Topical Vaginal Drug Delivery I: Effect of the Estrous Cycle on Vaginal Membrane Permeability and Diffusivity of Vidarabine in Mice

Hsu, Chen-Fu; Park, J.Y.; Ho, Norman F.H.; Higuchi, W.I.; Fox, Jeffrey L.

doi:10.1002/jps.2600720620

Cited by 16 publications

(7 citation statements)

References 7 publications

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“…Despite the high Ag load in the suppository, the actual dose received by the animal is far lower as evidenced by retained Ag in the suppository. In fact, the vaginal vault is generally a poor site for uptake of all but the smallest hydrophobic molecules (42,43). However, in these experiments the Ag exposure was for a relatively long and continuous time.…”

Section: Discussionmentioning

confidence: 94%

Vaginal Mucosa Serves as an Inductive Site for Tolerance

Black

Rohan

Cost

et al. 2000

The Journal of Immunology

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These data demonstrate that tolerance can be induced by vaginal Ag exposure. In these experiments, mice were given vaginal agarose gel suppositories containing either 5 mg OVA or saline for 6 h. Mice were given suppositories either during the estrous (estrogen dominant) or diestrous (progesterone dominant) stage of the estrous cycle. Mice were restrained during the inoculation period to prevent orovaginal transmission of the Ag. After 1 wk, mice were immunized s.c. with OVA in CFA. After 3 wk, mice were tested for delayed-type hypersensitivity responses by measuring footpad swelling and measuring in vitro proliferation of lymphocytes to Ag. Using ELISA, the magnitude of the serum Ab response was also measured. In some mice, FITC conjugated to OVA was used to track the dissemination of the protein into the systemic tissues. The magnitude of footpad swelling was significantly reduced in mice receiving OVA-containing suppositories during estrus compared with mice receiving saline suppositories. Concomitant decreases in the Ag-specific proliferative response were also observed in lymph node lymphocytes and splenocytes. Conversely, mice inoculated during diestrus did not show a decreased response to Ag by either footpad response or in vitro proliferation. Serum Ab titers in the estrus-inoculated mice did not decrease significantly. These data demonstrate that the reproductive tract can be an inductive site for mucosally induced tolerance. However, unlike other mucosal sites such as the lung and gastrointestinal tract, reproductive tract tolerance induction is hormonally regulated.

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Section: Discussionmentioning

confidence: 94%

Vaginal Mucosa Serves as an Inductive Site for Tolerance

Black

Rohan

Cost

et al. 2000

The Journal of Immunology

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“…It may also be possible to administer GnRH antagonists to women, either permanently as part of an intrauterine device, or just before intercourse, perhaps as part of a vaginal preparation. It has been suggested that the vaginal or uterine absorption of certain substances is poor (Bourin et al, 1983;Hsu et al, 1983;Corbo et al, 1989;Lau et al, 1992); therefore, the risk of the antagonists being absorbed through the mucosa into the systemic circulation and having a subsequent effect on pituitary secretion may be small.…”

Section: Discussionmentioning

confidence: 99%

Gonadotrophin-releasing hormone antagonists inhibit sperm binding to the human zona pellucida

Morales

Kerr²,

Oliva³

et al. 1999

Human Reproduction

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Previous work from our laboratory indicated that gonadotrophin-releasing hormone (GnRH) increases human sperm-zona pellucida binding. Here we present evidence that GnRH antagonists inhibit sperm-zona pellucida binding in humans. Motile spermatozoa (10(7) cells/ml) were incubated in modified Tyrode's medium at 37 degrees C, in 5% CO(2) in air. After 4.5 h, aliquots of spermatozoa were treated with saline (control) or with different concentrations of GnRH antagonists (test). Each sperm aliquot was then tested in the hemizona binding assay. In this assay, the control aliquot was incubated with half a human zona pellucida (hemizona) and the test aliquot was incubated with the matching half. After 20 min, the hemizonae were withdrawn and the number of zona-bound spermatozoa counted using phase-contrast microscopy. In addition, the effect of GnRH antagonists upon the pattern of sperm movement, frequency of sperm-zona pellucida collisions, and percentage of living and acrosome-reacted spermatozoa was determined. The results indicated that treatment with GnRH antagonists decreased the number of zona-bound spermatozoa and did not change the pattern of sperm movement, frequency of sperm-zona collisions, and percentage of acrosome-reacted spermatozoa. We suggest that this action of GnRH antagonists may be due to an effect on zona receptors on the sperm plasma membrane.

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“…Currently, there are no published reports describing the effects of anatomical and physiological changes due to estrus cycle on drug disposition after vaginal administration of compounds to mice. A single report from Hsu et al [14] using an excised vaginal membrane in a diffusion chamber indicated that the permeability coefficients for vidarabine, an antiviral drug with activity against herpes, were 10-100 fold higher during the diestrus stage compared to those in the estrus stage. Therefore, the objective of the present study was to evaluate the influence of the anatomical and physiological changes due to the estrus cycle of the mouse on SHetA2 disposition after vaginal administration, and SHetA2 pharmacodynamic endpoint, the reduction in the levels of cyclin D1 protein.…”

Section: Introductionmentioning

confidence: 99%

Influence of the estrus cycle of the mouse on the disposition of SHetA2 after vaginal administration

Mahjabeen

Hatipoglu

Benbrook

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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SHetA2 is a novel compound with the potential to treat cervical dysplasia, but has poor water solubility. A vaginal suppository formulation was able to achieve therapeutic concentrations in the cervix of mice, but these concentrations were variable. Histological analysis indicated that mice in the same group were in different stages of their estrous cycle, which is known to induce anatomical changes in their gynecological tissues. We investigated the effects of these changes on the pharmacokinetics and pharmacodynamics of SHetA2 when administered vaginally. Mice were synchronized to be either in estrous or diestrus stage for administration of the SHetA2 suppository. Pharmacokinetic parameters were calculated from the SHetA2 concentrations vs. time data. The reduction in the expression of cyclin D1 protein in the cervix was used as pharmacodynamic endpoint. Mice dosed during diestrus had a larger AUC (335 μg mL h), higher C (121.8 ± 38.7 µg/g) and longer t (30.3 h) compared to mice dosed during estrus (120 μg mL h, 44.6 ± 29.5 µg/g and 3.6 h respectively). Therapeutic concentrations of SHetA2 were maintained for 48 h in the cervix of mice dosed during diestrus and for only 12 h in the estrus group. The treatment reduced the expression of cyclin D1 protein in the cervix of mice in the estrus to a larger extent. These results indicate that the estrous cycle of mice influences significantly the disposition of SHetA2 after vaginal administration and may also influence its efficacy.

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Topical Vaginal Drug Delivery I: Effect of the Estrous Cycle on Vaginal Membrane Permeability and Diffusivity of Vidarabine in Mice

Cited by 16 publications

References 7 publications

Vaginal Mucosa Serves as an Inductive Site for Tolerance

Vaginal Mucosa Serves as an Inductive Site for Tolerance

Gonadotrophin-releasing hormone antagonists inhibit sperm binding to the human zona pellucida

Influence of the estrus cycle of the mouse on the disposition of SHetA2 after vaginal administration

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