg respectively. Our calculated theoretical minimal amount needed to protect against HIV infection is 2.00 mg. CONCLUSION: The best vehicle for retaining nonoxynol-9 in the vagina appears to be foam. Further research in the effectiveness of nonoxynol-9 in prevention of the spread of HIV infection should be directed toward the use of foam vehicles to deliver nonoxynol-9 to the vagina.

Administration, Intravaginal↗

Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protection against herpes simplex virus-2 in the genital tract.

Development of vaccines capable of preventing the transmission or limiting the severity of sexually transmitted viruses, such as HSV and HIV, will likely be dependent on the induction of potent long-lasting mucosal immune responses in the genital tract. Recently, synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs were shown to serve as potent adjuvants for the induction of mucosal immune responses. Here, we show that intranasal immunization with CpG ODN, plus recombinant glycoprotein B (rgB) of HSV-1, results in significantly elevated levels of specific anti-gB IgA Abs in vaginal washes that remained high throughout the estrous cycle. Additionally, dramatically elevated numbers of specific IgA Ab-secreting cells were present and persisted in the genital tract in response to intravaginal (IVAG) HSV-2 challenge. HSV-2-specific CTL were observed at moderate levels in the spleens of CpG or non-CpG ODN-immunized mice. In contrast, strong CTL responses were observed locally in the genital tissues of both groups following IVAG HSV-2 challenge. Interestingly, mice immunized intranasally with rgB plus CpG ODN, but not non-CpG ODN, were significantly protected following IVAG HSV-2 challenge. Measurement of virus in protected CpG-immunized mice revealed a log lower level of replication within the first few days after infection. In conclusion, these results indicate that intranasal immunization with CpG ODN plus protein mediates immunity in the female genital tract capable of protecting against a sexually transmitted pathogen.

Adjuvants, Immunologic↗

The effects of intravaginal clindamycin and metronidazole therapy on vaginal mobiluncus morphotypes in patients with bacterial vaginosis.

OBJECTIVE: The objective of this study was to compare the effects of treatments for bacterial vaginosis (BV) on vaginal Mobiluncus morphotypes. STUDY DESIGN: Analyses were performed on Mobiluncus scores from similarly conducted studies evaluating clindamycin vaginal single-dose cream (CVSDC) or metronidazole vaginal gel (MVG) in 55 patients with BV and with Mobiluncus morphotypes at baseline. RESULTS: Both treatment groups demonstrated significant reductions in Mobiluncus score. However, the Mobiluncus score at test-of-cure was lower in the CVSDC than in the MVG group (P=0.0471). More patients in the CVSDC group than in the MVG group achieved microbiologic (57.5% vs. 26.7%; P=0.04), clinical (57.5% vs. 26.7%; P=0.04), and therapeutic cures of BV (45.0% vs. 20.0%; P=0.09). CONCLUSION: Clindamycin reduces vaginal Mobiluncus morphotypes to a greater extent than metronidazole in patients with BV; this correlates with a higher BV cure rate.

Actinomycetales Infections↗

Bacterial vaginosis-associated microflora and effects of topical intravaginal clindamycin.

OBJECTIVES: The goals of this study were as follows: (1) to further define the microbiologic characteristics of bacterial vaginosis in nonpregnant women, (2) to evaluate the in vivo activity of topical intravaginal clindamycin and reference this activity to clinical cure, and (3) to evaluate for clindamycin-related emergence of species. STUDY DESIGN: Vaginal microflora was identified and quantified from 33 women with bacterial vaginosis at enrollment and 4 to 7 days after treatment with placebo or three different dosages of clindamycin administered twice daily for 5 days in a double-blind, randomized trial. RESULTS: Clindamycin eradicated and/or decreased counts of major bacterial vaginosis-associated microflora such as Gardnerella, gram-negative and gram-positive anaerobes, and Mycoplasma hominis; this was correlated with cure in 22 of 24 (92%) women. Altered flora (nonlactobacilli) among some of the women who received clindamycin appeared to be transient and without apparent adverse effects. CONCLUSION: Microbial (and clinical) results support use of clindamycin as effective treatment of bacterial vaginosis.

Administration, Intravaginal↗

The Toll-like receptor 7 (TLR7) agonist, imiquimod, and the TLR9 agonist, CpG ODN, induce antiviral cytokines and chemokines but do not prevent vaginal transmission of simian immunodeficiency virus when applied intravaginally to rhesus macaques.

The initial host response to viral infection occurs after Toll-like receptors (TLRs) on dendritic cells (DC) are stimulated by viral nucleic acids (double-stranded RNA, single-stranded RNA) and alpha interferon (IFN-alpha) and IFN-beta are produced. We hypothesized that pharmacologic induction of innate antiviral responses in the cervicovaginal mucosa by topical application of TLR agonists prior to viral exposure could prevent or blunt vaginal transmission of simian immunodeficiency virus (SIV). To test this hypothesis, we treated rhesus monkeys intravaginally with either the TLR9 agonist, CpG oligodeoxynucleotides (ODN), or the TLR7 agonist, imiquimod. Both immune modifiers rapidly induced IFN-alpha and other antiviral effector molecules in the cervicovaginal mucosa of treated animals. However, both CpG ODN and imiquimod also induced proinflammatory cytokine expression in the cervicovaginal mucosa. In the vaginal mucosa of imiquimod-treated monkeys, we documented a massive mononuclear cell infiltrate consisting of activated CD4(+) T cells, DC, and beta-chemokine-secreting cells. After vaginal SIV inoculation, all TLR agonist-treated animals became infected and had plasma vRNA levels that were higher than those of control monkeys. We conclude that induction of mucosal innate immunity including an IFN-alpha response is not sufficient to prevent sexual transmission of human immunodeficiency virus.

Administration, Intravaginal↗

Randomized trial of intracervical versus posterior fornix dinoprostone for induction of labor.

OBJECTIVE: To investigate whether intracervical placement of a sustained-release dinoprostone insert decreased the length of time to delivery when compared with placement in the posterior fornix. METHODS: Sixty-three patients were randomized to intracervical (n = 33) or posterior fornix (n = 30) placement of the initial dose. Dinoprostone was placed under direct visualization with a vaginal speculum and packing forceps. The patients and staff were blinded to the site of placement. Multiple end points were examined throughout labor. Student t test, Fisher exact test, Wilcoxon test, Mann-Whitney U test, and chi2 analyses were performed when appropriate. A P value of less than.05 was considered significant. RESULTS: Forty-six patients who required only a single dose of dinoprostone had a reduced time to delivery with intracervical (n = 24; 11.70 hours) compared with intravaginal (n = 22; 16.20 hours) placement (P =.025). There was also a reduced time to active labor (intracervical = 8.25 hours, posterior fornix = 11.50 hours; P =.083), ruptured membranes (intracervical = 10.25 hours, posterior fornix = 12.00 hours; P =.047), and request for initial pain medications (intracervical = 5.00 hours, posterior fornix = 11.25 hours; P =.025) with intracervical placement. There was no difference in number of patients managed with artificial rupture of membranes. There was no difference in maternal age, race, parity, maternal height or weight, or indication for induction. There was also no difference in cesarean delivery rate, antepartum fever, hyperstimulation, Apgar scores, birth weight, or umbilical artery pH. CONCLUSION: In patients who respond to a single sustained-release dinoprostone insert, intracervical placement decreases time to delivery without increasing the cesarean delivery rate, infectious morbidity, or other complications of labor.

Administration, Intravaginal↗

Vaginal misoprostol in termination of second trimester pregnancy.

OBJECTIVE: To study the effectiveness and complications of 600 micrograms of intravaginal misoprostol for terminating second trimester pregnancies. STUDY DESIGN: One hundred and seventy-two patients undergoing termination of pregnancy between March 1997 and April 1999 were studied. Each patient received 600 micrograms of intravaginal misoprostol every 12 hours until abortion occurred. RESULTS: The mean induction to abortion time was 24.1 +/- 21.6 hours. The percentage of women aborting within 24 and 48 hours was 68.6 and 89.5 respectively. There was no significant difference in the mean induction to abortion time and the percentage of women aborted within 48 hours between nulliparous and multiparous women. The mean amount of misoprostol used was 1405.5 +/- 1084.6 micrograms. Incomplete abortion occurred in 23.3% of women. The most common complication was temperature of more than 38 degrees C occurred in 41% followed by diarrhoea (20%), nausea and vomiting (15%). CONCLUSION: Six hundred micrograms of vaginal misoprostol is effective, but whether the 48 hours abortion rate can be improved with a large dose or shortened the time interval between doses, requires further study.

Abortifacient Agents, Nonsteroidal↗

[Local prevention of infection with metronidazole before vaginal hysterectomy--comparative effect compared with systemic prevention?].

A prospective clinical trial was designed to examine the influence of a local intravaginal application of metronidazole on postoperative infectious morbidity in 114 women undergoing vaginal hysterectomy. On the evening before vaginal hysterectomy, 51 patients received a vaginal suppository of metronidazole (500 mg). These patients were compared with a group of 63 patients who were given a single-shot prophylaxis with 1,500 mg cefuroxime intravenously. With regard to febrile morbidity, urinary tract infection and pelvic infection there was no significant difference in the two treatment groups. There was no statistically significant difference in the postoperative duration of hospital stay and additional antibiotic therapy between the two groups either. We did not see serious infections in our examination. Our results suggest that a local single-dose application of metronidazole in vaginal hysterectomy might have the same efficacy on postoperative infectious morbidity than a systemic antibiotic prophylaxis and that it can reduce antibiotic costs.

Administration, Intravaginal↗

Cervical ripening: a randomized comparison between intravaginal misoprostol and an intracervical balloon catheter combined with intravaginal dinoprostone.

OBJECTIVES: Our purpose was to compare the efficacy of intravaginal misoprostol and intracervical Foley catheter/intravaginal dinoprostone for cervical ripening. STUDY DESIGN: Patients admitted for induction of labor were randomized to receive intravaginal misoprostol 25 microg every 4 hours or intracervical Foley catheter/intravaginal dinoprostone 4 mg every 4 hours. Patients not entering active labor and having ruptured membranes or arrest of dilatation received intravenous oxytocin. RESULTS: Sixty-five patients received Foley catheter/dinoprostone gel and 62 patients received misoprostol. The mean time until cervical ripening was less in the catheter/gel group (7.5 +/- 3.4 vs 12.0 +/- 5.9 hours, p < 0.01). The mean time until vaginal delivery was less in the catheter/gel group (17.4 +/- 6.9 vs 21.2 +/- 7.5 hours, p = 0.004). Among vaginal deliveries, more patients in the catheter/gel group delivered within 24 hours (90% vs 69%, p = 0.013). CONCLUSIONS: Intracervical Foley catheter/intravaginal dinoprostone was associated with more rapid cervical ripening, shorter induction to vaginal delivery interval, and greater number of vaginal deliveries within 24 hours.

Administration, Intravaginal↗