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PubMed2006

Micronucleus induction by metronidazole in rat vaginal mucosa.

Metronidazole (MTZ) is used for the treatment of many infectious diseases, including vaginal infections. While data indicate that MTZ is mutagenic and induces micronuclei in rodents, there is no information on the genotoxicity of MTZ in epithelial vaginal cells or cervical cells. In the present study, we have instilled MTZ into the vagina of rats and evaluated the micronucleus (MN) frequency in proestrus rat vaginal mucosal cells. The first identified proestrus before treatment was used to establish basal proestrus micronucleated cell (PMNC) frequencies. Rats then were assigned to one of five groups: a negative control, three MTZ treatment groups (30, 50, or 100 mg/kg MTZ), and a positive control treated with 2.5 mg of 5-fluorouracil (5-Fu) per rat. Following treatment for five consecutive days, vaginal cell samples were taken daily until three cycles of estrus were completed. Smears prepared from the samples were evaluated for micronuclei in proestrus cells. No differences were found between the PMNC frequencies of the negative control and the 30 and 50 mg/kg MTZ groups. The group treated with 100 mg/kg MTZ, however, had significantly elevated PMNC frequencies in the first and second proestrus samples, while 5-Fu treatment produced significant increases in PMNC frequency in the second and third proestrus. These results indicate that topical administration of relatively high concentrations of MTZ is genotoxic in rat vaginal mucosa cells.

Administration, Intravaginal↗
PubMed1992

Outcome of herpes simplex virus type 2 infection in guinea pigs.

Factors that influence the outcome of genital herpes simplex virus (HSV) infection were explored in a guinea pig model. The viral inoculum required to establish infection in 50% of animals (ID50) was similar for inbred (strain 2) and outbred (Hartley) guinea pigs. However, the viral inoculum required to produce clinical disease in 50% of the animals (CD50) was 10 times greater for strain 2 compared to Hartley animals. HSV infection of both inbred and outbred animals was more likely to result in death of weanling than adult animals. The duration and severity of genital disease and the magnitude of vaginal viral replication were similar for strain 2 and Hartley animals in both young and adult animals. The lethal dose for 50% of animals (LD50) was 100-fold greater than the CD50 for Hartley animals, but the LD50 and the CD50 were equal in strain 2 guinea pigs. Viral cultures of homogenized neural tissues from infected animals revealed that HSV ascended to the level of the temporal cortex in strain 2 guinea pigs while virus was never recovered above the lumbar spinal cord in Hartley animals. Endogenous peripheral blood mononuclear cell-mediated cytolytic activity against HSV-infected targets was greater prior to HSV inoculation in survivors compared to animals that died. A fatal outcome of genital HSV-2 may relate to the failure to limit CNS viral replication. Death is more common among guinea pigs that have low endogenous HSV-directed natural killer activity, such as occurs among strain 2 and young animals whether inbred or outbred.

Administration, Intravaginal↗
PubMed2004

Gravity-induced coating flows of vaginal gel formulations: in vitro experimental analysis.

Efficacy of topical microbicidal drug delivery formulations against HIV depends in part on their coating distributions and retention on vaginal epithelium. This study focused on gravity-induced coating flows of vaginal gels, and effects of formulation composition and surface wettability on coating. We hypothesized that presence of a yield stress, and surface wettability, affect coating. Experiments imaged and analyzed coating flows of gels on inclined model hydrophilic or hydrophobic surfaces. The in vitro wettability conditions bracket those believed to exist on vaginal epithelium in vivo. Six commercial vaginal gels were studied: three polyacrylic acid-based (PAA) and three cellulose-based. Our research group uses these gels in complementary human in vivo studies and other in vitro experimental analyses; this study is a first step in linking the in vivo and in vitro measurements. Coating by PAA gels was different from cellulose-based gels: the former exhibited yield stresses, which prevented initial gel shape from deforming during sliding. Coating flows of cellulose gels depended upon surface wettability. The slipping rates of the PAA gels ranked inversely with fitted yield stress values. The coating flow rates of the cellulose gels (hydrophilic surface) did not correlate with consistency index, but ranked inversely with the shear-thinning index. This study introduces a simple methodology for comparing trial formulations and relating their flows to gel constituents and physical properties. It also suggests differences in coating by current commercial gels.

Administration, Intravaginal↗
PubMed2007

Biophysical analysis of prototype microbicidal gels.

The objective of this study was to evaluate the distribution and retention (deployment) of four prototype vehicles for delivery of prophylactic microbicides against vaginal HIV transmission. Study gels were created with different molecular compositions, producing different biophysical properties governing vaginal deployment. The study employed three techniques: direct rheological measurement of gel properties, direct observation of gel surface coating erosion, and dissolution by a vaginal fluid simulant, and mathematical modeling of gel squeezing flow processes. Results suggest significant differences in extent of vaginal coating after gel application and in erosion of these gel layers due to contact with ambient vaginal fluid and shearing. The relationships between gel rheological properties, coating flow and erosion of coating were not always anticipated from differences in gel molecular composition.

Administration, Intravaginal↗
PubMed2007

Temperature and pH sensitive hydrogels: an approach towards smart semen-triggered vaginal microbicidal vehicles.

Microbicides are drug delivery systems (DDSs) for the prevention of sexual transmission of HIV and other STDs. A topically applied vaginal microbicidal gel should provide uniform coating of vaginal tissue, retention of this gel layer prior to intercourse, and controlled release kinetics of antivirals to inactivate the viral load potentially introduced during sexual activity. Here, we describe the microbicide-oriented characterization of a DDS made with a dual pH sensitive and thermosensitive smart polymer gel composed of a random terpolymer of N-isopropyl acrylamide, butyl methacrylate, and acrylic acid. The system was engineered to coat vaginal tissue with a stable gel layer and to release entrapped model agents in a burst release profile in response to the presence of the infecting agent: semen. The gel rheology, layer erosion properties, model drug release kinetics, and cytocompatibility of the terpolymer system were studied. Negligible erosion of the gel in the presence of vaginal fluid simulant suggests prolonged retention. Burst release of molecular and macromolecular model compounds was observed when the system's pH changed from the vaginal pH to the pH of semen, and cytotoxicity studies showed that the terpolymer is equally cytocompatible as a commonly used polymeric vaginal carrier.

Administration, Intravaginal↗
PubMed1991

An unusual cause of recurrent chorea.

Recurrent chorea is described in a 61-year-old woman who had had chorea gravidarum when she was younger. The recurrent chorea appeared to be induced by a topical vaginal cream that contained conjugated estrogen. This case is consistent with the existence of a recurrent syndrome of hormone-induced chorea. The effect of estrogen on the basal ganglia is complex and not fully understood.

Administration, Intravaginal↗
PubMed1988

Artificial instillation of amniotic fluid as a new technique for the diagnostic evaluation of cases of oligohydramnios.

In cases of severe oligohydramnios, sonographic diagnosis is hampered by poor visibility and by increased fetal flexion. Therefore, 74 artificial instillations of amniotic fluid were performed in 50 pregnancies by sonographic guidance. Fetal diseases included Potter's syndrome, obstructive uropathy, cystic kidneys (20 cases); Meckel's syndrome, C. de Lange syndrome, cytomegaly fetopathy (1 case each); VATER association (2 cases); triploidy (5 cases); severe intrauterine growth retardation (8 cases); and premature rupture of membranes (12 cases). By improved sonographic visibility and the observation of fetal behaviour (drinking, filling of stomach and bladder, voiding of bladder after artificial instillation of amniotic fluid), the fetal anatomy could be studied more accurately, malformations could be identified or excluded, and bladder function could be examined. Thus, differentiation between fetuses without functioning kidneys and those with severe intrauterine growth retardation becomes possible. Further, re-aspiration on the day following instillation permitted determination of the karyotype. Finally, the artificial instillation of amniotic fluid is a hazardous intervention (rupture of membranes, labour) and should be reserved only for a small number of selected cases with diagnostically unclear oligohydramnios. For these cases, it seems to be the method of choice permitting a variety of diagnostic information to be obtained.

Administration, Intravaginal↗
PubMed2004

Sample size formula for proportional hazards modelling of competing risks.

To test the effect of a therapeutic or prognostic factor on the occurrence of a particular cause of failure in the presence of other causes, the interest has shifted in some studies from the modelling of the cause-specific hazard to that of the subdistribution hazard. We present approximate sample size formulas for the proportional hazards modelling of competing risk subdistribution, considering either independent or correlated covariates. The validity of these approximate formulas is investigated through numerical simulations. Two illustrations are provided, a randomized clinical trial, and a prospective prognostic study.

Administration, Intravaginal↗
PubMed2005

Structural accelerated failure time models for the effects of observed exposures on repeated events in a clinical trial.

Structural accelerated failure time models form a unique tool for the analysis of causal effects of observed exposures in randomized trials. When actual exposure levels are not completely controlled they may be selective, i.e. depend on unmeasured prognostic factors. Nevertheless, consistent randomization-based estimators have been derived for the effect of such exposures on a right-censored survival outcome. In this paper, we extend the methodology to allow for estimation of the structural effect of an experimental vaginal gel on repeated occurrences of genital lesions. The marginal distribution of each ordered event is modelled assuming a common treatment effect. Estimation is possible by inverting alpha-level tests using a robust variance estimator to allow for correlated repeated events. We discuss the logical constraints imposed by this model choice as well as new challenges posed on recensoring.

Administration, Intravaginal↗
PubMed1996

Use of intrauterine microdialysis to investigate methanol-induced alterations in uteroplacental blood flow.

Methanol is teratogenic in rodents; it has been postulated that this teratogenicity may be mediated in part by conceptal hypoxia. To construct a model to predict conceptal risk following maternal methanol exposure, conceptal disposition of methanol must be determined and any effects of such exposure on blood flow must be quantitated. In the present study, these toxicokinetic and toxico-dynamic parameters were evaluated by in vivo intrauterine microdialysis. Microdialysis probes were inserted into the uteri of Gestational Day (gd) 20 rats; methanol was administered as either an iv bolus (100 or 500 mg/kg) or infusion (100 or 1000 mg/kg/hr). In separate experiments, methanol (100 or 500 mg/kg) and 3H2O (20 microCi/kg) were administered iv to gd 20 and 14 rats and gd 18 mice. In both experiments, maternal blood and uterine microdialysate were collected and analyzed for methanol or 3H2O content. The methanol concentration-time data were consistent with saturable maternal elimination and apparent first-order transfer between maternal and conceptal compartments; at distribution equilibrium, conceptal methanol concentrations exceeded those in the dam by approximately 25%. The initial rate of conceptal permeation of methanol was proportional to the reciprocal of maternal blood methanol concentration (r2 = 0.910). Methanol also reduced significantly the rate of 3H2O uptake into the conceptus in a concentration-dependent fashion in gd 14 and 20 rats and gd 18 mice. These data indicate that methanol may decrease uteroplacental blood flow, decreasing methanol presentation to the conceptus and possibly producing conceptal hypoxia.

Administration, Intravaginal↗
PubMed1996

Topically applied human recombinant monoclonal IgG1 antibody and its Fab and F(ab')2 fragments protect mice from vaginal transmission of HSV-2.

A recombinant human anti-herpes simplex virus monoclonal IgG1, antibody and the corresponding Fab and F(ab')2 fragments were tested for efficacy in preventing vaginal transmission of HSV-2 infection in a well-established mouse model for genital herpes. IgG1, Fab, and F(ab')2 were approximately equally protective; vaginal delivery of 1-5 ng provided approximately 50% protection, and vaginal delivery of 400 ng completely protected mice from genital herpes infection (P < 0.001). These results suggest that topical applications of human monoclonal antibodies may be useful in developing new methods for preventing sexually transmitted disease.

Administration, Intravaginal↗
PubMed1995

Prevention of ovariectomy osteopenia in rats after vaginal administration of Hyaff 11 microspheres containing salmon calcitonin.

The benzyl ester of hyaluronic acid (Hyaff 11) is a highly mucoadhesive polymer and can be processed into microspheres that can effectively deliver incorporated drugs by closely adhering to the mucosal surface and by protecting the drug from enzymatic inactivation. In this study, Hyaff 11 microspheres have been investigated as novel delivery system for the vaginal administration of salmon calcitonin (sCT) to ovariectomized rats. Moreover, this particular animal model has been used to evaluate the biological activity of the polypeptide after vaginal and I.M. administration by measuring the skeletal effect of sCT. A total of 66 female rats were used: 6 rats served as the basal group; 12 were subjected to sham operation and left without pharmacological treatment; 48 underwent bilateral ovariectomy and these were divided at random into four groups of 12 animals. One group was not submitted to pharmacological treatment; another was treated daily with sCT I.M.; in the other two groups, the hormone was incorporated into Hyaff 11 microspheres and was daily administered by vaginal route as dry powder or dispersed in pessaries. Sixty days after surgery, rats were sacrificed and the proximal third of the right tibia was removed and prepared for histomorphometry. Treatment with sCT, independent of the administration route, largely prevented the bone volume loss of the nontreated ovariectomized group. Prevention mainly depended on the maintenance of the trabecular number and on the increase of the trabecular thickness. Independent of the administration procedure, sCT greatly reduced the increase of tartrate-resistant acid phosphatase-positive poly- and, particularly, mononucleated osteoclasts found in the nontreated ovariectomized group.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intravaginal↗
PubMed1995

Efficacy trial of topically administered interferon gamma-1 beta gel in comparison to laser treatment in cervical intraepithelial neoplasia.

OBJECTIVE: Dose dependent response of cervical intraepithelial neoplasia (CIN) to topically administered interferon (IFN) gamma was assessed and compared with conventional laser therapy. PATIENT AND METHODS: 33 women were included in a randomized phase II trial which was double blinded for IFN dosages. Twenty-four patients received IFN gamma-1 beta gel and a control group of nine patients was treated with laser surgery. 18 patients had smears suggesting CIN II and 15 patients had smears suggesting CIN III. The response was assessed 6 months after starting of IFN gamma-1 beta treatment or having laser surgery. RESULTS: Topical IFN gamma-1 beta treatment gave a cure rate of 42% independent of IFN dosage as compared to an 89% cure rate with laser therapy (P = 0.02). Patients with CIN II responded better compared with patients with CIN III. Current smokers showed a significantly lower cure rate whereas use of oral contraceptives (OC) did not influence response. High viral load with high risk types of human papillomaviruses (HPV) was associated with a better response.

Administration, Intravaginal↗
PubMedDate not supplied

Pathogenesis of urinary tract infections--amoxicillin induces genital Escherichia coli colonization.

The aim of this study was to examine whether a vaginal Escherichia coli colonization, mimicking the one seen in UTI-prone females, could be induced by amoxicillin administration. In adult cynomolgus monkeys, who carry the alpha-Gal-1-4-beta-Gal receptor for P-fimbriae, we have investigated the ability of a clinical isolate of P-fimbriated E. coli to colonize the mucous membranes of the genital tract. When the vagina was washed with a suspension of the P-fimbriated strain, a persistent colonization was obtained in only 17% (4/24) of the experiments. When such colonization attempts were performed during vaginal amoxicillin administration, a persistent and heavy colonization of the vagina occurred in 5/5 attempts. The findings do not contradict our hypothesis that antibiotics given to UTI-prone females may facilitate the establishment of the abnormal colonization of the genital tract.

Administration, Intravaginal↗
PubMedDate not supplied

Cephadroxil promotes vaginal colonization with Escherichia coli.

The aim of this study was to examine whether a vaginal Escherichia coli colonization, mimicking the one seen in UTI-prone females, could be induced by local cephadroxil administration. When five adult cynomolgus monkeys were given a vaginal flush with a P-fimbriated E. coli strain, none became persistently colonized. When such colonization attempts were preceded by cephadroxil administration a persistent colonization occurred in 9/10 experiments. Cephadroxil also promoted a spread of fecal E. coli strains to the vagina. Reduction of the anaerobic vaginal flora can explain the breakdown of the colonization resistance. Clinical observations suggest that accumulation of E. coli around the urethral orifice increases the risk of UTI. Therefore antibiotics which promote such colonization may increase the risk for UTI in susceptible patients. From this point of view antibiotics such as cephadroxil may be less suitable for treatment of UTI-susceptible patients.

Administration, Intravaginal↗