Drug concentration effect relationship of estradiol from two matrix transdermal delivery systems: Menorest and Climara.

OBJECTIVES: To relate the pharmacokinetics of estradiol to pharmacological effects. METHODS: Drug concentration effect relationship of estradiol from two matrix transdermal delivery systems, Menorest and Climara, was studied in a single centre, open, randomised, comparative crossover study. The trial consisted of two treatment periods, 14 days for each patch separated by a 4-week washout period. Blood hormone levels were followed during the second week of each treatment. Estradiol levels during treatments were related to three concentration levels previously proposed as efficacy or safety limits. The effect of treatment on FSH-levels was examined and the relationship between the levels of estradiol and FSH was described using an inhibitory sigmoidal I(max) model. Estrone levels and estradiol/estrone before and during treatment were followed. RESULTS: The C(average) of FSH during treatment was 38% lower than baseline plasma levels. Estradiol had an inhibitory effect on FSH with an I(max) of 0.68 and an IC(50) of 19 pg/ml. The fraction of time above the minimum concentration for therapeutic effect and the tolerability limit did not differ between the two treatments, whereas the fraction of time above the suggested threshold for osteoporosis prophylaxis was significantly larger for Menorest than for Climara (P<0.05). The low baseline estradiol/estrone ratios increased towards pre-menopausal levels during treatment. CONCLUSIONS: The drug concentration effect relationship of estradiol may be of use in evaluation of the effects of prophylactic estrogen therapy and to facilitate comparisons between different forms of estrogen treatments.

Bioavailability of estradiol from two matrix transdermal delivery systems: Menorest and Climara.

OBJECTIVES: To compare two estradiol transdermal matrix systems with regard to bioavailability, pharmacokinetics and tolerability. METHODS: A single centre, open, randomized, comparative cross-over study in 20 healthy postmenopausal women. Menorest with 3 or 4 days of suggested use and Climara with 7 days of suggested use (both 50 microg/24 h) were compared at steady state. Two 14-day treatment periods were separated by a 4 week washout. Plasma levels of estradiol were monitored during the second week of each treatment. Tolerability was assessed by open questions and inspection of the application site. RESULTS: There were no differences between the two treatments with regards to AUC, Cmax, Cmin, Caverage or fluctuations of plasma estradiol. Tmax was significantly shorter for Menorest than Climara. Cmax and Cmin were significantly higher for the second Menorest patch during the monitoring period compared to the first. All local reactions were mild and there were three cases of erythema with Menorest and a total of 21 skin reactions in 15 subjects with Climara. Systemic tolerability was similar between treatments with eight estrogen-related adverse events in eight subjects (period pains, uterine bleeding, mastodynia, headache and vaginal discharge) with Menorest and 13 events in ten subjects with Climara. CONCLUSIONS: The bioavailability of estradiol from the two matrix transdermal delivery systems Menorest and Climara was similar, but the products were not bioequivalent because Tmax was significantly shorter for Menorest than for Climara. Tolerability of treatment was good for both patches but with a higher number of local reactions and estrogen related adverse events for Climara.

17Beta-estradiol delivered by three different matrix patches 50 microg/day: a three way cross-over study in 21 postmenopausal women.

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.

A 24-month, double-blind, placebo-controlled multicentre pilot study of the efficacy and safety of nicergoline 60 mg per day in elderly hypertensive patients with leukoaraiosis.

In this pilot study, 72 non-demented and non-depressive elderly hypertensive patients with evidence of leukoaraiosis on cerebral computed tomography scan (Rezek score: > 16) were randomly assigned to receive either nicergoline 30 mg b.i.d. (n = 36) or a placebo (n = 36) for 24 months. All patients received antihypertensives and their hypertension was controlled under treatment. They were evaluated by nine neuropsychological tests exploring memory, concentration, verbal and motor performances, administered at baseline and at every six-month interval during the study period. At baseline, the two groups were comparable for all demographic and clinical characteristics, including cognitive functions, except for the delayed recall of the Auditory Verbal Learning Test (AVLT), which was better in the placebo group (P = 0.04). Changes in scores over time were compared between the two groups. At the last visit, patients on nicergoline (n = 31) were found to have deteriorated less or to have improved more on test scores than the patients on placebo (n = 30). Significant differences were observed for memory function (AVLT short term recall, P = 0.026; AVLT delayed recall, P = 0.013; and, Benton Visual Retention Test, P = 0.002) and attention and concentration (Letter Cancellation Test, P = 0.043; and, WAIS-R Digit Symbol subtest, P = 0.006). The Rezek score remained unchanged in the two groups. Tolerance of nicergoline was similar to that of placebo. In conclusion, this study shows that nicergoline 30 mg b.i. d. administered over a 24-month period attenuates the deterioration in cognitive functions in elderly hypertensive patients with leukoaraiosis. Whether these effects were specific for this type of white matter changes could not be determined in the context of this pilot study.

[Study methods of drugs in Alzheimer disease]. / Méthodes d'étude des médicaments dans la maladie de l'Alzheimer.

The availability of new drugs for Alzheimer's disease, with different pharmacological profiles, leads to a redefinition the relevant methodology for developing drugs in this indication, including the inclusion/exclusion criteria, the duration of the studies, and therefore, the relevant guidelines. This was the purpose of the Giens Round-table devoted to the new methodology for drug development in Alzheimer disease.

The effects of nitrous oxide on behavior and physiological parameters during conscious sedation with a moderate dose of chloral hydrate and hydroxyzine.

The purpose of this study was to determine differences in heart rate (HR), blood pressure (BP), peripheral oxygen saturation (pO2), expired CO2 (CO2), and behavior (using two scales) comparing nitrous oxide/oxygen (N2O) with oxygen (O2) alone in 20 children (mean age 45 +/- 5.1 months) sedated with chloral hydrate (CH) and hydroxyzine in a double-blind crossover design. Administration of CH (40 mg/kg) and hydroxyzine (2 mg/kg) was held constant for each patient visit; however, N2O (50%) was administered during one visit and O2 (100%) at the other in a randomly determined manner. Physiologic and behavioral parameters were collected during eight specific procedural events (e.g., administration of local anesthesia). Data were analyzed with a repeated-measures ANOVA, one-way ANOVA, t-test, Kruskal Wallis ANOVA, and descriptive statistics. There was no statistically significant difference in any physiologic or behavioral parameter as a function of inhalation agent. However, significant differences were found for certain physiological parameters (i.e., HR [F = 5.41, P < 0.001], pO2 [F = 6.04, P < 0.001], and CO2 [F = 2.33, P < 0.027]) and all behavioral measures (% crying [F = 2.82, P < 0.008], % quiet [F = 5.38, P < 0.001], % movement [F = 3.88, P < 0.001], and % struggle [F = 2.83, P < 0.007]) of one scale (Ohio State University Behavioral Rating Scale [OSUBRS]) as a function of procedural events. Although no statistically significant differences were attributable to inhalation agent, evidence suggests that N2O resulted in less crying and struggling and more quiet behaviors than O2. Significant correlations existed between sub-categories of the two behavioral rating scales, suggesting some association between the scales. One may conclude from the results of this study that moderate doses of CH and hydroxyzine in combination with nitrous oxide are not associated with any significant potentiation effects on physiologic parameters compared with the same oral agents with oxygen alone. Certain procedural events (e.g., administration of local anesthesia) do result in patient responses that affect specific behaviors and physiology. Although the effects of N2O may not be statistically significant, generally it produces an attenuation in physiological and behavioral responses as measured under the conditions of this study.

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

Differentiation changes in cord blood T lymphocytes induced by synthetic C-terminal peptides of thymosin alpha 1.

Thymosin fraction 5 and its component thymosin alpha 1 has been reported to play a regulatory role in the later stages of T lymphocyte differentiation. Previous studies from our group have also demonstrated that thymosin fraction 5 can induce changes in purine degradative enzymes and in surface antigenic markers of cord blood lymphocytes, which have been shown to be immature compared with normal adult lymphocytes. Birr et al., have shown that the C-terminal region of thymosin alpha 1 is essential for the biological activity. In this study, the effects of these synthetic peptide fragments on cord blood T lymphocytes were studied. After incubation with different peptide sequences, cord blood lymphocytes were analysed for surface antigenic markers (OKT4/OKT8) and for purine degradative enzymes (PNP, 5 NT). In the range of 1.3 X 10 to 1.3 X 10(-5)M, one of the eleven peptides examined (sequence 13-19) exhibited activity approximately equal to that of the parent peptide thymosin alpha 1: increase in activity of 5'NT (p less than 0.01) and reduction of cells positive for OKT4 (p less than 0.01). Another sequence (20-28) was able to induce an increase in 5'NT only and a third one (20-25) a reduction of cells positive for OKT4. The results obtained in this study confirm that the C-terminal region contains molecular signals for T cell differentiation.

Terminal differentiation of cord blood lymphocytes induced by thymosin fraction 5 and thymosin alpha 1.

Cord blood lymphocytes (CBL) have been shown to be functionally immature compared with normal circulating adult lymphocytes (NAL). Differentiation of T cells is associated with changes in surface antigenic markers and in the pattern of purine degradative enzymes. Previous studies have demonstrated that thymosin fraction 5 (TMS-F5) and thymosin alpha 1 (TMS-alpha 1) can induce in vitro differentiation of murine T-cell precursors and human thymocytes. We have investigated the effects of TMS-F5 and TMS-alpha 1 on the pattern of the purine degradative enzymes adenosine deaminase, purine nucleoside phosphorylase, and ecto-5'-nucleotidase (5'NT) of CBL and on the phenotypic markers from the OKT series 3, 4, 8 and 11. Other than a significantly reduced level of 5'NT activity (P less than 0.001) and an elevated percentage of OKT4+ cells (P less than 0.01), CBL demonstrated the same immunological and biochemical patterns as NAL. Incubation of CBL with TMS-F5 (150 micrograms/ml) and TMS-alpha 1 (1 microgram/ml) for 40 h caused a significant rise in 5'NT level and decrease of cells positive for OKT4, resulting in a pattern characteristic of NAL. Thus TMS-F5 might induce the terminal differentiation of CBL, and TMS-alpha 1 seemed to be the active component.