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Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a dimethyl sulfoxide extraction protocol and high-performance liquid chromatography analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R 2 =   0.80), but the correlation was not significant for MVC or TFV. For the sustained-release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel-tissue mimic may be a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures.

The classical teaching was that twisted adnexa should be resected and not untwisted, so as not to increase the risk of pulmonary embolism (PE). A patient recently was seen who developed PE after adnexal resection. Because this complication followed the conventional management of salpingo-oophorectomy, the literature was examined for cases of adnexal torsion and PE to see if the operative management (untwisting vs. excision without untwisting) could be implicated as a contributing factor. Three hundred nine cases of adnexal torsion managed by untwisting and 672 cases treated by adnexectomy without detorsion (untwisting) were found. The incidence of PE after adnexal torsion was 0.2 percent, and this incidence was not increased when the adnexa were untwisted. Therefore, we conclude that detorsion of twisted adnexa does not increase the risk of PE, compared with excision without untwisting. PE does occur in cases in which adnexal resection is performed without untwisting. Thus, detorsion of twisted adnexa should be considered at laparoscopy or laparotomy without fear of increasing the incidence of PE.

Insulin resistance and glucose intolerance are common features of polycystic ovary syndrome (PCOS). We have investigated the effect of glucose on the fractional glucose disappearance in patients with PCOS and in age- and weight-matched control subjects. The minimal model method as applied to a frequently sampled intravenous glucose tolerance test was employed. The insulin sensitivity index (Si) and glucose effectiveness (SG) were calculated with the MINMOD program. Testosterone, androstenedione and free testosterone concentrations were significantly higher in PCOS subjects. Glucose-induced glucose clearance (SG) and insulin sensitivity were significantly lower in PCOS subjects than controls [SG: 2.7 +/- 0.3 versus 1.8 +/- 0.1 x 100/min; P less than 0.01; Si: 133.4 +/- 20.0 versus 65.6 +/- 6.4/min (nmol/ml)]. Six PCOS women had an SG value within the normal range (greater than 2.0 x 100/min) but had a similar Si to that found in PCOS women with abnormal SG. We suggest that independent alterations in both glucose- and insulin-mediated glucose uptake occur in patients with PCOS. The underlying disturbance in glucose effectiveness may be similar to that found in familial non-insulin dependent diabetes mellitus.

To test whether sustained midfollicular estrogen concentrations sensitize the pituitary response to GnRH in the continued presence of a GnRH stimulus, six female monkeys with regular menstrual cycles were administered hourly pulses of GnRH in the presence or absence of an sc estrone implant. Three were studied in a sequence of 2- to 8-week blocks of 1) control, 2) hourly pulses of exogenous GnRH (6 micrograms/1 min), 3) hourly GnRH pulses plus an estrone (E1) implant, and 4) the E1 alone. In the other three animals the sequence was 1) control, 2) E1, 3) E1 implant plus hourly GnRH pulses, and 4) GnRH pulses only. E1 increased mean estradiol concentrations from 55 pg/ml to 100 pg/ml and the corresponding E1 concentrations from 95 pg/ml to 160 pg/ml. LH concentrations, excluding midcycle surges, were 10.9 +/- 2.2 (SEM) ng/ml, 12.6 +/- 1.5 ng/ml, 11.7 +/- 1.5 ng/ml, and undetectable (less than 6 ng/ml) for the control, GnRH, GnRH plus E1, and E1-treatment periods, respectively. Of note was the suppression of LH concentrations to undetectable levels by midfollicular concentrations of estrogen during the E1-alone treatment period, and the return of LH concentrations to normal follicular phase levels by the application of exogenous GnRH support. This observation suggested that an estrogen negative feedback signal can suppress endogenous GnRH. To further examine this hypothesis we applied the same protocol to two hypogonadal female monkeys. E1 capsule placement increased the mean estradiol concentration from 22 to 61 pg/ml and suppressed LH and FSH to undetectable levels. When hourly pulses of GnRH (6 micrograms/1 min) were supplied, mean LH and FSH increased to 29.8 and 14.9 ng/ml, respectively. These studies demonstrate that elevation of estrogen concentrations to midfollicular levels does not sensitize the pituitary to GnRH stimulation, and pituitary sensitization is therefore unlikely to be important as a cause of elevated LH secretion in anovulatory states, such as the polycystic ovaries syndrome. In the hypogonadal monkeys, a 5-fold decrease in gonadotropin concentrations occurred in spite of full exogenons GnRH support, consistent with a hypophyseal site of estrogen negative feedback action. However, the GnRH clamp did prevent the complete suppression of LH and FSH noted when only estrogen was applied, consistent with an additional negative feedback effect on the hypothalamus. Although this same phenomenon is observed in the eugonadal monkeys, it appears unlikely that a hypothalamic site of estrogen inhibition plays a significant role during the menstrual cycle, otherwise the progressive rise in follicular phase estrogen concentrations would, by arresting GnRH secretion, abort folliculogenesis.

Increased understanding of maternal-fetal carbohydrate homeostasis together with modern perinatal technology now provides a more rational basis for obstetric management of the pregnant diabetic patient. These concepts were applied at MacDonald House in the care of 96 diabetic pregnant women over a two-year period. Pregnancy outcomes were compared with prior experiences with the same group of women. The perinatal mortality rate was reduced from 13.5 to 4.2%, and the rate of macrosomia (infants large for gestational age) was reduced from 30.9 to 17.7%. Patients with gestational diabetes, with a prior loss rate of 8.3%, suffered no losses in the current series. Maternal age was not found to correlate with an untoward outcome in this subgroup.

The effect of ethinyl estradiol treatment on the plasma levels of cortisol, corticosterone, deoxycorticosterone, progesterone, testosterone, dehydroepiandrosterone sulfate, delta4-androstenedione, and estrone was studied in eight women. All the subjects had undergone ovariectomy and hysterectomy at least one year prior to this study. The systemic concentration of cortisol and the binding of cortisol were significantly increased, paralleling the increased transcortin concentration due to ethinyl estradiol treatment. Corticosterone concentration was also significantly increased after three days of estrogen administration and this level continued to be higher than normal as long as patients were treated with estrogens, but there was no change in the plasma concentration of deoxycorticosterone. The plasma levels of progesterone testosterone, dehydroepiandrosterone sulfate, delat4-androstenedione and estrone or the ratio of estrone to delta4-androstenedione did not change with ethinyl estradiol treatment. These observations suggest that the administered estrogen increased the transcortin concentration and had only a limited effect on adrenocortical steroidogenesis.