Thomas Gräser

Insomnia related to postmenopausal syndrome and hormone replacement therapy: sleep laboratory studies on baseline differences between patients and controls and double‐blind, placebo‐controlled investigations on the effects of a novel estrogen–progestogen combination (Climodien®, Lafamme®) versus estrogen alone

Differences in sleep and awakening quality between 51 insomniac postmenopausal syndrome patients and normal controls were evaluated. In a subsequent double‐blind, placebo‐controlled, comparative, randomized, three‐arm trial (Climodien 2/3 = estradiol valerate 2 mg + the progestogen dienogest 3 mg = regimen A, estradiol valerate 2 mg = regimen EV, and placebo = regimen P), the effects of 2 months of hormone replacement therapy were investigated, followed by a 2‐month open‐label phase in which all patients received Climodien® 2/2 (EV 2 mg + dienogest 2 mg = regimen A*). Polysomnography at baseline demonstrated significantly deteriorated sleep initiation and maintenance, increased S1 and decreased S2 in patients. Subjective sleep and awakening quality, well‐being, morning drive, wakefulness, memory and reaction time performance were deteriorated too. Treatment with both regimen A and regimen EV induced a moderate, although nonsignificant, improvement in the primary efficacy variable wakefulness during the total sleep period compared with baseline, while under placebo no changes occurred. Secondary efficacy variables concerning sleep initiation and maintenance, and sleep architecture showed similar findings. The apnea and apnea–hypopnea indices improved significantly under regimen A, compared with both baseline and placebo. Subjective sleep and awakening quality improved significantly after regimen A and EV compared with baseline, with the drug‐induced changes being superior to those induced by placebo. In the open‐label phase, subjective sleep quality improved further, significantly in the former regimen A group. Awakening quality, somatic complaints and morning thymopsyche did not yield any significant findings. Concerning morning noopsychic performance, memory improved significantly after regimen A compared with baseline, fine motor activity after regimen EV. Reaction time performance increased with all three compounds. In conclusion, Climodien significantly improved subjective sleep quality, the apnea and apnea–hypopnea indices of insomniac postmenopausal syndrome patients, while it only marginally improved variables concerning objective sleep and awakening quality.

Different mechanisms of hypoxic relaxation in canine coronary arteries and rat abdominal aortas

Summary: Hypoxia causes complex changes in vascular tone of isolated blood vessels. This study was performed in rings with and without endothelium of rat abdominal aortas and canine coronary arteries suspended in organ chambers for isometric tension recording. In both aortic and coronary rings with endothelium precontracted with a half‐maximal concentration of phenylephrine or prostaglandin F2&agr;, respectively, hypoxia induced transient relaxations (20 ± 2 and 15 ± 3%, respectively); removal of the endothelium prevented the response in aortas, but not coronary arteries. The transient hypoxic relaxation was followed in both preparations by endothelium‐dependent contractions (EDCs). Hypoxic relaxations were prevented by indomethacin (10 μM) in canine arteries, but not in rat aortas. The inhibitor of nitric oxide (NO) synthase, N&ohgr;‐nitro‐L‐arginine (30 μM), inhibited hypoxic relaxations in intact rat aortas, but left those in coronary arteries unchanged. Similar results were obtained with methylene blue and LY 83583. In preparations without endothelium, sodium nitroprusside (30 nM) elicited a reappearance of hypoxic relaxations in the rat but not the dog coronary artery. Thus, hypoxic relaxation is mediated by a prostaglandin in the dog coronary artery, but by endothelium‐derived NO in the rat aorta. As the response was dependent on the level of contraction, this suggests that the release or action of NO decreases with increasing tone.

Influence of Dienogest on Ovulation in Young Fertile Women

AbstractObjective: To determine the minimal oral dose of dienogest that will reliably and safely inhibit ovulation in healthy women with normal menstrual cycles. Design and Setting: Randomised, open, four-arm, phase II study involving one control cycle followed by one treatment cycle. Over 21 days patients received one of four oral doses of dienogest 0.5, 1.0, 1.5 or 2.0mg daily. Blood sampling for several hormones was performed on 13 days of each cycle. Participants: Forty-two healthy women were enrolled in the study. Because of an anovulatory control cycle and other reasons, nine of these volunteers did not start the treatment. 33 participants (mean age 24 ± 2 years) completed the study according to the protocol. Main Outcome Measures: Inhibition of ovulation was assessed by serum levels of progesterone, oestradiol, luteinising hormone and follicle-stimulating hormone. Safety and tolerability was measured by pre- and post-study medical examinations, cycle control, laboratory (blood and urine) tests, and incidence and severity of adverse events. Results: Dienogest 0.5mg inhibited ovulation in two-thirds of the participants. Doses of dienogest ranging from 1.0 to 2.0mg inhibited ovulation in all patients who completed the study. No serious adverse events were observed at any dose. The frequency of dysmenorrhoea was lower during the treatment cycle than during the control cycle. Increases in cycle duration and reductions in the duration of menstrual flow and serum dienogest levels were dose dependent. Conclusions: Dienogest 1.0mg is the minimal daily dose needed to inhibit ovulation in healthy individuals with normal ovulatory cycles. Dienogest was well tolerated at doses of up to 2.0mg and showed good control of withdrawal bleeding and dysmenorrhoea. Dienogest is suitable for use as the progestin compound in oral contraceptives.

Influence of hormonal contraceptives on microbial flora of gingival sulcus

To determine a possible influence of two different hormonal contraceptives on bacterial microflora of gingival sulcus, subgingival plaque samples of 29 healthy women aged between 20 and 32 years were investigated bacteriologically before subjects took a contraceptive and 10 and 20 days after subjects started the medication. In 14 women, and oral contraceptive containing 0.02 mg ethinyl estradiol and 0.15 mg desogestrel (preparation A) was used, and 15 women took a contraceptive containing 0.03 mg ethinyl estradiol and 2.00 mg dienogest (preparation B) daily over 21 days. There were no changes in clinical parameters of the teeth investigated during 3 weeks of the study. The periodontopathogenic bacteria Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were never detected throughout the study. On the other hand, the periodontopathogenic species Prevotella intermedia was found in plaque samples of 22 women. The content of this microorganism showed only a little change between the pretreatment period and plaque sampling after 10 days of contraceptive treatment, but a striking increase occurred after 20 days of contraceptive treatment, especially in the preparation A group. In this respect, there was a significant difference between preparations A and B.

Effect of cilazapril and indomethacin on endothelial dysfunction in the aortas of spontaneously hypertensive rats.

Chronic hypertension is associated with impaired endothelial function [i.e., reduced synthesis/release of endothelium-derived relaxing factor (EDRF) and increased synthesis/release of endothelium-derived contracting factor (EDCF)] in both animals and humans. Although it is not known whether endothelial dysfunction is the consequence and/or an important pathogenetic cause of hypertension, the goal of effective antihypertensive therapy should include restoration of normal endothelial function as well. Because angiotensin I-converting enzyme (ACE) inhibitors are effectively used in the treatment of hypertension, the aim of the present study was to test whether in vivo treatment of spontaneously hypertensive rats (SHRs) with the ACE inhibitor cilazapril improves endothelial function in the isolated thoracic aorta of SHRs. Treatment of SHRs with cilazapril (10 mg/kg/day orally for 2 weeks) resulted in a significant decrease in blood pressure and normalization of endothelium-dependent relaxation evoked by acetylcholine (ACh) and adenosine diphosphate (ADP). However, cilazapril treatment had no significant effect on endothelium-dependent contractions evoked by 5-hydroxytryptamine (5-HT; serotonin) and prostaglandin F2 alpha (PGF2 alpha). In contrast, in vitro treatment of isolated thoracic aortas with indomethacin (10(-5) M) normalized endothelium-dependent relaxations to ACh and ADP as well as inhibited endothelium-dependent contractions to 5-HT and PGF2 alpha. These results suggest that the ACE inhibitor cilazapril increases the synthesis/release of EDRFs whereas indomethacin prevents the synthesis/release of cyclo-oxygenase-derived EDCFs in the endothelium of rat aorta. The exact mechanism of action of ACE inhibitors on endothelial dysfunction remains to be determined.

Effects of hormone replacement therapy on perceptual and cognitive event-related potentials in menopausal insomnia

The influence of a combined estrogen-progestin regimen (Climodien, Lafamme) on auditory event-related potentials (ERPs) was investigated in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase (Climodien 2/3=estradiol valerate 2 mg+the progestin dienogest 3 mg, EV=estradiol valerate 2 mg, and placebo), followed by an open-label phase in which all patients received Climodien 2/2 (estradiol valerate 2 mg+dienogest 2 mg). Both the double-blind and the open-label phase lasted 2 months. ERPs were recorded from 19 EEG leads in a two-tone odd-ball paradigm in 49 patients aged between 46 and 67 yr with the diagnosis of insomnia (G 47.0) related to postmenopausal syndrome (N 95.1). Climodien reduced standard N1 and target P300 latencies as compared to placebo, while EV did not affect N1 latency but similarly reduced P300 latency. Climodien increased N1, P2 and P300 amplitudes dose-dependently, predominantly at frontal leads. Estrogen alone had only minor effects on ERP amplitudes. The shortening of standard N1 latency and enhancement of N1 and P2 amplitudes indicates a positive effect of Climodien on perceptual processing, most likely due to vigilance improvements also observed in EEG mapping. Concerning target P300, it seems that estradiol is responsible for the improvement in stimulus evaluation time, as reflected by the shortening of the peak latency, while dienogest seems to account for the improvement in cognitive information processing capacity, whereby 3 mg induced a more pronounced augmentation of P300 amplitudes than 2 mg. Based on the spatial distribution of this increase, it can be speculated that Climodien mainly affects the more frontally distributed P3a subcomponent, which is associated with attention and orientation. Furthermore, the observed changes in ERP-components are consistent with recent studies showing significant positive effects of hormone replacement therapy on cholinergic functions. Thus, Climodien seems to be of interest in preventing cognitive decline and treating cognitive disorders in postmenopausal women. Indeed, there is increasing evidence of beneficial effects of estrogen in dementia. Our present findings suggest that the estrogen effects may be augmented by dienogest.

Hypoxic Contraction in Isolated Rat Abdominal Aorta: Role of Endothelium and Vascular Smooth Muscle

The effect of severe hypoxia on the vascular tone of isolated rat aortic rings with and without endothelium was studied. Hypoxia induced transient contractions that were significantly more pronounced in preparations with endothelium. These responses were reproducible during two consecutive episodes of hypoxia. With increasing concentrations of phenylephrine (EC 10 to EC 100) the amplitude of endothelium-dependent hypoxic contractions decreased. Indomethacin, the inhibitor of cyclooxygenase, had no effect on hypoxic contractions whereas substances that decrease the cyclic GMP content of vascular smooth muscle cells (methylene blue, nitro-L-arginine) inhibited hypoxic contractions. M&B 22948, a substance that increases the cyclic GMP level, augmented hypoxic contractions. Low concentrations of exogenous donors of nitric oxide (sodium nitroprusside, SIN-1) caused the appearance or significantly augmented hypoxic contractions in preparations without endothelium. This was not observed with the cyclic AMP-depen...