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Biomedical subjects

C Christiansen

Publications and source records attributed to C Christiansen.

At least 253 records · Page 14Linked to original sources
PubMed1992

No secular increase in the prevalence of vertebral fractures due to postmenopausal osteoporosis.

We examined whether the prevalence of vertebral fractures in otherwise healthy, 70-year-old Danish women had increased during an interval of 10 years. The population-based epidemiological study included two age-matched groups of postmenopausal women. Group 1 consisted of 70-year-old women (n = 386) living in a defined area of suburban Copenhagen recruited in 1979 for an epidemiological study. Of the 285 women who were entered, 173 were judged healthy, without secondary causes of osteoporosis. Group 2 was recruited by sending questionnaires to all women aged 68-72 years living in the same area in 1989. Of the 512 women who attended a medical screening, 387 were found to be without secondary causes of osteoporosis and had a spinal radiograph. Radiographs of the thoracolumbar spine were assessed for vertebral fracture by five radiological methods. There was no significant difference between the two groups in the prevalence of vertebral fractures and the 95% confidence intervals overlapped completely in all methods. The prevalence rates varied by method from about 35% to more than 80% but the distribution of fracture types was similar in the two groups. We conclude that the prevalence of vertebral fractures due to postmenopausal osteoporosis has not increased since 1979 in otherwise healthy women residing in suburban Copenhagen, and that comparison of prevalences between studies requires that they use the same method of radiological assessment.

Aged↗
PubMed1992

One measurement of serum total cholesterol is enough to predict future levels in healthy postmenopausal women.

PURPOSE: The purpose of this study was to investigate how well a single or double measurement of serum total cholesterol represents the spontaneous, future level in a particular person. SUBJECTS AND METHODS: The spontaneous fluctuations in serum total cholesterol levels in 169 healthy early postmenopausal women were followed during the course of 12 years. Serum total cholesterol was measured enzymatically. RESULTS: The initial measurement and the long-term level of serum total cholesterol were highly related (p less than 0.0001). The long-term level (calculated for each woman as the area under the curve of serum total cholesterol versus time) was not statistically significantly different from the initial level (mean difference: 0.036 +/- 0.046 mmol/L [mean +/- SEM], NS). The initial serum total cholesterol level was then used to classify each woman into a high or a low cholesterol group, according to the current recommendations. The predictive value of an initial total cholesterol value in the high level (greater than or equal to 6.2 mmol/L) group was 84%, when compared with the long-term level. The predictive value of an initial total cholesterol level below 6.2 mmol/L was 80%. No improvement in these parameters was found when the average of the initial two (or three, when the difference exceeded 0.9 mmol/L) measurements were used as the baseline value. The fluctuations in serum total cholesterol levels were mainly due to short-term variations. CONCLUSION: For screening purposes, one measurement of serum total cholesterol in a woman gives a good estimate of the long-term level. The current data indicate that repeated measurements of serum total cholesterol do not improve the predictability of future cholesterol levels. The data also suggest that, at least in postmenopausal women with an elevated level of serum total cholesterol, one should proceed immediately to lipoprotein analysis for further risk assessment.

Blood Specimen Collection↗
PubMed1992

Secretory endometrial protein PP14 in serum from post-menopausal women receiving continuous combined oestradiol-cyproterone acetate: correlation with serum hormone concentrations and bleeding patterns.

The secretory endometrial protein PP14 was measured in serum from 49 healthy, early post-menopausal women receiving continuous combined oestradiol valerate/cyproterone acetate (2 mg E2V + 1 mg CPA daily) or placebo over a period of 2 years. In the hormone group, serum PP14 increased from 2.1 micrograms/l to a maximum of 8.1 micrograms/l after 1 month of treatment, then fell after 3 months to 3.8 micrograms/l and remained at that level for the rest of the 2-year period. After the first month, the occurrence of uterine bleeding was associated with significantly increased serum PP14 levels. Bleeding was not correlated with the serum concentration of 17 beta-oestradiol (E2) or CPA, or the CPA/E2 ratio. Serum PP14 was significantly dependent on the serum concentration of E2, but not on that of CPA. The present data confirm that serum PP14 levels reflect the secretory phase of the endometrium and that bleeding during continuous combined hormone replacement therapy is probably caused by a sub-optimal hormonal balance.

Androgen Antagonists↗
PubMed1992

Prevention and treatment of osteoporosis: a review of current modalities.

This review evaluates response to treatment with various preventive and therapeutic agents in osteoporotic and immediately postmenopausal women. Measurements obtained by several methods are taken in the forearm, spine, and overall skeleton of treatment and placebo groups. Estrogen and estrogen-progestogen combinations, vitamin D metabolites, calcium, fluoride, calcitonin, bisphosphonates, and anabolic steroids are assessed in comparison with placebo and with each other. The efficacy of estrogen-progestogen hormone replacement therapy (HRT) is confirmed as an effective prevention for osteoporosis in postmenopausal women. Early data on nasal salmon calcitonin indicate that it is a promising agent for both prevention and treatment of established osteoporosis. A new estrogen-progestogen combination, oral estradiol and norethisterone acetate (E2 + NETA), has produced greater increases in both cortical and trabecular bone mass than other reported osteoporosis treatments.

Anabolic Agents↗
PubMed1992

Serum placental protein 14 (PP14) reflects endometrial status during hormone replacement therapy.

Healthy post-menopausal women were randomly assigned to treatment groups receiving 28 day treatment cycles of oestradiol valerate (2 mg, days 1-28) sequentially combined with levonorgestrel (75 micrograms, days 17-28) (n = 19); oestradiol valerate (2 mg, days 1-28) continuously combined with cyproterone acetate (1 mg, days 1-28) (n = 18), or placebo (n = 22). Treatment continued for 2 years. After therapy, the women receiving the sequential combination had an early secretory phase (74%) or atrophic endometrium (26%). All women receiving the continuous combination or placebo had inactive or atrophic endometrium, or the tissue was inadequate for assessment. Biochemical parameters of endometrial secretion [oestradiol dehydrogenase (EDH), isocitrate dehydrogenase (ICDH)] measured in endometrial tissue and placental protein (PP14) measured in serum were all low in the groups receiving the continuous combination and placebo. During sequential treatment, all biochemical parameters showed significantly higher mean values. Serum PP14 accurately reflected this pattern. Furthermore, in the sequentially treated group, serum PP14 correlated highly significantly with EDH (r = 0.70; P less than 0.001) and ICDH (r = 0.57; P = 0.01). These correlations were of the same magnitude as the correlations between the endometrial markers, which indicates that serum PP14 reflects the endometrial status. Furthermore, serum PP14 measurements at 3 months and at 2 years of treatment were highly correlated, reflecting the long-term validity of the measurement. The present data suggest that PP14 measured in serum may be used to assess endometrial status. Further studies are required to determine whether serum PP14 will discriminate pathological endometrial conditions.

Cyproterone Acetate↗
PubMed1992

Effect of menopause and hormone replacement therapy on urinary excretion of pyridinium cross-links: a longitudinal and cross-sectional study.

OBJECTIVE: To study longitudinally the effect of the menopause and hormone replacement therapy on the new markers of bone resorption: urinary excretion of pyridinoline and deoxypyridinoline. DESIGN AND PATIENTS: Urinary pyridinoline and deoxypyridinoline were measured every 3 months for 2-3 years in 15 healthy women aged 45-54 years. Nine remained premenopausal and six became post-menopausal during the study. Urinary pyridinoline and deoxypyridinoline were also measured before and after 3 months of either placebo or hormone replacement therapy in 65 post-menopausal women, aged 45-54 years, who were participating in a double-blind study. MEASUREMENTS: Urinary pyridinoline and deoxypyridinoline were measured in fasting urine samples by spectrofluorometry after high performance liquid chromatography and corrected for creatinine excretion. RESULTS: Urinary pyridinoline and deoxypyridinoline remained almost constant during the premenopausal period. Both started to increase 6 months after the last menstrual bleeding and the mean post-menopausal values were 30-50% higher than the premenopausal values in the same subjects (values in nmol/mmol creatinine given as mean +/- SEM: urinary pyridinoline (premenopausal) = 29 +/- 2 vs urinary pyridinoline (post-menopausal) = 38 +/- 6, P < 0.05; urinary deoxypyridinoline (premenopausal) = 8 +/- 1 vs urinary deoxypyridinoline (post-menopausal) = 12 +/- 1, P < 0.05). Three months of post-menopausal hormone replacement therapy decreased (P < 0.001) both to premenopausal levels. CONCLUSION: Urinary pyridinoline and deoxypyridinoline, new markers of bone resorption, remain fairly constant in the years before the menopause and start to increase about 6 months after the last menstrual bleeding. This increase is reversed by hormone replacement therapy.

Amino Acids↗
PubMed1992

Progestogens do not affect aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits.

Cardiovascular disease is a major killer in postmenopausal women in the industrialized societies. To investigate the effect of progestogen and 17 beta-estradiol replacement therapy on atherogenesis, we studied 60 cholesterol-fed ovariectomized rabbits for 13 weeks. They were randomly assigned to four groups of 15 rabbits each and received oral treatment with norethisterone acetate, levonorgestrel, 17 beta-estradiol, or placebo. The active treatment groups achieved serum hormone concentrations, which produced physiological effects on the uterus. No significant differences in serum total cholesterol or ultracentrifuged lipoproteins (very low density, intermediate density, low density, or high density lipoproteins) were found between the four groups during the experimental period. There were no significant differences between the progestogen and placebo groups in the aortic accumulation of cholesterol. The estradiol group had only accumulated about half the aortic cholesterol as compared with the placebo group and the progestogen groups (p less than 0.05). The antiatherogenic effect of 17 beta-estradiol was estimated to be equal to a 40-50% reduction in serum total cholesterol. These findings suggest that two commonly prescribed 19-nortestosterone-derived progestogens, which are considered to be "atherogenic," do not affect atherogenesis in cholesterol-fed ovariectomized rabbits, whereas 17 beta-estradiol produces a significant antiatherogenic effect that is independent of lipid metabolism in plasma, possibly the result of a direct action on the arterial wall.

Analysis of Variance↗
PubMed1992

Serum bone gamma-carboxyglutamic acid protein in a longitudinal study of infants: lower values in formula-fed infants.

Bone gamma-carboxyglutamic acid protein [BGP (osteocalcin)] is a protein synthesized by osteoblasts and incorporated in the bone matrix. Serum BGP is a sensitive marker of bone formation, and it parallels the growth velocity curve during childhood and adolescence. Serum BGP was measured at the age of 2, 6, and 9 mo in a cohort study of nutrition and growth in 91 healthy infants. At 2 mo, the mean BGP value (+/- SD) was 275 +/- 87 ng/mL in infants exclusively breast-fed, and 80 +/- 44 ng/mL in formula-fed infants. At 6 mo, the values were 142 +/- 58 ng/mL and 55 +/- 30 ng/mL, and at 9 mo 75 +/- 39 ng/mL and 45 +/- 19 ng/mL in partially breast-fed and formula-fed infants, respectively. The differences were significant (p less than 0.001) at all three ages. At 2 and 9 mo, breast-milk intake was measured by test-weighing. Serum BGP was positively correlated to breast milk intake (mL/kg body wt) at 2 mo (r = 0.59, p less than 0.001) and 9 mo (r = 0.41, p = 0.06). When breast-feeding was stopped, the high BGP concentrations were not sustained. There were no significant differences in linear growth velocity between breast-fed and formula-fed infants and no correlation between BGP values and linear growth velocity. We speculate that either a factor in human milk or the level of minerals in human milk causes the high BGP values. Moreover, if the higher values are associated with increased osteoblast activity, then the remodeling or the mineralization of bone might be different in infants not being breast-fed.

Age Factors↗
PubMed1992

Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women.

To investigate whether bone resorption exhibits a diurnal variation in healthy premenopausal women, we measured urinary excretion of pyridinoline and deoxypyridinoline cross-links (U-Pyr/Cr and U-D-Pyr/Cr) every 3 h over a 24-h period in 12 healthy premenopausal women (mean +/- 1 SD age, 32 +/- 5 yr). To study diurnal variation, U-Pyr/Cr and U-D-Pyr/Cr are the best available markers of bone resorption for a diurnal variation study, as they are not influenced by diet. Plasma osteocalcin and serum alkaline phosphatase (markers of bone formation) were also measured. A marked diurnal rhythm was observed in U-Pyr/Cr and U-D-Pyr/Cr, with the peak between 0500-0800 h and the nadir between 1400-2300 h. The fluctuation was 2-fold over the 24-h period, with a mean fall of 25-35% between 0800-1100 h. This study demonstrates a marked diurnal variation in the new biochemical markers of bone resorption, U-Pyr/Cr and U-D-Pyr/Cr, in premenopausal women. Furthermore, this study emphasizes the importance of regulating the time of the urine sample taken for measuring urinary pyridinium cross-links for clinical investigations as well as in clinical practice.

Adult↗
PubMed1992

Changes in calcanean bone mineral occurring spontaneously and during hormone replacement therapy in early post-menopausal women.

The spontaneous calcanean bone loss occurring in healthy early post-menopausal women and the effect of two hormone replacement therapies (HRT's) were investigated in a longitudinal study. There was no difference between the right and left calcanean BMC or BMD (p > 0.15). The spontaneous bone loss was similar at all the skeletal sites measured, with a mean spontaneous loss in calcanean BMD of 1.6% over one year. Both HRT's significantly (p < 0.01) prevented the bone loss from all skeletal sites irrespective of the weight-bearing or content of trabecular bone, and (for the weight-bearing bones) there was even a gain in calcanean BMC and BMD and spinal BMD (p < 0.01). Bone mineral of the calcaneus and the spine correlated equally to body weight (r approximately 0.4, p < 0.001), whereas bone mineral in the forearm was not correlated to body weight. The correlations between the changes in bone mineral at the sites measured were all significant (r approximately 0.2-0.4).

Bone Density↗
PubMed1992

Two new combinations of estrogen and progestogen for prevention of postmenopausal bone loss: long-term effects on bone, calcium and lipid metabolism, climacteric symptoms, and bleeding.

Bone mass, calcium and lipid metabolism, climacteric symptoms, bleeding, blood pressure, and weight changes were studied in 62 healthy postmenopausal women at 3-month intervals throughout 2 years of treatment with continuous estradiol valerate (2 mg) plus cyproterone acetate (1 mg), sequential estradiol valerate (2 mg) plus levonorgestrel (75 micrograms), or placebo. During the 2 years of the study, bone mineral content of the distal and ultradistal regions of the forearm (measured by single-photon absorptiometry) remained unchanged in the hormone groups, whereas bone mineral content at these sites decreased by 5 and 6%, respectively, in the placebo group. Bone mineral density in the spine (measured by dual-photon absorptiometry and dual-energy x-ray absorptiometry) increased by 3-4% in the hormone groups and decreased by 2% in the placebo group. Biochemical estimates of bone turnover (serum alkaline phosphatase and fasting urinary calcium/creatinine) decreased significantly to premenopausal levels in the hormone groups, but remained unchanged in the placebo group. Serum concentrations of total and low-density lipoprotein cholesterol were significantly reduced by 5-10% (P less than .05-.01) in the estradiol + cyproterone acetate group and by 10-15% (P less than .001) in the estradiol valerate + levonorgestrel group. There were no significant changes in high-density lipoprotein cholesterol in the hormone groups. Virtually no changes were observed in the placebo group. Climacteric symptoms and hot flushes were significantly reduced in both hormone groups compared with the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Density↗
PubMed1992

Treatment-induced cyclic variations in serum lipids, lipoproteins, and apolipoproteins after 2 years of combined hormone replacement therapy: exaggerated cyclic variations in smokers.

OBJECTIVE: To study the long-term effect of cigarette smoking on cyclic variations in serum lipids, lipoproteins, and apolipoproteins following combined hormone replacement therapy. METHODS: One hundred eighteen healthy, early postmenopausal women were followed for 2 years in a randomized, placebo-controlled study. Four treatment groups received estradiol, either sequentially combined with levonorgestrel (75 micrograms), medroxyprogesterone acetate (10 mg), or desogestrel (150 micrograms), or continuously combined with cyproterone acetate (1 mg). Two groups received placebo. Serum lipids, lipoproteins, and apolipoproteins were measured at well-defined times. Information on smoking habits was elicited by questionnaire. RESULTS: We found statistically significant cyclic variations in apolipoprotein A1 in the levonorgestrel group (6.7%; 95% confidence interval [CI] 1.1-12.7%) and the desogestrel group (7.4%; 95% CI 2.9-12.1%). The cyclic variations in high-density lipoprotein (HDL) cholesterol were highly statistically significant in the levonorgestrel group (24.9%; 95% CI 10.2-39.2%). When women from sequential regimens were combined, further analysis showed that smokers had significantly larger cyclic variations in HDL cholesterol (P less than .01) and apolipoprotein A1 (P less than .05) than non-smokers. CONCLUSIONS: Sequentially combined hormone replacement therapy produces cyclic variations in HDL cholesterol and apolipoprotein A1 for at least 2 years. In addition, cigarette smoking is associated with an exaggeration of the cyclic effect of treatment on these indices.

Androgen Antagonists↗
PubMed1992

Sequential estrogen and progestogen therapy: assessment of progestational effects on the postmenopausal endometrium.

Healthy postmenopausal women were randomly assigned to groups receiving 28-day treatment cycles of estradiol (E2) valerate (2 mg, days 1-21) combined with medroxyprogesterone acetate (10 mg, days 12-21) (N = 18), 17 beta-estradiol (1.5 mg, days 1-24) combined with desogestrel (150 micrograms, days 13-24) (N = 20), or placebo (N = 18). The progestational effects on the endometrium were assessed by histology, uterine bleeding pattern, and biochemical markers of secretion measured in endometrial tissue (E2 and isocitrate dehydrogenase) and serum (placental protein 14). After 2 years of therapy, 24 women in the hormone groups had secretory endometrium and 13 had atrophic endometrium; in the placebo group, the results were one and 15, respectively. Withdrawal bleeding generally started between days 9-12 after the addition of progestogen in the E2-medroxyprogesterone acetate group, and between days 14-17 in the E2-desogestrel group. All three biochemical markers of secretion were increased in each of the hormone-treated groups compared with the placebo group (P less than .01-.001). Serum placental protein 14 was twice as high in the secretory as in the atrophic phase (P less than .01). Isocitrate dehydrogenase, but not E2 dehydrogenase, was also higher in the secretory phase (P less than .05). Only serum placental protein 14 was significantly related to the uterine bleeding pattern (P less than .01). We conclude that serum placental protein 14 reflects both endometrial histology and bleeding pattern and may be a useful marker of progestational effects on the endometrium. The markers of secretion measured in endometrial tissue are not as reliable for endometrial histology or bleeding pattern.

Desogestrel↗
PubMed1991

Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study.

OBJECTIVE: To examine the role of peak bone mass and subsequent postmenopausal bone loss in the development of osteoporosis and the reliability of identifying women at risk from one bone mass measurement and one biochemical assessment of the future bone loss. DESIGN: Population based study. SETTING: Outpatient clinic for research into osteoporosis. SUBJECTS: 178 healthy early postmenopausal women who had participated in a two year study in 1977. 154 of the women underwent follow up examination in 1989, of whom 33 were excluded because of diseases or taking drugs known to affect calcium metabolism. MAIN OUTCOME MEASURES: Bone mineral content of the forearm and values of biochemical markers of bone turnover. RESULTS: The average reduction in bone mineral content during 1977-89 was 20%, but the fast losers had lost 10.0% more than had the slow loser group (mean loss 26.6% in fast losers and 16.6% in slow losers; p less than 0.001). Prediction of future bone mineral content using baseline bone mineral content and estimated rate of loss gave results almost identical with the actual bone mineral content measured in 1989. Seven women had had a Colles' fracture and 20 a spinal compression fracture. The group with Colles' fracture had low baseline bone mineral content (34.7 (95% confidence interval 31.3 to 38.1) units v 39.4 (38.1 to 40.8) units in women with no fracture) whereas the group with spinal fracture had a normal baseline bone mineral content (38.1 (35.0 to 41.1) units) but an increased rate of loss (-2.4 (-3.5 to -1.3)%/year v -1.8 (-2.1 to -1.5)%/year in women with no fracture). CONCLUSIONS: One baseline measurement of bone mass combined with a single estimation of the rate of bone loss can reliably identify the women at menopause who are at highest risk of developing osteoporosis later in life. The rate of loss may have an independent role in likelihood of vertebral fracture.

Age Factors↗
PubMed1991

Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis.

Vertebral osteoporosis, a common disorder in elderly women, is characterized by a wide spectrum of bone turnover abnormalities on iliac crest biopsy. The level of bone formation can be assessed noninvasively by measuring serum osteocalcin, whereas conventional biochemical markers of bone resorption lack specificity and do not reflect bone resorption assessed from histology. We measured the urinary excretion of pyridinoline crosslinks Pyr and D-Pyr, a specific marker of bone and cartilage collagen degradation, along with serum osteocalcin and urinary hydroxyproline, in 36 elderly women with vertebral osteoporosis who had a simultaneous iliac crest biopsy. Urinary pyridinoline crosslinks, but not hydroxyproline, correlated significantly with histologic resorption, assessed by the osteoclast surface (r = 0.35, p less than 0.05 for Pyr; r = 0.46, p less than 0.01 for D-Pyr). In addition, Pyr and D-Pyr were correlated with the bone formation rate as well as serum osteocalcin, with correlation coefficients ranging from 0.69 to 0.80, p less than 0.0001. These data indicate that Pyr and D-Pyr are sensitive markers of bone turnover in elderly women with vertebral osteoporosis. The poor correlation between the level of urinary collagen crosslinks and histological assessment of bone resorption indicates the low sensitivity of iliac crest histomorphometry in the measurement of resorption rate of the skeleton.

Aged↗
PubMed1991

Potential risk factors for development of postmenopausal osteoporosis--examined over a 12-year period.

In a longitudinal study, we investigated the influence of risk factors on bone mass at menopause and postmenopausal bone loss in 121 healthy postmenopausal women. These women had completed a 2-year prospective study in 1979 and a follow-up examination in 1989. Measurements of the bone mineral content in the distal forearm (single photon absorptiometry) were performed 9 times during the initial study and once at the follow-up examination. Bone mass at menopause (initial measurement), rate of early postmenopausal bone loss, and the subsequent rate of bone loss over 10 years were thus determined. In addition, the bone mineral density of the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry (DXA) in 1989. Information about risk factors was assessed by standardized questionnaires and included reproductive history and lifestyle factors (intake of calcium and vitamin D supplements, consumption of alcohol and caffeine, smoking habits, and physical activity). Lactation, oral contraceptive use, and dietary calcium intake above 1500 mg per day was associated with significantly increased bone mass at menopause. The number of pregnancies reduced the rate of early postmenopausal bone loss, whereas moderate alcohol consumption reduced the subsequent rate of bone loss. Smoking significantly reduced femoral bone mineral density. In conclusion, the present prospective study showed that some of the examined putative risk factors positively influenced bone mass at menopause, especially calcium intake, whereas the postmenopausal bone loss was virtually unaffected. Assessment of risk factors in postmenopausal women thus seems to have limited value for reducing future risk of osteoporosis.

Aged↗
PubMed1991

Long-term treatment of established osteoporosis with intranasal calcitonin.

We examined the long-term effects of intranasal administration of salmon calcitonin on bone and calcium metabolism in women with established osteoporosis (forearm fracture). Over a period of 5 years, 14 women received discontinuous calcitonin (200 IU) plus calcium (500 mg) daily for 3 years or 4 years. To allow assessment of the optimum duration of therapy, patients in whom treatment had been for shorter intervals were also included. At the end of the first 2 years, a group receiving placebo had lost significantly more bone from their spines and forearms than the group receiving calcitonin in the first year (P less than 0.01). In the 14 women who completed a further 3 years on calcitonin, the bone mineral contents of the spines increased continually. Bone loss in the forearm was arrested for 1 year. Treatment lasting for about 2 years prevented bone loss in both areas. Treatment for 3 years resulted in net gains in spinal bone but no further benefits in relation to forearms. Biochemical parameters of bone turnover (serum alkaline phosphatase levels, plasma bone Gla protein levels, and fasting urinary hydroxyproline/creatinine levels) exhibited similar declines irrespective of the duration of treatment. It is concluded that long-term intranasal treatment with calcitonin produced net gains in spinal bone and that optimum response in forearms was achieved using discontinuous therapy. The ratio between periods with and without treatment was between 1:2 and 2:3.

Administration, Intranasal↗