Article

17β‐Estradiol Matrixpatch Removal and Reapplication in Postmenopausal Women: Theoretical Predictions with an Oscillating Diffusion Coefficient Model

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Abstract

The pharmacokinetic performance of a matrix system for transdermal beta-estradiol (E(2)) delivery after multiple consecutive dosing in postmenopausal women undergoing hormone replacement therapy was investigated. The E(2) plasma profiles determined during the third application in 16 postmenopausal women were compared with results obtained in a published clinical study using the same patch in 24 postmenopausal women without E(2) pretreatment; they were compared with a theoretical diffusion/pharmacokinetic model. A conventional theoretical model with constant model parameter (CPM) obtained from in vitro mass balance experiments in a Franz cell type set up described successfully the transdermal E(2) bioavailability parameter AUC(0-96h) (4341.9 +/- 1513.1; calculated 4250.8) and C(average) (45.0 +/- 13.2; calculated 41.2). Also, experimentally, there was no significant drop in E(2) plasma values after patch removal and reapplication; this was corroborated by calculations. Accumulation of E(2) did not occur when several patches were applied consecutively over a period of 3 weeks. Steady state was achieved following application of the first patch. However, the differences between recorded E(2) plasma profiles and theoretical results detected at specific measurement points cannot be explained by the CPM model. Experimentally obtained plasma profiles were always lower in the morning and higher in the evening than predicted on the basis of the model. Measurements of in vivo skin temperature in the postmenopausal women showed oscillating temperature profiles in the form of a cosinor function: The temperature mesor of untreated postmenopausal women was 34.8 degrees C with an acrophase at 17.0 o'clock (95% CI: 14.30-19.30) and an amplitude of +/- 0.4 degrees C (p = 0.1). During the application of the patch the average temperature next to a patch rose 0.3 degrees C, which was statistically significant (p = 0.1). In the skin under the application of the matrix patch a mesor temperature was detected as 35.6 degrees C with an amplitude of +/- 0.5 degrees C with an acrophase at 17.51 o'clock (95% CI: 14.30-21.00) (p = 0.05). The temperature period was 24 h for all measurements and the maximum temperature was observed at about 16.30 h, and a minimum at about 5.00 h. A linear dependency was detected in in vitro experiments between the log of E(2) permeability and the temperature for stripped skin, epidermis/dermis layer, as well as for the matrix. Modeling of E(2) plasma profiles with oscillating diffusion coefficients (ODM1) with a sine wave function results in this equation: D(1) = D(0x) + Da(x).sin(k.t). D(0x) is the diffusion coefficient determined at 35.6 degrees C, k is 1/24 h, D(a) is the diffusion coefficient of the temperature amplitude, h is hour, and x stands for the respective diffusion layer. It was shown that the experimental E(2) plasma profile variations are more pronounced than can simply be explained by skin temperature variations alone (ODM1 model). A simplex fit with an oscillating diffusion coefficient in the form of a sine wave function for the stratum corneum (ODM2 model) resulted in a temperature amplitude of 1.1 degrees C, about twice as high as was determined in the in vivo measurements (ODM2 model). Therefore, other circadian parameterlike blood flow might superimpose the temperature profile. The improvement in data analysis by incorporating oscillating diffusion coefficients (ODM1 and 2) over CPM was judged from a comparison of experimental data with the calculated plasma profiles with the AIC, Akaikes model selection criterion, which allows ranking between models because it is independent of the scaling of the data points. ODM1 and ODM2 improved the data analysis over CPM by allowing better calculation of experimental C(max), t(max), the time to reach to C(max), and the fluctuation, f. No difference between CPM, ODM1, or ODM2 was found for the bioavailability parameter C(average) and AUC(0-96h).

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... For many years, the results of both arms of the Women′s Health Initiative (WHI) were translated into very cautious, even negative recommendations in regard to the use of postmenopausal hormones [2,3]. Only recently, the International Menopause Society, the North American Menopause Society and the Endocrine Society expressed their opinions in formal statements, which were generally more favorable. ...
... A recent article in Obstetrics and Gynecology, written by several key WHI investigators, addresses the same issues by summarizing the WHI data in a rational way. This is in line with that of most non-WHI opinion leaders, supporting the prescription of E2 hormone therapy to young, healthy, symptomatic menopausal women, ascertaining treatment efficacy on the one hand while relieving the worries concerning its safety in this target population on the other hand [2,3]. ...
... Although it is concluded among opinion leaders and menopause societies that it is appropriate to treat women with symptoms at the onset of menopause, because there is no proven therapy for primary prevention, in some women the use of HRT for this role may at least be justified [3]. As there is a newly sparked interest in E2 delivery, several questions still remain concerning E2 steady state delivery, the relationship between pharmacokinetics and dynamics, as well as a comparison between oral and transdermal pharmacokinetics and pharmacodynamics. ...
There is a renewed interest in the delivery of estradiol (E2) for the reduction of menopausal symptoms in young symptomatic menopausal women. This paper compares experimentally and theoretically obtained E2 plasma values by oral and transdermal delivery and compares them with relevant menopausal symptoms. Two independent previously published studies were compared, which each contained 42 young symptomatic menopausal women. Experimentally obtained plasma values at days 1, 7 and 21 were compared with a theoretical model, taken from the literature, for describing plasma values for an oral immediate release formulation, consecutively for 21 days. Menopausal symptoms were determined in the steady state for oral and transdermal delivery with the Kuppermann index, previously not reported. In the case of oral delivery, estradiol was compared with estradiol valerate. Previously published results for transdermal delivery of E2 showed that the matrix system establishes a steady state condition with the application of the first patch. Excellent agreement between theoretically predicted and experimentally obtained E2 plasma values for oral delivery in menopausal women was obtained. Circadian E2 plasma levels were observed continuously for transdermal delivery, were seen in oral delivery during first application and disappeared when steady state was achieved. Application of the prodrug E2-valerate delayed the maximum plasma peak from 1 pm to 4 pm, similar to the transdermal matrix patch. Investigating menopausal symptoms determined with the Kuppermann index did not reveal differences between oral or transdermal “E2 kinetic (hot flushes) relationship”. This relationship was similar to symptomatic women suffering from hot flushes in untreated menopausal women or premenopausal women. Different menopausal symptoms required different E2 plasma levels: the average E2 levels higher than 23 pg/mL in plasma did abolish insomnia in 50% of postmenopausal women, with 28 pg/mL is needed to suppress 50% of dysthymia; however, rather high levels of 41 pg/mL are needed to suppress 50% of hot flushes, suggesting a rather complex mechanism beyond an E2 receptor mediated process. There is a difference in the steady state between oral and transdermal E2 delivery. Steady state condition is achieved in the first application of a matrix patch, whereas with the application of a tablet the steady state is achieved in transdermal delivery within 12–14 days. Our reported calculated missed intake of a E2 tablet shows that E2 plasma levels drop for 4 days consecutively. Our conducted study has several limitations: firstly, no cross-over was conducted, but a rather cumbersome mathematical modeling; secondly, healthy women with no accompanying severe diseases were included in this study. The higher the oral dose, the higher the E2 steady state levels, but the time to achieve steady state levels is independent from the E2 dose.
... This metric would help estimate when to replace the monolithic patch. Research shows that repeated applications of the device can be used as a strategy to maintain a steadystate flux [7], leading to an effective drug concentration in the blood stream [8,9]. Similar to the TDDS 1 device, a single time constant can also be derived to predict the time (t eff ) it takes to release the drugs from the matrix. ...
... Considering that: Product designers can use the effective time constant to estimate the performances of TDDS 1 and TDDS 2. The method provides manufacturers with an analytical tool to help estimate the time it takes the medication to begin working after the application of a patch of type TDDS 1. In studies involving removal and reapplication of transdermal matrix systems [8,9,17], the method developed for TDDS 2 can be adapted to estimate how long a person has to wear the patch. In addition, calculation of t eff is straightforward and does not involve the solution of a system of partial differential equations. ...
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... Increasing the application period and/or reducing the removal period would produce a more continuous delivery [21] and, therefore, a relatively constant plasma drug concentration. Clinical and theoretical studies show no significant drop in b-estradiol plasma concentration after patch removal and reapplication [25,26]. A steady-state bestradiol plasma level was achieved following application of the first patch. ...
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The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.
It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.
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Synopsis The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy. Pharmacodynamic Properties 17β-Estradiol is the predominant estrogen produced by the ovaries in premenopausal women. Administration of transdermal estradiol to postmenopausal women (in dosages of 0.05 to 0.2 mg/day) elevates plasma estradiol concentrations into the range observed in premenopausal women at the early to mid follicular stage. Plasma estrone concentrations are increased to a much lesser degree and a physiological plasma ratio of estradiol to estrone (approximately 1: 1) is thus produced. As a result of the increased plasma estradiol concentrations, plasma concentrations of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are decreased and vaginal cytology is converted to a pattern resembling that found in premenopausal women, with improvement of the maturation and karyopyknotic indices. Bone resorption is inhibited, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and an increase in bone mineral density has been achieved in patients receiving long term treatment. Transdermal estradiol has a less marked effect than oral estrogens on lipid and lipoprotein metabolism; the plasma lipid profile does not appear to be significantly altered by short term treatment, but some studies of ⩾ 6 months’ duration have reported potentially beneficial changes in various lipid and lipoprotein fractions. Pharmacokinetic Properties The estradiol transdermal therapeutic system is designed to deliver estradiol at a constant rate for up to 4 days. Currently, 3 sizes of delivery system are available, with nominal delivery rates of 0.025, 0.05 and 0.1 mg/24 hours. Following application of transdermal estradiol to intact skin, maximum plasma estradiol concentrations are attained in postmenopausal women within 2 to 8 hours. Steady-state plasma concentrations of estradiol are linearly proportional to the dose administered; mean levels of around 23, 40, 75 and 100 ng/L occur in women with pretreatment estradiol levels ⩽ 10 ng/L from administration of 0.025, 0.05, 0.1 and 0.2 mg/day, respectively. Plasma levels of estradiol during transdermal therapy and reduction in menopausal symptoms, plasma FSH concentrations and urinary excretion of calcium are closely related. Estradiol is mainly metabolised in the liver, the major metabolites being estrone and estriol and their conjugates, which are considerably less potent than estradiol. The bulk of the metabolites are excreted in the urine as glucuronides and sulphates, although some enterohepatic recirculation may occur. Within 24 hours of removal of transdermal delivery systems, plasma concentrations of estradiol and estrone, and urinary excretion of estradiol and estrone conjugates, return to pretreatment levels. The plasma elimination half-life of estradiol is approximately 1 hour irrespective of the route of administration and the metabolic plasma clearance rate is between 650 and 900 L/day/m2. Therapeutic Use The efficacy of transdermal estradiol as estrogen replacement therapy in peri- or postmenopausal women has been evaluated in noncomparative, placebo-controlled and comparative clinical trials. Dosages ranging from 0.025 to 0.2mg daily have been used. In studies of ⩾ 2 months duration, treatment has generally been cyclical (3 weeks on, 1 week off) and sequential progestagen therapy has usually been administered for 5 to 12 days per cycle to patients with an intact uterus, in order to minimise endometrial proliferation. Climacteric symptoms — hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability — have been eliminated or significantly improved during transdermal estradiol replacement therapy. In comparative studies transdermal estradiol has demonstrated efficacy in the control of climacteric symptoms at least equivalent to those of oral estradiol preparations, ethinylestradiol and conjugated estrogens, and subcutaneous estradiol implants or estradiol/prasterone depot injections. Data from preliminary studies suggest that transdermal estradiol, usually with sequential progestagen, is also effective in other indications for which estrogen therapy is prescribed, such as contraception and as hormone replacement therapy in patients with premature ovarian failure or bilateral oophorectomy participating in fertility programmes. Although transdermal estradiol inhibits bone resorption, few data are currently available regarding its effect on the incidence of osteoporosis and fractures in treated menopausal women. Analysis of patient acceptability of the transdermal route for estrogen replacement in several studies indicated that > 70% of patients preferred transdermal estradiol over oral or injectable therapies. Adverse Effects A significant proportion of patients experience dermatological reactions to the transdermal delivery device. Although these mostly consist of transient erythema/itching at the site of application, which can be minimised by rotation of patch application sites, severe irritation leading to discontinuation of therapy occurs in about 2.5 to 7% of patients overall. Otherwise, transdermal estradiol therapy is generally well tolerated, the most common systemic adverse symptoms being typical estrogenic effects, such as breast tenderness and spotting/bleeding and general effects such as fatigue, abdominal bloating and nausea, which result in discontinuation of treatment in < 4% of patients. Estrogenic stimulation of the endometrium occurs with transdermal estradiol therapy and coadministration of a sequential progestagen (which may also produce a more acceptable bleeding pattern) is therefore recommended for patients with an intact uterus in order to minimise endometrial proliferation. Unlike oral estrogens, transdermal estradiol does not stimulate hepatic metabolism and consequently plasma concentrations of renin substrate, sex hormone-, thyroxine- and cortisol-binding globulins and clotting factors are not elevated. It has been suggested that transdermal estradiol might be associated with a lower incidence of adverse effects than oral estrogen replacement therapies because of the lower circulating estrogen concentrations involved and the lack of untoward effects on liver metabolism. However, this has not been confirmed in comparative studies to date; generally, adverse effects have been comparable in patients receiving transdermal estradiol and those receiving oral or injectable estrogens. Dosage and Administration The recommended initial dosage of transdermal estradiol for the treatment of menopausal symptoms is 0.05mg daily, which may be increased in cases of inadequate response after 2 to 3 weeks’ treatment, or decreased if breast discomfort or breakthrough bleeding occur. For maintenance therapy the lowest effective dose should be used. Treatment may be continuous or may be given in 4-week cycles (3 weeks on/1 off). Sequential progestagen treatment should be administered for 10 to 12 days per month to patients with an intact uterus. The transdermal estradiol delivery system should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, leiomyoma of the uterus, endometriosis, vaginal bleeding of unknown origin, severe renal, hepatic, or cardiac disease and active or previous thromboembolic disease.
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Circulating plasma levels of 17β-estradiol after the administration of fixed dosages of 17β-estradiol show great variability depending upon product formulation, route of administration, and interindividual variation in absorption and metabolism. Two new 17β-estradiol transdermal delivery systems, Systen 50 (also called Evorel®) and Menorest®50 have recently been approved in Europe for the treatment of climacteric symptoms. Both transdermal systems deliver 17β-estradiol at a rate of 50 µg/day. The present study was undertaken to compare the plasma profiles of 17β-estradiol delivered by these 2 products in 30 healthy postmenopausal women according to a randomised, monocentric, single-blind, crossover protocol. Two 4-day patch application periods were separated by a 7-day washout period. Plasma 17β-estradiol concentrations were determined 24 hours and 30 minutes before and then 0, 2, 4, 8, 12, 24, 48, 60, 72, 84 and 96 hours after the first patch administration. 17β-Estradiol measurements were performed using a specific direct radioimmunoassay developed at the French Fondation de Recherche en Hormonologie laboratory. Bioequivalence was assessed by analysis of variance. The results demonstrated that the 2 products were similar in terms of maximum plasma concentration; however, mean concentration, concentration at 96 hours and area under the concentration-time curve were significantly (p < 0.05) greater with Menorest®50. Furthermore, 17β-estradiol concentrations decreased more rapidly with Systen®50 than with Menorest®50. These differences in the plasma profiles of 2 transdermal systems both delivering 50 µg/day of 17β-estradiol may have important clinical consequences both in terms of tolerance and effectiveness.
Article
The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.
Article
The objective of this study was to evaluate the pharmacokinetics of estradiol and estrone, at steady-state, after repeated applications of Menorest® delivering 0.025, 0.050 and 0.100mg estradiol daily, and to determine the plasma concentration/administered dose relationship. It was an open randomised crossover study, with 3 treatment periods of 10.5 days separated by two 12-day intervening washout periods. Randomisation was conducted according to a latin square design. The clinical part of the study was carried out at CAP (Centre d’Activité Pharmacologique), Montpellier, and plasma estradiol and estrone concentrations were determined at CEPHAC (Centre d’Etudes et de Recherche en Pharmacie Clinique), St Benoit, France. The study included 30 healthy postmenopausal women, volunteers aged between 42 and 70 years (mean 59.13 ± 6.90 years). Each transdermal system dosage was applied for 3 successive 3.5-day wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system dosage at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. After the third application of patches releasing 0.025, 0.050 and 0.100 mg/day, a linear relationship was established between the administered dose and the estradiol pharmacokinetic parameters [area under the plasma concentration-time curve from time 0 to 84 hours (AUC0–84h), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin) and average plasma concentration (Cav)]. This relationship did not exist between plasma estrone concentrations and estradiol administered doses, although these concentrations increased with the increased dosage. Adverse events were neither serious nor unexpected; none required discontinuation of the treatment, and their incidence was higher with the highest doses. Erythema and skin wrinkling were the most frequent cutaneous reactions — their frequency (related to the number of applications) was increased from 26 to 44% for erythema and from 2 to 40% for skin wrinkling when the administered dose increased from 0.025 to 0.100 mg/day. It was concluded that the linear relationship established between plasma estradiol concentrations and administered doses constitutes the basis for the dosage adjustment to the individual needs of postmenopausal women in the range 0.025 to 0.100 mg/day, and allows adjustment of the dose to deliver the minimum effective level of estrogen.
Article
Objective: The relative bioavailability of estradiol from two matrix transdermal delivery systems, Alora (0.05 mg/day when applied for 3-4 days) and Climara (0.05 mg/day when applied for 7 days), was evaluated in this two-period, randomized crossover study. Design: A total of 27 healthy, postmenopausal women completed this study. Each subject received four successive doses of Alora every 84 h (3.5 days) and two doses of Climara every 168 h (7 days) in a randomized sequence without a washout period. Serial serum samples were collected over a 7-day period during the second week of each treatment. Samples were analyzed for estradiol and estrone using a validated radioimmunoassay method. Pharmacokinetic analyses were conducted using baseline-corrected parameters. Results: Fluctuations in serum estradiol levels were 44% higher for Climara, as indicated by the ratio of Cmax/Cmin. Because the Cmin values for the two regimens were similar, the differences in fluctuation reflected the difference in their Cmax values (49.8 pg/ml for Alora, 67.7 pg/ml for Climara.) The estradiol AUC[Greek small letter tau with macron above] for Climara was 124% (95% CI 115.6-133.7) of the value for Alora. Conclusions: Serum estradiol concentrations were maintained at a more constant level during twice-weekly application of Alora than during once-weekly application of Climara. Both regimens were generally well tolerated and no serious skin or other adverse effects were reported by the subjects. However, Alora exhibited better skin tolerability as indicated by a lower incidence of moderate skin erythema. In addition, there was less adhesive transfer to skin at the application site with Alora. (Menopause 1998;5:107-112. (R) 1998, The North American Menopause Society.) (C)1998The North American Menopause Society
Article
The problems of removal of a transdermal patch, (1) without applying a new patch, and (2) with applying a new patch to a different skin location, are studied. The critical parameter for understanding these problems is R, the product of the pharmacokinetic elimination constant and the diffusional time lag. From the solution to the patch removal problem, it is evident that transdermal delivery can often be terminated rapidly compared to other forms of drug delivery. When R ⪢ 0.4 and the diffusional time lag is long, however, the rate of termination of transdermal delivery is relatively slow. The patch re-application problem is used to study deviations from zero-order transdermal delivery in a multiple dosing regimen. For all R, transdermal delivery is remarkably close to zero order even during the period when the patch is replaced. In the worst case of R ⪢ 1.6, the concentration of drug in the blood does not exceed 1.5 times the steady-state blood level.
Article
Purpose. The aim of our study was to clarify the kinetic performance of a membrane controlled reservoir system (MCRS) for -estradiol (E2) under in vitroconditions by determination of the role of membrane and adhesive layer on E2flux control. Methods. E2and ethanol fluxes across EVA membrane or membrane coated with adhesive from saturated solutions in defined ethanol/PBS mixtures were measured in the symmetric and asymmetric configuration. Physicochemical parameters of the EVA membrane were determined. Results. The E2flux across the 9% EVA membrane steadily increased with increasing ethanol concentrations in both configurations, due to enhanced uptake of E2by the polymer and increasing membrane diffusivity. Permeation across the EVA membrane coated with an adhesive layer in the symmetric and asymmetric configuration increased up to maximum values of 0.80 0.14 (g cm–2 h–1and 0.37 0.02 g cm–2 h–1, respectively, at 62.5% (v/v) ethanol. The fluxes then decreased with further increase in the volume fraction of ethanol due to a dramatically reduced permeability of the adhesive layer. For the asymmetric case, a linear dependence of E2on ethanol fluxes was observed. Conclusions. The E2flux from MCRS is strictly dependent on reservoir ethanol concentrations, whereas the adhesive layer represents the rate controlling barrier at high ethanol levels (>70% v/v).
Article
Purpose. The aim of our study was to investigate the high fluctuations of Estradiol (E2) plasma levels transdermally delivered in postmenopausal women by a commercially available membrane controlled reservoir system (MCRS). Methods. The transdermal E2 flux either out of a complete MCRS or across its membrane out of defined ethanol water mixtures was determined, as well as E2 plasma profiles in 6 postmenopausal women produced by a MCRS. Results. The transdermal in vitro E2 flux rate out of a complete MCRS, claimed to deliver 25 g/day, increased steadily, reaching a maximum value of 2.06 0.58 (g/h at 30 to 40 hours and decreased to a rate of about 0.5 (g/h from 60 to 90 hours. No statistically significant differences between plasma profiles calculated from the in vitro investigation and derived from a clinical study could be identified. The E2 flux in defined ethanol/water mixtures across MCRS-membrane, adhesive and skin layer increased with increasing ethanol concentrations up to a maximum of 227 34 ng/cm2/h at an ethanol concentration of 62.5% (V/V) and decreased with further increase in the volume fraction of ethanol. Conclusions. In vitro as well as in vivo investigations showed high fluctuation of E2 plasma profiles in postmenopausal women produced by the MCRS. These fluctuations are caused by a non-constant input rate of E2 which may be due to changing ethanol concentrations in the reservoir of the MCRS.
Article
Plasma luteinizing hormone, follicle-stimulating hormone, and estradiol were measured at 20-minute intervals for 24-hours in seven pubertal premenarchal girls whose sleep was monitored polygraphically. A circadian variation in plasma estradiol was demonstrated with the highest values occurring during the day (1400-1600 hours) and lowest values during sleep, a time when gonadotropin secretion was augmented.
Article
Nine pregnant rhesus monkeys maintained in constant low level lighting (5 Lux) from 56-80 days gestation (dGA) onward were studied to assess the presence or absence of circadian maternal body temperature and maternal plasma hormone variations. Maternal arterial blood samples were taken every 4 h in six monkeys (105-120 dGA) for 48-56 h and every 2 h in three monkeys (108-115 dGA) for 60 h. Maternal intraabdominal temperature was recorded continuously. Cosinor analysis was used to determine circadian rhythmicity. Individual endogenous timekeeping was demonstrated by 1) free-running circadian variations in maternal body temperature in all nine animals, 2) consistent internal acrophase relationships between the maternal body temperature and maternal plasma cortisol rhythm, and 3) idiosyncrasy of the temporal relationship of detectable rhythms to the external environment in individual animals. Only one animal had a significant maternal plasma ACTH rhythm, whereas the presence of 24-h variations in the other hormones varied in individual animals. The mean +/- SD acrophase profiles in hours from the temperature acrophase in those animals who showed significant rhythms were 19.7 +/- 0.6 (n = 8) for cortisol, 19.4 +/- 2.4 (n = 6) for dehydroepiandrosterone sulfate, 8.3 +/- 1.1 (n = 6) for progesterone, and 18.9 +/- 1.6 (n = 3) for estradiol. We conclude that 24-h variations in maternal plasma hormones are truly endogenously generated and not passively dependent on the light-dark cycle. The maternal circadian system regulates the 24 h temporal organization of endogenous plasma hormone variations. We hypothesize that rhythms in cortisol, dehydroepiandrosterone sulfate, progesterone, and estradiol during pregnancy are directly or indirectly governed by the maternal hypothalamus via the circadian oscillatory output of the maternal adrenal.
Article
Published permeability coefficient (K p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K p upon MV (or MW) and K oct. It is found that the existence of an “aqueous-polar (pore) pathway” across the SC is not necessary to explain the K p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K oct ranging from −3 to + 6), the postulated upper limiting value of K p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.
Article
The protection afforded by postmenopausal oestrogen replacement against cardiovascular disease is not fully explained by changes in plasma lipoproteins. To investigate the effect of oestrogen on arterial tone, Doppler ultrasound was used to assess blood flow characteristics in the internal carotid arteries of 12 postmenopausal women. Patients were studied pretreatment and at weeks 4, 6, 9, and 22 of therapy with transdermal oestradiol 50 micrograms/day. The pulsatility index (PI), which is thought to represent impedance to blood flow distal to the point of sampling, was measured from the flow velocity waveform. 11 of the 12 patients were within 5 years of menopause; 1 was 8 years postmenopausal but had experienced bleeding 4 years after menopause. In the 11 women there was a highly significant correlation (r = 0.77) between time since menopause and baseline PI. A similar correlation (r = 0.74) was observed when the episode of postmenopausal bleeding was redefined as time of menopause in the twelfth patient. For all 12 patients, there was a significant negative correlation (r = -0.70) between change in PI during transdermal oestradiol therapy and mean of baseline plus week 22 PI value. For all correlations between changes in PI and time since menopause, the longer the time the greater the fall in PI. These results, and previous observations of a reduction in uterine artery PI with oestradiol treatment, suggest that oestrogen has a generalised effect on the arterial system.
Article
The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.
Article
The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE1S, 2.5 mg/day) and oestradiol valerate (E2V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 micrograms/day) were compared in 8 post-menopausal women, using a randomized cross-over design. The end points measured in peripheral plasma included oestrone (E1), oestradiol (E2), oestriol (E3), oestrone sulphate (E1S), oestradiol sulphate (E2S) and oestriol sulphate (E3S). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed. The plasma levels of E3 were invariably below the detection limit (220 pmol/l). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E3S) following PE1S administration than those recorded after E2V ingestion. The terminal half-lives of the circulating oestrogens measured after PE1S administration did not differ from those found after E2V administration. After 21 days of PE1S administration (in combination with LNG for the last 10 days), the maximum levels of all the oestrogens (except those of E2) were significantly higher than those seen after the first dose. No such difference was observed after E2V administration. There was no difference between the effects of the two treatment regimens with regard to the E1/E2 ratios, but the E1/E1S ratios were significantly lower after PE1S treatment than after E2V administration. It is concluded that, compared with an equivalent dose of PE1S, daily repeated oral administration of E2V yields consistently lower peripheral plasma levels of E2 and its principal metabolites. However, in contrast to PE1S therapy, prolonged administration of E2V does not result in an accumulation of the circulating oestrogens measured.
Article
There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.
The influence of clothing on skin temperature distributions of the torso was investigated during and after cold exposure. Volunteers were cooled for one hour at 5 degrees C while wearing clothing designed to have insulation which was intended to be relatively uniformly distributed. Three different thicknesses of clothing were used. Following thermistor measurements of skin temperatures during the cold exposures, clothing was quickly removed from the upper parts of the body to enable thermographic investigations of the temperature distributions of the front of the bare torso. The evolution of temperature distributions were then studied at different ambient temperatures (5 degrees C and 20 degrees C) as a function of the thickness of the insulation which had previously been worn. The patterns of the temperature distributions, and the range and standard deviation of torso temperatures were all found to be relatively constant in spite of the different thicknesses of clothing worn or in the time-variant mean torso temperatures which resulted. The front torso sites normally used for the determination of mean skin temperatures were found to be on portions of the torso which were cooler than the surrounding regions. It was concluded that a site midway between the umbilicus and a nipple yields a more accurate estimate of mean torso temperature in the conditions of the present study.
The statistical test of hypothesis of no difference between the average bioavailabilities of two drug formulations, usually supplemented by an assessment of what the power of the statistical test would have been if the true averages had been inequivalent, continues to be used in the statistical analysis of bioavailability/bioequivalence studies. In the present article, this Power Approach (which in practice usually consists of testing the hypothesis of no difference at level 0.05 and requiring an estimated power of 0.80) is compared to another statistical approach, the Two One-Sided Tests Procedure, which leads to the same conclusion as the approach proposed by Westlake based on the usual (shortest) 1-2 alpha confidence interval for the true average difference. It is found that for the specific choice of alpha = 0.05 as the nominal level of the one-sided tests, the two one-sided tests procedure has uniformly superior properties to the power approach in most cases. The only cases where the power approach has superior properties when the true averages are equivalent correspond to cases where the chance of concluding equivalence with the power approach when the true averages are not equivalent exceeds 0.05. With appropriate choice of the nominal level of significance of the one-sided tests, the two one-sided tests procedure always has uniformly superior properties to the power approach. The two one-sided tests procedure is compared to the procedure proposed by Hauck and Anderson.
Several theories describing percutaneous drug absorption have been proposed, incorporating the mathematical solutions of differential equations describing percutaneous drug absorption processes where the vehicle and skin are regarded as simple diffusion membranes. By a solution derived from Laplace transforms, the mean residence time MRTand the variance of the residence time VRTin the vehicle are expressed as simple elementary functions of the following five pharmacokinetic parameters characterizing the percutaneous drug absorption: (1) k d, which is defined as the normalized diffusion coefficient of the skin, (2) kc, which is defined as the normalized skin-capillary boundary clearance, (3) the apparent length of diffusion of the skin ld, (4) the effective length of the vehicle lv, and (5) the diffusion coefficient of the vehicle Dv. All five parameters can be obtained by the methods proposed here. Results of numerical computation indicate that: (1) concentrationdistance curves in the vehicle and skin approximate two curves which are simply expressed using trigonometric functions when sufficient time elapses after an ointment application; (2) the most suitable condition for the assumption that the concentration of a drug in the uppermost epidermis can be considered unchanged is the case where the partition coefficient between vehicle and skin is small, and the constancy of drug concentration is even more valid when the effective length of the vehicle is large; and (3) the amount of a drug in the vehicle or skin and the flow rate of the drug from vehicle into skin or from skin into blood becomes linear on a semilogarithmic scale, and the slopes of those lines are small when Dv is small, when the partition coefficient between vehicle and skin is small, when lv is large, or when kc is small. A simple simulation method is also proposed using a biexponential for the concentration-time curve for the skin near the skin-capillary boundary, that is, the flow rate-time curve for drug passing from skin into blood.
Article
The flux of He and O2 through intact adult human skin was measured at various inspired concentrations and skin temperatures. The skin surface was then stripped with cellophane tape to alter the diffusional conductance of the stratum corneum. He flux for stripped skin was used to estimate skin perfusion as a function of local temperature, and diffusional conductance for O2 was estimated from O2 flux and perfusion. The flux of He or O2 at constant skin temperature can be related to inspired concentration by a simple linear model. Increasing surface temperature in the range 33-43 degrees C produced a much larger increase in O2 flux than in He flux for intact skin. Skin stripping greatly increased skin O2 flux. Estimated skin conductance for O2 showed a more marked temperature dependence than estimated skin perfusion. The results suggest that raising skin temperature in the range 38-43 degrees C has only a modest effect on skin perfusion and that stratum corneum conductance may have a major role in the large increase of O2 flux with temperature.
Article
After physiological or surgical menopause, women are suddenly deficient in their main estrogenic hormone, 17 beta-estradiol. Only a very small amount of estradiol is still produced from adrenal precursors. More than 50 per cent of all postmenopausal women suffer for varying periods of time from the symptoms of this estrogen deficiency, most notably vasomotor instability (hot flashes) and sleep disturbances. The trophic symptoms of estrogen deficiency have longer lasting and cumulative consequences: accelerated loss of bone density that eventually increases the risk of fractures, genitourinary atrophy resulting in dyspareunia and urinary atrophy; and lipoprotein changes with increased risk of coronary heart morbidity and mortality. Today estrogen deficiency is mainly treated by oral estrogens--either conjugated equine estrogens or estradiol--in milligram doses far in excess of what would be required by the parenteral route. Taken orally, estradiol is largely transformed to estrone through metabolism in the liver. Certain undesirable side effects of estrogen therapy (e.g., increased renin substrate) are caused by the unphysiologic nature of the oral route of administration. Dosage forms for parenteral estrogen administration have been widely studied: vaginal or percutaneous creams, intranasal solutions, and sublingual tablets. All of these result in a pronounced, transient elevation of plasma concentrations of estradiol and a minor increase of estrone. An improved regimen, which produces more constant plasma concentrations, is achieved with an experimental estradiol implant or with a vaginal ring delivering estradiol. These studies demonstrate that daily estradiol doses of 0.2 mg and less are effective in reducing hot flashes. Effective doses of conjugated estrogens and estradiol administered by different routes achieve estradiol plasma concentrations of similar magnitude (between 35 and 100 pg/ml). Estrone plasma levels vary widely with these different regimens and do not seem to be directly related to efficacy. In summary, the literature indicates that efficacy of estrogen replacement for the treatment of the menopausal symptoms appears to relate to the magnitude of estradiol plasma levels; effective therapy is achieved by an estradiol regimen that maintains plasma estradiol levels of at least 35-55 pg/ml. Efficacy of estrogens in the prevention of osteoporosis as assessed by densitometry has been demonstrated for conjugated oral estrogens.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
A novel patch containing 17 beta-Estradiol exhibits improved kinetic profiles compared to the currently available leading transdermal product. The blood concentrations produced by the newly developed matrix patch are stable over 3 to 4 days, thus avoiding the occurrence of 17 beta-Estradiol peaks in the blood. In an additional clinical study an almost linear relationship could be identified between the patch size (Test patch: 7.25, 14.5 and 29.0 cm2) and the obtained 17-estradiol bioavailability (judged on AUC, cmax, c(ave), Cmin). These results are corroborated by the additional in vitro experiments. An almost constant drug delivery rate of 48 micrograms +/- 15 micrograms/day of 17 beta-Estradiol per 13.85 cm2 patch over 4 days can be detected through excised human skin. No statistically significantly different transdermal flux rates of 17 beta-Estradiol were detected in 3 different batches of the transdermal drug delivery system in vitro. Statistical evaluations were performed with the 3-Way-Anova test on the 0.05 significance level. This newly developed product presents a kinetically optimized transdermal 17 beta-estradiol patch for hormone substitution therapy.
Article
The temperature dependence of in vitro permeation through human epidermal membrane (HEM) was determined for urea, mannitol, tetraethylammonium ion (TEA), and corticosterone. The effect of temperature upon HEM electrical resistance was also measured. The majority of the experiments involved measuring the permeability coefficients of a specific permeant at 27 degrees C and 39 degrees C for a given HEM sample, the electrical resistance was also measured at each temperature. Similar experiments were also conducted with a model synthetic porous membrane. The effect of temperature was quantitated as the ratio of the permeability at 39 degrees C to the permeability at 27 degrees C for each permeant. These ratios observed for HEM with urea, mannitol, and TEA as the permeants were 1.66 +/- 0.05, 1.76 +/- 0.14, and 1.71 +/- 0.11, respectively. The change in temperature was shown to have a similar effect upon the electrical conductance of the HEM samples. The observed ratio for corticosterone permeation was 4.5 +/- 0.4. The experimental ratios observed for the three polar/ionic permeants were shown to approach those obtained from the model porous membrane and differed greatly from the ratio observed for the more lipophilic corticosterone, indicating differences in the effective transport mechanism/pathway for these classes of permeants. The permeability of urea was also observed to be inversely proportional to the electrical resistance of the HEM samples; this relationship was shown to be independent of temperature over the temperature range studied. The temperature dependence data and the observed relationship between urea permeability and electrical resistance strongly support the existence of a porous permeation pathway through the HEM as an operative diffusional route for polar-ionic permeants.
Article
Postmenopausal hot flashes are characterized by sweating and peripheral vasodilation and occur more frequently during increased heat loads. The circadian rhythm of core body temperature (TC) is well known and suggests that hot flashes will be most frequent when core temperature is highest. This hypothesis has not been tested previously. Ten symptomatic and six asymptomatic postmenopausal women were recruited from advertisements and screened. Each received 24-h ambulatory monitoring of sternal skin conductance levels to detect hot flashes, ambient temperature, skin temperature, and TC. The last measure was recorded using an ingested radiotelemetry pill. Cosinor analysis demonstrated a circadian rhythm (P < 0.02) of hot flashes with a peak at about 1825 h. TC values of the symptomatic women were lower than those of the asymptomatic women (P < .05) from 0000-0400 h and at 1500 and 2200 h. The majority of hot flashes were preceded by elevations in TC. Thus, elevated TC may serve as one trigger of menopausal hot flashes.
Article
The purpose of this study was to evaluate the role of the opioid system and the estrogen environment in the nocturnal secretion of melatonin in women with secondary amenorrhea (SA). Nocturnal melatonin concentrations in patients with SA were significantly higher than in normal women (p < 0.01 vs. women with normal menstrual cycles). There were significant negative correlations between cumulative melatonin levels (between 8 p.m. and 8 a.m.) and serum estradiol-17 beta (r = -0.561, p < 0.01) and between peak serum melatonin values and serum estradiol-17 beta concentrations (r = -0.608, p < 0.01) in SA. Intravenous administration of a conjugated estrogen (Premarin 20 mg) significantly suppressed nocturnal melatonin secretion (p < 0.05), but a continuous intravenous infusion of naloxone (1.6 mg/h from 8 p.m. to 6 a.m.), an opiate antagonist, did not affect nocturnal melatonin secretion in SA. Our findings suggest that elevated nocturnal melatonin secretion may be related to low estrogen levels, but that it is not mediated by the opioid system.
Article
Although estrogen replacement therapy (ERT) has proven highly effective in preventing both the short- and long-term adverse clinical outcomes associated with menopause, it is important to recognize that the pharmacokinetic and metabolic effects of ERT vary with dosage and route of delivery. One of the most promising methods of administering ERT is the transdermal therapeutic system (TTS), or "patch," the efficacy of which is comparable to that of other forms of ERT, but whose unique pharmacokinetic profile may confer several distinct clinical advantages over the oral route. The present article addresses some of the key pharmacokinetic and metabolic differences between these two dosing forms, with particular emphasis on their respective effects on gonadotropins, hemostasis and coagulation, lipid metabolism, hepatobiliary function, and bone. An extensive review of clinical experience accrued over the past decade suggests that transdermal ERT is a viable alternative to oral ERT.
Article
The aim of this study was to investigate the possible relationship between variations in local skin and body temperatures, and a subcutaneous hyperaemia response during sleep in humans. Nocturnal subcutaneous blood flow (SBF) was measured in the lower legs of 9 subjects for 8-12 h under outpatient conditions. The core temperature was measured by a tympanic membrane temperature sensor, and the local skin temperature was measured by a skin temperature sensor. The 133Xe wash-out technique with portable CdTe(Cl) detectors was used for measurement of the SBF. The SBF increased significantly (P < 0.0001) after 1 h sleep, with the hyperaemia persisting for 2 h. During the hyperaemic phase, the local skin temperature increased significantly (P < 0.0001) and then decreased again in the post-hyperaemic phase (P < 0.01). The core temperature decreased significantly during the measurement period (P < 0.01). Separate ordinary linear regression analyses revealed no significant correlations between the measured temperature parameters and the blood flow levels during sleep. The results indicate no governing role of the local skin or body temperatures on the local SBF. The local skin temperature increased significantly secondary to the nocturnal subcutaneous hyperaemia (i.e. active vasodilatation), which is believed to be involved in a thermoregulatory effector mechanism.
Article
The effects of testosterone (10(-3) M, 10(-6) M, and 10(-9) M) and 17 beta-estradiol (10(-3) M and 10(-9) M) were looked for upon isoproterenol-stimulated melatonin release by perifused pineal glands removed from male rats and female rats in diestrus. Two different times of a 12/12 hour light/dark cycle, i.e., 7 and 19 hours after light onset, were documented in order to look for the existence of a circadian stage-dependence of the hormone effects. Both testosterone (45-60%) and estradiol (60-80%) markedly increased melatonin release by glands removed during the dark span and not during the light span. These results show a direct effect of gonadal hormones on pineal melatonin release and strongly suggest a time-related effect of these hormones on pineal function.
Article
The bioavailability of estradiol (CAS 50-28-2; E2) from a new "matrix type" estradiol transdermal patch (Dermestril; Test patch) was compared to that of the widely used "liquid-reservoir, membrane-controlled type" transdermal patch (Reference patch) in a two-way randomized cross-over study on 28 healthy postmenopausal women, during a single 4-day application of 2 patches (total content 8 mg E2, total nominal release rate 100 micrograms E2 in 24 h). Evaluated from the AUC0-96h, the extent of bioavailability was practically the same for the two patch types. Conversely the rate of bioavailability was significantly different, because from the Reference patch the release rate is fast in the first 24 h, leading to an E2 peak at 8 h and to a Cmax in average at 23 h. But after the 2nd day the release/absorption rate declines markedly, leading to E2 serum concentrations at the 3rd and 4th days possibly below the effective threshold. From the Test patch the release/absorption rate of E2 is more constant, leading to sustained E2 concentrations during the 4 days of application, with smaller fluctuations than during application of the Reference patch. In conclusion the Test patch can be considered practically bioequivalent to the Reference patch with regard to the extent of absorption, but not with regard to the rate of absorption, because the E2 concentrations in serum are more constant during the application of the Test transdermal patch than during the application of the Reference.
Article
Objective: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 μg per day of 17β-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. Results: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.
Article
Circadian temperature, cortisol, and thyroid-stimulating hormone (TSH) rhythms during a constant routine were assessed in 6 female controls and 6 female patients with hypersomnic winter depression (seasonal affective disorder, SAD) before and after morning bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bed rest for 27 hours while rectal temperature, cortisol, and TSH levels were assessed. The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared to the controls 5:42 AM vs. 3:16 AM (p < .005); with bright light treatment, the minimum advanced from 5:42 AM to 3:36 AM (p = .06). The minimum of the cortisol rhythm was phase-delayed in the SAD group compared to the control group, 12:11 AM vs. 10:03 PM (P < .05); with bright light treatment, the minimum advanced from 12:11 AM to 10:38 PM (P = .06) [corrected]. The acrophase of the TSH rhythm was not significantly phase-delayed in SAD subjects compared to control, though the trend appeared to be toward a phase-delay (p = .07). After bright light therapy, the TSH acrophase was not significantly different in the SAD subjects; the trend was a phase-advance (p = .09). Overall, the data suggest that circadian rhythms are phase-delayed relative to sleep in SAD patients and that morning bright light phase-advances those rhythms.
Article
The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17 beta-estradiol (CAS 50-28-2, E2) after the application of two types of matrix patches for the transdermal delivery of E2: MenorestTM (the test patch) with delivery rates of 37.5, 50 and 75 micrograms E2/day and a reference patch with a delivery rate of 50 micrograms E2/day. All 3 test patches were identical in composition, achieving different transdermal E2 delivery rates by variations in the surface area (11.0, 14.5 and 22.5 cm2). All 4 patches were each worn by 24 postmenopausal women over a 4-day period (i.e. 96 h), each of the 4 treatment periods being separated by a 7-day wash-out period according to a randomized, 4-way crossover design. Blood samples were collected before and 3, 6, 9, 12, 24, 34, 48, 58, 72, 84, and 96 h after each patch application. Plasma E2 concentrations were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h; Cmax, tmax, Cmin, Caverage. The course of the E2 plasma levels over the total test period (96 h) was relatively constant for all patches. For the test patch, a linear relationship between the pharmacokinetic parameters and the different patch areas (i.e. dosages of 37.5, 50, 75 micrograms E2/d) could be shown (correlation coefficient 0.99). The resulting Cmax values for the patch were: 44.2, 58.3, and 92.1 pg E2/ml, corresponding to Caverage values of 39.5, 45.5, and 70.6 pg E2/ml. The reference patch and the test patch, at a dose of 50 micrograms E2/d, were similar in terms of Cmax, while the Caverage, AUC0-96h and Cmin were significantly higher with the test patch. The systemic bioavailability of the reference patch was comparable to that of the test patch at a dose of 37.5 micrograms E2/d: AUC0-->96h 3017.5 +/- 1312.4 pg/ml.h for the reference patch and 3375.9 +/- 1254.7 pg/ml.h for the test patch. A physical model for the calculation of the course of the E2 levels was used to describe the experimentally determined data. However, in the evening, periodically higher E2 plasma levels were observed for all patches than in the morning. From these results it can be concluded that E2 plasma profiles produced by the test patch are reproducible, and in the physiological range consistent with the early to mid follicular level in the premenopausal woman over 4 days (96 h), correlating with the doses administered (37.5-50-75 micrograms E2/d). Additionally, the systemic bioavailability of the test patch at a dose of 37.5 micrograms E2/d is comparable to that of the reference patch at a dose of 50 micrograms E2/d.
Article
Although circadian rhythms have been described for many human functions, there are minimal data on circadian rhythms related to skin physiology. This study investigated the circadian rhythmicity of skin variables related to skin barrier function in humans. We measured transepidermal water loss, stratum corneum moisture, skin surface pH, and skin temperature in 16 healthy volunteers (nine men and seven women, aged 23-53 y). Subjects were sampled every 2 h in two sessions over a 24 h span. Twelve samples were obtained for each variable in the following sites: forehead, forearm, upper back, and shin. We used cosinor analysis and ANOVA to validate observed differences. Time-dependent rhythms were detected in most skin variables except in stratum corneum hydration. We found a statistically significant circadian rhythmicity characterized by cosinor analysis in transepidermal water loss, skin surface pH, and skin temperature on the forearm, forehead, and shin. Peak-trough differences occurred in all locations. The values of the same variables measured at different sites correlated positively, whereas the values of the different variables did not. These results suggest that skin permeability is higher in the evening and night than in the morning. These data may be clinically relevant in several aspects applied to skin physiology and topical drug application.
Article
The aim of our study was to investigate the high fluctuations of Estradiol (E2) plasma levels transdermally delivered in postmenopausal women by a commercially available membrane controlled reservoir system (MCRS). The transdermal E2 flux either out of a complete MCRS or across its membrane out of defined ethanol water mixtures was determined, as well as E2 plasma profiles in 6 postmenopausal women produced by a MCRS. The transdermal in vitro E2 flux rate out of a complete MCRS, claimed to deliver 25 microg/day, increased steadily, reaching a maximum value of 2.06 +/- 0.58 microg/h at 30 to 40 hours and decreased to a rate of about 0.5 microg/h from 60 to 90 hours. No statistically significant differences between plasma profiles calculated from the in vitro investigation and derived from a clinical study could be identified. The E2 flux in defined ethanol/water mixtures across MCRS-membrane, adhesive and skin layer increased with increasing ethanol concentrations up to a maximum of 227 +/- 34 ng/cm2/h at an ethanol concentration of 62.5% (V/V) and decreased with further increase in the volume fraction of ethanol. In vitro as well as in vivo investigations showed high fluctuation of E2 plasma profiles in postmenopausal women produced by the MCRS. These fluctuations are caused by a non-constant input rate of E2 which may be due to changing ethanol concentrations in the reservoir of the MCRS.
This study examined the thermoregulatory responses of men (group M) and women (group F) to uncompensable heat stress. In total, 13 M [mean (SD) age 31.8 (4.7) years, mass 82.7 (12.5) kg, height␣1.79␣(0.06) m, surface area to mass ratio 2.46␣(0.18) m2 · kg−1 · 10−2, Dubois surface area 2.01 (0.16) m2, %body fatness 14.6 (3.9)%, V˙O2peak 49.0 (4.8) ml · kg−1 · min−1] and 17 F [23.2 (4.2) years, 62.4 (7.7) kg, 1.65 (0.07) m, 2.71 (0.14) m2 · kg−1 · 10−2, 1.68 (0.13) m2, 20.2 (4.8)%, 43.2 (6.6) ml · kg−1 · min−1, respectively] performed light intermittent exercise (repeated intervals of 15 min of walking at 4.0 km · h−1 followed by 15 min of seated rest) in the heat (40°C, 30% relative humidity) while wearing nuclear, biological, and chemical protective clothing (0.29 m2 ·°C · W−1 or 1.88 clo, Woodcock vapour permeability coefficient 0.33 i m). Group F consisted of eight non-users and nine users of oral contraceptives tested during the early follicular phase of their menstrual cycle. Heart rates were higher for F throughout the session reaching 166.7 (15.9) beats · min−1 at 105 min (n = 13) compared with 145.1 (14.4) beats · min−1 for M. Sweat rates and evaporation rates from the clothing were lower and average skin temperature (\(\)) was higher for F. The increase in rectal temperature (T re) was significantly faster for the F, increasing 1.52 (0.29)°C after 105 min compared with an increase of 1.37 (0.29)°C for M. Tolerance times were significantly longer for M [142.9 (24.5) min] than for F [119.3 (17.3) min]. Partitional calorimetric estimates of heat storage (S) revealed that although the rate of S was similar between genders [42.1 (6.6) and 46.1 (9.7) W · m−2 for F and M, respectively], S expressed per unit of total mass was significantly lower for F [7.76 (1.44) kJ · kg−1] compared with M [9.45 (1.26) kJ · kg−1]. When subjects were matched for body fatness (n = 8 F and 8 M), tolerance times [124.5 (14.7) and 140.3 (27.4) min for F and M, respectively] and S [8.67 (1.44) and 9.39 (1.05) kJ · kg−1 for F and M, respectively] were not different between the genders. It was concluded that females are at a thermoregulatory disadvantage compared with males when wearing protective clothing and exercising in a hot environment. This disadvantage can be attributed to the lower specific heat of adipose versus non-adipose tissue and a higher percentage body fatness.
Article
The relative bioavailability of estradiol from two matrix transdermal delivery systems, Alora (0.05 mg/day when applied for 3-4 days) and Climara (0.05 mg/day when applied for 7 days), was evaluated in this two-period, randomized crossover study. A total of 27 healthy, postmenopausal women completed this study. Each subject received four successive doses of Alora every 84 h (3.5 days) and two doses of Climara every 168 h (7 days) in a randomized sequence without a washout period. Serial serum samples were collected over a 7-day period during the second week of each treatment. Samples were analyzed for estradiol and estrone using a validated radioimmunoassay method. Pharmacokinetic analyses were conducted using baseline-corrected parameters. Fluctuations in serum estradiol levels were 44% higher for Climara, as indicated by the ratio of Cmax/Cmin. Because the Cmin values for the two regimens were similar, the differences in fluctuation reflected the difference in their Cmax values (49.8 pg/ml for Alora, 67.7 pg/ml for Climara.) The estradiol AUC for Climara was 124% (95% CI 115.6-133.7) of the value for Alora. Serum estradiol concentrations were maintained at a more constant level during twice-weekly application of Alora than during once-weekly application of Climara. Both regimens were generally well tolerated and no serious skin or other adverse effects were reported by the subjects. However, Alora exhibited better skin tolerability as indicated by a lower incidence of moderate skin erythema. In addition, there was less adhesive transfer to skin at the application site with Alora.
Article
The aim of our study was to clarify the kinetic performance of a membrane controlled reservoir system (MCRS) for beta-estradiol (E2) under in vitro conditions by determination of the role of membrane and adhesive layer on E2 flux control. E2 and ethanol fluxes across EVA membrane or membrane coated with adhesive from saturated solutions in defined ethanol/PBS mixtures were measured in the symmetric and asymmetric configuration. Physicochemical parameters of the EVA membrane were determined. The E2 flux across the 9% EVA membrane steadily increased with increasing ethanol concentrations in both configurations, due to enhanced uptake of E2 by the polymer and increasing membrane diffusivity. Permeation across the EVA membrane coated with an adhesive layer in symmetric and asymmetric configuration increased up to maximum values of 0.80+/-0.14 micrograms X cm-2 X h-1 and 0.37+/-0.02 micrograms X cm-2 X h-1, respectively, at 62.5% (v/v) ethanol. The fluxes then decreased with further increase in the volume fraction of ethanol due to a dramatically reduced permeability of the adhesive layer. For the asymmetric case, a linear dependence of E2 on the ethanol fluxes was observed. The E2 flux from MCRS is strictly dependent on reservoir ethanol concentrations, whereas the adhesive layer represents the rate controlling barrier at high ethanol levels (> 70% v/v).
Article
Theoretically, a positive relation is expected between skin temperature and the percutaneous penetration of topically applied substances. The aim of the present study was to evaluate the influence of the temperature on the in vitro percutaneous penetration of dihydrotestosterone. Hairless rat skin was mounted in static diffusion cells placed in a water bath at different temperatures (28.6, 35.1 and 38.2 degrees C, respectively). Different vehicles were tested as well as the addition of penetration promoting molecules such as oleic acid and limonene. A saline buffer was used as the receptor phase. Penetration through the skin was evaluated by means of scintillation counting of the radiolabelled dihydrotestosterone. Experiments were followed for a period of 29 h. The total amount of penetrant, dihydrotestosterone, as well as the flux, were calculated from these kinetics. Our results demonstrate a temperature effect with the highest penetration at 38.2 degrees C. The vehicle was also found to influence the penetration of dihydrotestosterone in a significant way. Furthermore, limonene presented better penetration promoting properties compared with oleic acid.
Article
The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17beta-estradiol (E2) after the application of three matrix patches for the transdermal delivery of E2: Menorest, Tradelia, and Estraderm MX claiming to deliver a dosage of 50 microg E2/day. All three patches were each worn randomly by 21 postmenopausal women volunteers over a 4-day period (i.e. 96 h). Each of the three treatment periods were separated by an at least 7 day wash out period according to a randomized, 3-way crossover design. Blood samples were taken from the antecubital vein before and 3, 6, 9, 12, 24, 28, 33, 48, 57, 72, 81, and 96 h after application. E2 plasma values were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h, Cmax, Tmax, Cmin, C(average). The time to reach the maximal E2 value of 32 h was the only pharmacokinetic parameter which was identical for all three patches. Menorest produced the highest E2 bioavailability judged by the AUC0-96h = 3967.8 +/- 1651.8 pg/ml, C(average) = 41.3 +/- 21.3 pg/ml, Cmin = 36.8 +/- 8.6 pg/ml. Tradelia showed statistically not significantly smaller C(average) = 38.9 +/- 17.0 pg/ml, AUC0-96h = 3737.9 +/- 1637.6 pg/ml x per h, and Cmin = 33.8 +/- 26.7 than Menorest. Estraderm MX showed lowest E2 plasma profiles Cmax = 38.9 +/- 25.1 pg/ml, C(average) = 33.2 +/- 17.1 pg/ml, AUC0-96 = 3192.1 +/- 1646.0 pg/ml per x h. Menorest showed the smallest fluctuation over the entire test period, similar to Estraderm MX, while Tradelia showed the highest E2-fluctuation (P < 0.01): Tradelia exhibited the highest Cmax = 48.0 +/- 20.3 pg/ml. When E2 baseline levels, prior to patch application are subtracted individually from the produced E2 plasma level, Estraderm MX is not bioequivalent to Menorest (P < 0.05). A circadian curve pattern of the E2 plasma level was observed for all patches: in the evening higher E2 plasma level were always detected compared with the morning, however, less pronounced with Estraderm MX. Individual comparison of AUC0-96h of each patch exhibited a large interindividual variability of 2000-8000 pg/ml per h for all three patches but relatively small individual variability: women with high E2 bioavailability (high responders) maintained high bioavailability in all applied patches, women identified as low and medium responders remained the same regardless of the applied patch. Menorest produced in 2/3 of all postmenopausal women with the highest E2 bioavailability (AUC0-96h), Tradelia was found in less than 1/3 (28.6%), and Estraderm MX in only one postmenopausal woman. Menorest only produced the highest reduction in postmenopausal symptoms together with Tradelia. Estraderm MX produced a smaller reduction in postmenopausal symptoms compared to Menorest and Tradelia. The observed side-effects were approximately equal in all three patches, with a maximum value after 72 h. It can be concluded that the three patches for the transdermal delivery of E2 claiming to deliver 50 microg E2/day differed from each other in their pharmacokinetic performance, although statistically not significant: Menorest exhibited the highest C(average), AUC and Cmin, and the lowest fluctuation, followed by Tradelia and Estraderm MX.