Comparison of Alora estradiol matrix transdermal delivery system with oral conjugated equine estrogen therapy in relieving menopausal symptoms. Alora Study Group.

OBJECTIVE: To compare the efficacy of two strengths of an estradiol matrix transdermal delivery system with daily oral doses of conjugated equine estrogens in reducing the frequency of moderate-to-severe hot flushes in postmenopausal women. DESIGN: The design of the study provided for the following treatment regimens: an estradiol transdermal delivery system (Alora 0.05 or 0.1 mg/day) administered twice weekly or oral doses of conjugated equine estrogens (CEE 0.625 or 1.25 mg) administered daily were given to 321 highly symptomatic postmenopausal women for 12 weeks following a randomized, parallel-group, double-blind, double-dummy design. RESULTS: Results indicate no statistically significant differences at any time point in mean frequency or mean percentage reduction in frequency of moderate-to-severe hot flushes between patients given Alora 0.1 mg/day and those receiving CEE 1.25 mg/day. Similarly, no significant differences were observed at any time in mean frequency of moderate-to-severe hot flushes between the Alora 0.05 mg/day and CEE 0.625 mg/day groups, although the group receiving CEE 0.625 mg/day exhibited a statistically greater percentage reduction than the Alora 0.05 mg/day group at weeks 3, 4 and 8. By week 12, these two treatments were statistically indistinguishable. There were no serious or unexpected adverse events with the two transdermal systems and local skin tolerability was excellent. Other estrogenic effects such as restoration of vaginal cytology, breast tenderness and unexpected vaginal bleeding were comparable between transdermal and oral administration groups except for a lower incidence of bleeding in those women receiving the lower dose transdermal regimen.

Bioavailability of oestradiol from the Alora (0.1 mg/day) oestradiol matrix transdermal delivery system compared with Estraderm (0.1 mg/day).

This open-label, randomised, two-way crossover study compared the steady-state bioavailability of oestradiol administered by way of a new oestradiol matrix transdermal delivery system (Alora 0.1 mg/day) with that of Estraderm (0.1 mg/day) in 24 subjects. Serum oestradiol, oestrone and oestrone sulphate concentrations were determined by measurement of blood samples. Mean SD pre-dosing, nonadjusted oestradiol levels for Alora (71.9 27.0 pg/ml) were substantially higher than those for Estraderm (26.7 9.7 pg/ml), while peak oestradiol concentrations were comparable. Consequently, fluctuations in steady-state levels were substantially smaller for Alora than for Estraderm; the fluctuation index values (\[C- C ])/ max min C ) were significantly lower for Alora (0.97 0.23) than av for Estraderm (1.68 0.45). Oestradiol levels remained constant over the dosing interval with Alora but decreased significantly after 48 hours with Estraderm. The bioavailability of oestradiol with Alora was 127 56% that of Estraderm. Oestrone and oestrone sulphate data showed the same qualitative and quantitative differences between the two systems. Both systems were well tolerated. In summary, Alora delivered more oestradiol to the systemic circulation with greater consistency and over a longer time than did Estraderm.

Double-masked, multicenter study of an estradiol matrix transdermal delivery system (Alora) versus placebo in postmenopausal women experiencing menopausal symptoms. Alora Study Group.

This 12-week, double-masked, double-dummy, randomized, parallel-group study compared the efficacy and safety of an estradiol matrix transdermal delivery system (Alora) in two strengths (50-microgram/d estradiol and 100-microgram/d estradiol) with placebo in postmenopausal women who were experiencing at least 60 moderate-to-severe hot flushes per week. In 273 postmenopausal women, the reduction in the frequency of moderate-to-severe hot flushes was significantly better than placebo within 2 weeks of initiating therapy in the 100-microgram/d group and within 3 weeks of initiating therapy in the 50-microgram/d group. The reduction in hot flushes for both active treatment groups remained significantly different from placebo throughout the 12-week trial. Improvement in vaginal cytology profile (maturation index) was observed in both active treatment groups. Serum estradiol concentrations were elevated to early-to mid-follicular levels, in proportion to dose, and the estradiol/estrone ratio remained within the expected premenopausal range. The incidence of estrogen-related side effects was modest but greater in the active treatment groups than in the placebo group: Breast pain was reported in 4.5% of the patients in the 50-microgram/d group, 5.3% of patients in the 100-microgram/d group, and none of the patients in the placebo group. Breakthrough bleeding occurred in 3.4% of women in the 50-microgram/d group, 20.2% of women in the 100-microgram/d group, and 4.4% of women in the placebo group. Only 3 (1.1%) patients terminated treatment because of skin reactions. This study demonstrates that this estradiol matrix transdermal delivery system is effective in the treatment of menopausal symptoms, while providing the skin tolerability desired by patients.

Transport of beta-estradiol in freshly excised human skin in vitro: diffusion and metabolism in each skin layer.

This paper describes an experimental and theoretical evaluation of beta-estradiol (E2) transport in post-surgery fresh human skin in vitro. Necessary auxiliary experimental methods were newly developed for these studies. The experimental fluxes of E2 and the metabolite, estrone (E1), using the dermis, stripped skin, and split-thickness skin were consistent with a model considering the human skin as a three-layer (stratum corneum, viable epidermis, and dermis) membrane with the enzyme activity mainly residing in the basal layer of the viable epidermis. The diffusion and metabolism parameters for each skin layer were determined in the overall transdermal transport of E2. Compared to fresh hairless mouse skin, fresh human skin appears more resistant to the stratum corneum diffusion of E2 and is much less capable of metabolizing E2 to E1. These in vitro results have been extrapolated to the possible in vivo human skin situation with blood vessels directly beneath the viable epidermis providing "sink" conditions a short distance from the dermo-epidermal junction. The model analysis has demonstrated that there would be less metabolism and that a much smaller amount of the transdermal metabolite (E1) would be taken up by the blood capillary due to the shorter dermis path length for permeants in vivo than in the in vitro case using dermatomed split-thickness skin.

Hypoglycemic and insulin response to a continuous intravenous infusion of CGP-35126 recombinant human insulin-like growth factor-I (rhIGF-I) in healthy males.

Recombinant human insulin-like growth factor-I (rhIGF-I) produced by expression in a yeast vector was evaluated in seven normal men to determine effects on plasma glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF-I at a rate of 21.4 micrograms/kg/hour. Each infusion lasted for 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (P > .05) from their pre-dose levels. Compared with the saline (control) infusion, serum glucose levels were statistically lower (P < .05) 2 hours into the rhIGF-I infusion. These lower glucose levels were maintained until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF-I, but decreases in insulin levels occurred after the rhIGF-I hypoglycemic effect. This observation suggests that suppression of insulin levels may be due to secondary hypoglycemia rather than to a direct rhIGF-I effect. This study demonstrated the desired rhIGF-I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF-I may have potential clinical utility in hyperglycemic states.

Quantitative evaluation of aqueous isopropanol enhancement of skin flux of terbutaline (sulfate). I. Ion associations and species equilibria in the formulation.

It has been reported previously that saturated terbutaline sulfate in aqueous isopropanol significantly enhances the terbutaline flux through human skin in vitro. This paper demonstrates that the effect of isopropanol on the permeant species in the formulation contributes to the flux enhancement. This demonstration is based on studies involving measurements of conductivity and pKa as well as NMR spectroscopy in isopropanol-water mixtures. Increasing isopropanol concentration inhibits the proton dissociation of terbutaline and results in the ion associations between the protonated terbutaline and its counterion, sulfate anion. The species present in the formulation include protonated terbutaline, the negatively charged terbutaline-sulfate (1:1) ion pair, and the neutral terbutaline-sulfate (2:1) ion triplet. The results of the studies provide the basis for a quantitative evaluation of the species equilibria in solutions of terbutaline sulfate. The saturated terbutaline sulfate in 60% isopropanol produces the maximum concentration of the neutral ion triplet. This result is almost parallel to the terbutaline skin flux, which maximized at 60-80% isopropanol.

Quantitative evaluation of ethanol effects on diffusion and metabolism of beta-estradiol in hairless mouse skin.

The influence of low levels of ethanol on the simultaneous diffusion and metabolism of beta-estradiol (E2 beta) in hairless mouse skin was quantitatively evaluated. A wide range of diffusion/metabolism experiments was conducted with full-thickness skin, stripped skin, and dermis at the various ethanol levels. The experiments were carried out in a two-chamber diffusion-cell system where ethanol was present in both the donor and the receiver chambers at equal concentrations. Analysis of the experimental data with several enzyme distribution models further showed that the best model was that for which the enzyme activity resided totally in the epidermis and near the basal layer of the epidermis. The ethanol effects were separated and quantified in terms of the diffusion and metabolism parameters. Aqueous ethanol, even at low concentrations (greater than or equal to 25%), was found to have two important effects on E2 beta transport: ethanol functions as an inhibitor of the enzymatic conversion of E2 beta to estrone (E1) in the viable epidermis, and ethanol is able to enhance the transport of permeants across the lipoidal pathway of the stratum corneum.

Cotransport of estradiol and ethanol through human skin in vitro: understanding the permeant/enhancer flux relationship.

The thermodynamic and kinetic limits of ethanol-enhanced estradiol skin transport have been investigated by studying the relationship between estradiol and ethanol steady-state flux in the cotransport of permeant and enhancer in situations in which there exists an enhancer solvent gradient across the skin ("asymmetric" configuration). For aqueous ethanol solution saturated with estradiol, the flux of estradiol across the human epidermal membrane is empirically observed to be linear with the ethanol flux. A physical model approach has been used to determine the basis of this empirical linearity and to predict permeant/enhancer transport across the skin for the asymmetric configuration. Enhancement factors, determined with a balanced ethanol concentration across the skin ("symmetric" configurations), are used to predict fluxes in the asymmetric configurations. The model demonstrates that ethanol enhances the stratum corneum transport of estradiol and of itself by increasing the respective diffusion coefficients at lower concentrations (less than 50%) and by both increasing the diffusion coefficients and decreasing the membrane activity coefficients at moderate concentrations (50 to 75%). The model also demonstrates that the permeant flux, in general, is not linear with the cotransported enhancer flux.

The structure of depressive symptoms in the elderly.

In a structured sample of 100 male and 100 female minimally impaired patients, aged 60 years and over, females were more depressed. Varimax factor analysis demonstrated four factor groupings which have clinical relevance - Depression, Anxiety, Cognitive impairment, and Psychosomatic disorder; their relative importance is different in males and females. Analysis of variance of the scores of clusters generated by cluster analysis demonstrated four groups of subjects - normal, mildly depressed, moderately depressed with borderline dementia and disability, and severely depressed with moderate dementia and frank disability. In the mildly and moderately depressed, symptoms of anxiety predominated.

Depression, dementia and disability in the elderly.

A structured sample of mobile elderly patients in a rural community practice was assessed on validated rating scales for depression, dementia and disability. A total of 62% of the sample was abnormal on at least one variable. The overall prevalence of depression was 13%; the overall prevalence of dementia was either 10 or 18% depending on the criterion of Mental Test Score (MTS). Depression and dementia were related, depression being more common in females. In depressed and demented patients, MTS was age-related in those over 60 years; in depression alone, MTS was not age-related. Dementia was age-related, particularly over the age of 75. Disability increased with age and was more common in females. Disability was associated with both depression and dementia.

A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms.

Patients whose postmenopausal symptoms were being satisfactorily controlled with conjugated equine estrogens, either 0.625 mg/day (n = 57) or 1.25 mg/day (n = 67), participated in a study that compared the efficacy of these oral regimens with that of 17 beta-estradiol, 0.1 mg/day, administered through intact skin. The study was a multicenter, double-blind, randomized, parallel-group trial during which two thirds of the patients who received each dosage of conjugated equine estrogens were changed to an estradiol transdermal system while the remainder continued with conjugated equine estrogens. A total of 124 patients was included in the analysis of efficacy. The analysis revealed no significant differences between the estradiol transdermal system and conjugated equine estrogens in control of hot flushes or other postmenopausal symptoms and no statistically significant differences between treatment groups in regard to estrogen-related side effects. Minor topical reactions to the transdermal systems were reported during only about 20% of study weeks. Thus, transdermal estradiol, 0.1 mg/day, appears to be equally effective as conjugated equine estrogens, 0.625 or 1.25 mg/day, for controlling postmenopausal symptoms and is well tolerated.

Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement.

This open-label, multiple-crossover study compared the pharmacokinetics and pharmacodynamics of transdermal 17 beta-estradiol and two oral forms of estrogen replacement therapy in postmenopausal women. The transdermal systems delivered either 0.025, 0.05, or 0.1 mg/day; oral dosages were 2 mg of micronized 17 beta-estradiol or 1.25 mg of conjugated equine estrogens. Transdermal estradiol provided serum and urinary levels of estradiol conjugates typical of the early follicular phase of the premenopausal woman and an estradiol/estrone ratio that approximated 1. The increments of both serum and urinary estradiol showed dose proportionality. Serum levels of estradiol obtained 24 hours after oral administration of estrogens were in a range similar to the steady-state levels obtained with transdermal estradiol delivery. Oral estrogens, however, induced an excessive rise in estrone to levels far beyond those observed in premenopausal women. Continuous application of transdermal estradiol over 3 weeks did not result in any accumulation of estradiol or estradiol conjugates. After only three doses of oral estrogens, there were signs of retention of estrogens. Suppression of gonadotropins by oral and transdermal administration of estrogens was in a similar range. This observation supports the conclusions that levels of circulating estradiol are relevant to efficacy, and that excessively high levels of estrone after oral administration of estrogens merely represents a nonphysiologic precursor or metabolite pattern.

Normal erythrocyte sedimentation rate in the elderly.

Two hundred subjects aged 60-89 were selected for a study aimed at defining a reference range for the erythrocyte sedimentation rate in the elderly. The study extended a previous survey in subjects aged 20-65. The results confirmed that the sedimentation rate increases with age and that women have higher values than men but suggested that over half of elderly patients with disease would have rates within the previously defined "normal" range. It is therefore suggested that an erythrocyte sedimentation rate exceeding 19 mm in the first hour in elderly men and 22 mm in the first hour in elderly women warrants investigation.

Tremor and senile parkinsonism.

A study of 100 Day Hospital patients showed that 26 elderly patients with mild Senile Parkinsonism and varying degrees of dementia had subclinical tremor with the same frequency as Parkinson's Disease and distinguishable by amplified recordings from those of Parkinson's Disease and Senile Tremor. A significant history of cerebro-vascular disease was obtained in one-half of these patients. The recording of tremor is shown to be of value in diagnosing Parkinsonism and in assessing response to treatment.