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  • hypertension  (103)
  • Calcium  (80)
  • Springer  (183)
  • American Association for the Advancement of Science
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  • 1984  (55)
  • 1982  (45)
  • 1981  (43)
  • 1980  (40)
  • 1929
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  • Springer  (183)
  • American Association for the Advancement of Science
  • Blackwell Publishing Ltd
  • Springer Nature
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  • 1980-1984  (183)
  • 1925-1929
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  • 1984  (55)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Monatshefte für Chemie 112 (1981), S. 149-156 
    ISSN: 1434-4475
    Keywords: Calcium ; Gallium ; Oxygen ; Single Crystal ; X-Ray
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The hitherto unknown compound Ca3Ga4O9 was prepared and investigated by X-ray single crystal methods. Ca3Ga4O9 has orthorhombic symmetry:a=1435.8;b=1682.5;c=532.1 pm; space group C 2v 11 −Cmm2,Z=6. The tetrahedra network (circles of 4 and 5 GaO4-tetrahedra) and the surrounding of Ca2+ are described and discussed with respect to other oxogallates.
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  • 2
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    Calcified tissue international 33 (1981), S. 409-416 
    ISSN: 1432-0827
    Keywords: Bone Cells ; Cyclic AMP ; Calcium ; Parathyroid hormone ; Prostaglandin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary We have examined the influence of extracellular Ca2+ on cyclic AMP metabolism in an osteoblast-enriched population of bone cells isolated from the calvaria of rat fetuses. The cyclic AMP1 response to stimulators of cyclic AMP formation (PTH and PGE2), but not basal cyclic AMP levels, increased progressively as the extracellular Ca2+ concentration was raised from 0.2 to 4.0 mM. The response to changes in extracellular Ca2+ were rapid (within 3.5 min), and the level of responsivity that characterized each Ca2+ concentration persisted for at least 6 h when the Ca2+ concentration was kept constant. The effect of Ca2+ spanned the entire time course of PTH action, was not accompanied by altered excretion of cyclic AMP from the cells, and was evident at low as well as at high hormone concentrations. Ca2+ augmented the action of PTH in the presence as well as in the absence of cyclic AMP phosphodiesterase inhibitors, and failed to decrease cyclic AMP phosphodiesterase activity in the short term. Mn2+ and, to a smaller degree, Ba2+ substituted for Ca2+ in promoting the cyclic AMP response to PTH. Verapamil, an inhibitor of Ca2+ penetration, blunted the Ca2+-mediated increments in the cyclic AMP response, and the divalent cation ionophore A23187 enhanced these increments. These results indicate that Ca2+ and other cations are positive effectors of the stimulated cyclic AMP response in isolated bone cells. Accumulation into an as yet unknown cellular compartment may be required for the cation effect. The data are most consistent with enhancement of adenylate cyclase reactivity as the mode of cation action.
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  • 3
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    Calcified tissue international 30 (1980), S. 209-216 
    ISSN: 1432-0827
    Keywords: Calvarium ; cAMP ; Vitamin D3 metabolites ; Calcium ; Parathyroid hormone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Results from in vitro works suggest that 1,25- and 24,25-dihydroxyvitamin D3 (1,25-(OH)2D3 and 24,25-(OH)2D3) act on bone via different mechanisms. The present investigation was performed to study the effect of these two metabolites and of their precursor 25-hyxdroxyvitamin D3 (25-(OH)D3) on bone cAMP content in vitro. Rats' paired half calvaria were incubated under sterile conditions with one vitamin D3 derivative (10−13 to 10−9 M) or with ethanol (0.005 ml for 15 min to 24 h in 1 ml medium containing 0, 0.2, 1, 2, or 3 mM calcium. In some experiments: (a) cycloheximide (10−5M) was added simultaneously with the vitamin D3 metabolites; (b) 1–84 bPTH (5 × 10−8 M) was added for 5 or 15 min at the end of the 24 h incubation. Calvaria were immersed in 1 ml TCA 5% 4°C and homogenized. The cAMP was extracted with diethylether and measured by a competitive protein binding assay. Results bring further evidence for a particular effect of low doses of 24,25-(OH)2D3 (10−9 to 10−12M) and of 25-(OH)D3 (10−9 to 10−11M) on bone, different from that of 1,25-(OH)2D3: cAMP content was higher in 24,25-(OH)2D3- or 25-(OH)D3-treated and lower in 1,25-(OH)2D3-treated calvaria than in ethanol-treated ones with 1 mM calcium. The 1,25-(OH)2D3 effect persisted in calcium-free medium whereas 25-(OH)D3 and 24,25-(OH)2D3 effects could not be observed with 0 mM nor with 3 mM calcium. The required duration of the preincubation (over 1 h) as well as the inhibitory action of cycloheximide may suggest an involvement of protein synthesis in the vitamin D3 metabolites effects. Neither 1,25-(OH)2D3 nor 24,25-(OH)2D3 affected the PTH-induced increase in bone cAMP content.
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  • 4
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    Calcified tissue international 32 (1980), S. 201-206 
    ISSN: 1432-0827
    Keywords: Magnesium ; Parathyroid hormone ; Secretion ; In vitro ; Calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary In a well-defined in vitro perifusion system, the effects of extracellular magnesium concentration (Mg) on parathyroid hormone (PTH) secretion by bovine parathyroid tissue were examined. At Mg less than 0.8 mM, the ability of the glands to secrete hormone maximally in response to low calcium (Ca) stimulation was progressively impaired. Low Mg also impaired the ability of isoproterenol, dibutyryl cyclic AMP and theophylline to stimulate hormone release. The defect in hormone release at low Mg observed in vitro was analogous to the well-documented inhibition of secretion observed in vivo. Increases in Mg from 0 to 0.8 mM rapidly repaired the defect in hormone secretion. At Mg above 1.0 mM there was a Ca-like effect on hormone release, with a progressive decrease in secretion at increased Mg. Although its mechanism is not yet clear, the low Mg effect appears to impair principally the process of hormone release rather than its biosynthesis or storage.
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  • 5
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    Calcified tissue international 36 (1984), S. 139-144 
    ISSN: 1432-0827
    Keywords: 1,25(OH)2-vitamin D ; Weight loss ; Phosphate ; Calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary During a review of 42 metabolic studies in healthy women and men we observed that serum 1,25-(OH)2-D concentrations were directly correlated to the observed daily changes in body weight (r=0.68;P〈0.001) and to caloric intake/kg/day (r=0.39;P=0.01). These relationships could not be accounted for by related and physiologically expected changes in serum Ca or iPTH concentrations. However, serum 1,25-(OH)2-D concentrations were observed to be inversely correlated to serum PO4 levels (r=−0.44;P=0.004). In addition, serum PO4 levels were inversely correlated to the daily changes in body weight (r=−0.40;P=0.009). Since dietary sodium intake averaged 142 mmol/day, it is unlikely that the observed changes in weight were the result of changes in salt and water balance. Thus it seems reasonable to speculate that serum 1,25-(OH)2-D concentrations may vary directly with energy balance, as reflected by changes in body weight. This effect may be mediated by alterations in PO4 metabolism. The accurate assessment of serum 1,25-(OH)2-D levels thus appears to require several measurements over time periods during which body weight is stable.
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  • 6
    ISSN: 1432-0827
    Keywords: Electromagnetic field ; Bicarbonate ; Phosphate ; Calcium ; Fluoride ; Osteogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The present studies are aimed at establishing molecular correlations in the interaction of very low frequency electromagnetic fields with biological systems. Ca-uptake by chick embryo tibia rudiment in short-term culture was a useful model. Tibiae of 8- to 10-day-old chick embryos were incubated 60 min in simplified culture media in the presence of45Ca at 37.5±0.5°C either inside or outside pulsating electromagnetic fields. Radioactivity count in the medium was the most accurate method for determining Ca-uptake by the rudiment. The effect of the fields on the Ca-uptake depended markedly on the chemical composition of the culture medium: bicarbonate was indispensable; glucose or sucrose was important; phosphate was potentiating; ethanol, Mg2+, and NaF were stimulating. The field had no effect in (a) blank medium without tibia, (b) tibiae that had been altered by fixation with aqueous glutaraldehyde, (c) nonliving artificial systems endowed with great or small ion sorption capacity. The unique bicarbonate effect with living systems and the passive behavior of nonliving ion sorbing systems prompt the suggestion that the electromagnetic field probably couples with specific processes, such as a bicarbonate-dependent Ca2+ ATPase and the active ion transport, at the cell membrane level. The molecular mechanisms remain to be established.
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  • 7
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    Calcified tissue international 36 (1984), S. 194-199 
    ISSN: 1432-0827
    Keywords: Benzo(B)Thiophene-2-Carboxylic Acid ; Bone cells ; Calcium ; Cyclic AMP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The purpose of the present study was to investigate the mechanism of action on bone of Benzo(B)Thiophene-2-Carboxylic Acid (BL-5583). BL-5583, at a dose range of 0.01–100 µg/ml, inhibited spontaneous as well as A23187 and PTH-induced bone resorption in tissue culture. This compound also decreased calcium uptake in both osteoclastic and osteoblastic enriched bone cell populations obtained by sequential collagenase digestion of 1–2 day newborn rat calvariae. The decrease occurred after a 5 min. incubation with45Ca and BL-5583. The effective dose range was 0.01–100 µg/ml. No effect on leucine incorporation or lactic acid production by bone cells was observed. BL-5583 also induced a transient decrease in calcium uptake in skin cells isolated from fetal rats by collagenase digestion, suggesting a lack of tissue specificity for this compound. No effect on cyclic AMP in isolated bone cells was observed with the same dose range that produced a calcium effect.
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  • 8
    ISSN: 1432-0827
    Keywords: Saliva ; Calcium ; Phosphate ; Ion-binding ; Supersaturation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Previous ultrafiltration studies indicated that up to one-half of the calcium and two-thirds of the phosphate in human salivary secretions may be bound by salivary proteins. Since this binding is an important variable in determining the extent of salivary supersaturation with respect to calcium phosphate salts, and since the amount of binding reported is surprisingly large, calcium and phosphate ion-binding by salivary macromolecules has been reexamined. From experiments using equilibrium dialysis, it was found that (1) the fraction of salivary calcium involved in macromolecular complexes ranges from a few percent for unstimulated secretions, to no more than about 10% for stimulated glandular salivas, and (2) salivary proteins do not bind phosphate ions to any significant extent. These findings, and experiments using an improved ultrafiltration membrane, indicate that the earlier results were artifacts of the ultrafiltration technique. Fractionation of salivary proteins, followed by equilibrium dialysis measurements, showed that the anionic proline-rich proteins and a basic proline-rich glycoprotein are responsible for most of the calcium binding now observed. The finding that macromolecular complexes of salivary calcium and phosphate have been overestimated in the past, leads to the conclusion that salivary calcium and phosphate ion activities in stimulated salivary secretions may be up to 50 to 100% higher than previously thought. Revised values were therefore used to recalculate the degree of salivary supersaturation with respect to calcium phosphate salts. The results indicate that stimulated salivary secretions are supersaturated with respect to dicalcium phosphate dihydrate; this is a substantially greater degree of supersaturation than previously reported.
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  • 9
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    Calcified tissue international 32 (1980), S. 229-236 
    ISSN: 1432-0827
    Keywords: Bone ; Ion influxes ; Calcium ; Phosphate ; Exchange
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Quantitative measurements were made of the ion fluxes of calcium and phosphate into and from calvaria (mouse or rat) when clamped in specially designed micro-Ussing chambers. The effects of varying concentrations of calcium were examined on the influx and efflux of calcium and of its counterion, phosphate. A comparable series of experiments was performed with varying phosphate concentrations. Both ions, as their concentrations increased, depressed their own influx, increased their own efflux, and significantly increased the equilibrium concentration, E/K, supported by the calvaria. Similarly, both ions, as their concentrations increased, affected the influx or efflux of their counterion only slightly but did depress the counterion's equilibrium level, E/K, significantly. In spite of these changes it was shown that calvaria effectively buffered the medium at physiological concentrations of calcium and phosphate. The buffering capacity, however, was small, and the balance, E/K, was modified by small uptake or loss of either ion. The small size of the interacting mineral pool was confirmed by direct measurement of the rapidly exchanging fractions of both calcium or phosphate. They were only ∼1% of the total ions present. The significance of these findings is discussed.
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  • 10
    ISSN: 1432-0827
    Keywords: Calcium ; Vitamin D deficiency ; 1,25(OH)2D3 ; Parathyroidectomy ; Parathyroid hormone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Studies presented here were designed to investigate further the basis for an impaired cAMP response to parathyroid hormone (PTH) in osteoblastlike calvarial bone cells isolated from vitamin D-deficient rat pups. The goal was to perturb Ca, PTH, and vitamin Din vivo in order to see which factors might be responsible for the impairedin vitro bone cell cAMP response. Pups either were parathyroidectomized (PTX) 3–5 days, implanted with osmotic minipumps delivering high doses of PTH, given repeated, high doses of 1,25(OH)2D3, or were D-deficient (-D, i.e., born and suckled by D-deficient mothers). Osteoblastlike bone cells, isolated by sequential enzyme digestion and centrifugation, were exposed to PTH for 5 min in the presence of a phosphodiesterase inhibitor. In bone cells isolated from -D rat pups, both basal and PTH-induced cAMP accumulation were significantly lower than in +D bone cells. Earlier, we had shown that two daily injections of -D pups with 50 ng 1,25(OH)2D3 restores this reduced bone cAMP response of -D pups toward normal. In the present study, neither basal nor PTH-induced bone cell cAMP accumulation was affected by subjecting D-replete pups to PTX, PTH infusion, or repeated high doses of 1,25(OH)2D3 despite the fact that each treatment markedly changed serum Ca or serum immunoreactive PTH. The results indicate that the impaired bone cell cAMP response seen in -D pups is not a direct result of chronic hypocalcemia and that the “heterologous desensitization” seenin vitro with added 1,25(OH)2D3 could not be duplicated byin vivo treatment of +D pups with supraphysiologic doses of 1,25(OH)2D3. Finally the lack of alteration in the bone cell cAMP response to PTHin vitro after chronic PTH infusionin vivo fails to support the notion that the impaired response in -D bone cells can be explained entirely by “homologous desensitization” induced by high circulating levels of PTH in the hypocalcemic, -D rat pup.
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  • 11
    ISSN: 1432-0827
    Keywords: Calcitonin ; Parathyroid hormone ; Calcium ; Newborn ; Fracture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Determinations of serum calcium (Ca), phosphorus (P), calcitonin (CT), and parathyroid hormone (PTH) were carried out in 36 full-term newborn infants with fracture of the clavicle (CF) and in 46 normal neonates (N). At the 6th hour of life the CF neonates demonstrated lower serum Ca and higher serum CT in comparison with normal infants. In the hours following, no significant differences between the two groups for the Ca levels were found, whereas serum CT remained significantly higher in the CF newborns at the 24th, 48th, and 72nd hour of life. Significant differences between normal and CF infants in the PTH serum levels were detected only at the 48th hour, when PTH was lower in the CF newborns. The results of this investigation indicate that the fracture of the clavicle is a significant and peculiar factor in stimulating CT secretion. Serum Ca level appeared to be controlled by CT rather than auto-regulating the secretion of the hormone.
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  • 12
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    Calcified tissue international 33 (1981), S. 365-368 
    ISSN: 1432-0827
    Keywords: Absorptiometry ; Osteoporosis ; Spinal bone ; Bone mineral content ; Neutron activation ; Calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Dual-photon absorptiometry using153Gd (44 and 100 keV) was used to measure the bone mineral content (BMC) of the trunk and of the total body (TBBM) in 7 volunteers with no overt bone disease. These values were compared to those obtained with partial-body neutron activation of calcium (trunk Ca). The trunk Ca seemed to represent best a 60 × 30 cm area; the correlation coefficient with the corresponding BMC in that area was 0.97 (SEE ⋍ 7%). Trunk Ca was also highly correlated with TBBM (r=0.96; SEE=8%) and with radius BMC (r=0.92; SEE=11%), but the correlations with the BMC of smaller subareas of the trunk were lower (r⋍0.9; SEE ∼ 12%). The BMC of the lumbar spine was only moderately correlated with trunk Ca, radius BMC and TBBM (r ∼ 0.82; SEE ∼ 18%), and only slightly more associated with trunk BMC (r ∼ 0.88; SEE ∼ 14%). The BMC of the combined lumbar-thoracic spine showed higher correlations with trunk Ca, radius BMC and TBBM (r ∼ 0.87; SEE ∼ 13%), and trunk BMC (r=0.93; SEE ∼ 10%). An accurate and sensitive measure of spinal status requires a direct measurement of that area.
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  • 13
    ISSN: 1432-0827
    Keywords: Bone cells ; Cyclic AMP ; Calcium ; Ascites fluid resorptive protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The effects of a bone resorptive protein isolated from human cancer ascites fluid on bone cell calcium and cyclic AMP were studied with fetal rat cells. The osteoclast-activating factor increased bone cell calcium uptake at 37°C and 4°C with no direct effects on calcium efflux. Concentrations of the resorptive factor that increased in vitro bone resorption and cell calcium uptake had no effect on cyclic AMP. The effects of the protein on calcium uptake were not specific for bone cells, and large increases were also observed in isolated fetal rat skin cells. These studies suggest that increases in the permeability of the cell membrane to calcium are involved in the mechanism of action of the ascites fluid resorptive protein.
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  • 14
    ISSN: 1432-0827
    Keywords: Hydroxyapatite ; Dissolution ; Pyrophosphate, Diphosphonates ; Calcium ; Phosphate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Pyrophosphate and diphosphonate ions have been said to diminish the dissolution of hydroxyapatite crystals, because they lower the equilibrium concentrations of calcium and phosphate ions in the bulk solution around hydroxyapatite crystals in a closed system. However, in a closed system these effects are not necessarily due to an effect on dissolution alone. In this paper we have used a continuous flow system to study the effects of pyrophosphate and two diphosphonates, ethane-1-hydroxy-1,1-diphosphonate and dichloromethane diphosphonate, on the dissolution of hydroxyapatite. All three compounds decreased markedly the rate of dissolution of hydroxyapatite as well as the exchangeable pools of calcium and phosphate ions around the cystals.
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  • 15
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    Calcified tissue international 31 (1980), S. 231-238 
    ISSN: 1432-0827
    Keywords: Magnesium ; Bone ; Calcium ; Parathyroid gland
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Calcium homeostasis and bone pathology were studied in weanling rats fed a low (70 ppm) magnesium diet for 2–21 days. The rats developed significant, progressive hypercalcemia after 6 days on the diet. The increase in blood calcium was accompanied by progressive hypoactivity of the parathyroid gland (PTG), as determined by histologic and morphometric analyses. Thus hyperactivity of the PTG could not have been responsible for the hypercalcemia observed. Histologic examination of femora and humeri from magnesium-deficient rats showed progressive subperiosteal hyperplasia, consisting of undifferentiated osteoprogenitor cells and fibrous tissue, after 7 days of deficiency. The presence of unmineralized osteoid tissue in the metaphyses indicated that mineralization was not proceeding normally. The alterations in differentiation of osteoprogenitor cells, together with the failure of mineralization, resulted in significantly lower rates of bone formation (as measured by fluorochrome labeling) in the magnesium-deficient rats. Basophilic cementing lines and inactive osteocytes in the cortices of bones from magnesium-deficient rats indicated that bone resorption was also severely reduced in magnesium deficiency. We postulate that bone magnesium depletion (66% by day 21) has a direct negative effect on osteoblastic and osteocytic activity, and may explain, in part, the decreased responsiveness of bone to parathyroid hormone (PTH) that has been observed in magnesium-deficient animals.
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  • 16
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    Calcified tissue international 32 (1980), S. 45-53 
    ISSN: 1432-0827
    Keywords: Dentin ; Periodicity ; Allometry ; Calcium ; Sulfur
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary We have described differences in the aspects of biological rhythms for calcium and sulfur deposition on the labial and lingual sides of the growing rabbit incisor, where growth occurs along a spiral axis. The calcium oscillations appear to be smoother on the labial side than on the lingual side. The lingual side is characterized by high-frequency rhythms with high amplitudes which possess the greatest percent of the power (Fourier analysis). These observations also reflect a difference in behavior of the mean Ca concentration across the labial and lingual sides. Sulfur rhythms on the labial side have higher amplitudes than those on the lingual side, but systematic differences in distribution of power between high and low frequencies is not as pronounced as in the case of Ca. The differences in Ca rhythms reflect differences in the growth rates of incisors on either side of the spiral axis. The labial side grows slightly faster than the lingual side, and its odontoblasts secrete Ca along the spiral axis and toward the pulp cavity at the same time. Thus the resultant direction of growth is more nearly opposite the extension of the occlusal end on the labial side, and Ca is consequently deposited over a wider area relative to that on the lingual surfaces. On the lingual side, Ca is deposited within a more limited area, and growth must therefore be continuous at high frequencies. The distribution of Ca on both sides of the tooth reflects these differences in growth rate and periodicity in two ways. First, given a unit area of tooth, the calcium concentration on the labial side is less than that of the lingual side. Second, whereas the calcium concentration on the labial side declines rapidly from the enamel-dentin junction to the pulp cavity, it is uniformly high across the lingual side because its growth is more continuous at high frequencies.
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  • 17
    ISSN: 1432-0827
    Keywords: 1α-Hydroxy vitamin D3 ; 1,25-Dihydroxyvitamin D3 ; Calcium ; Transport ; Intestine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The timed sequence of events following the oral administration of 1α-hydroxy vitamin D3 (1αOHD3) to rachitic chicks was compared to that following a comparable dose of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). RNA polymerase activity was maximally increased 20% by 1αOHD3 within 1 to 2 h and returned to control values after 8 h. Alkaline phosphatase activity was stimulated by 4 h and was maximal (3- to 5-fold increase) at 24 h. Calcium binding protein (CaBP) was detected initially within epithelial cells at the proximal end of the villus (just above the crypt) 6 to 8 h after 1αOHD3 administration, in epithelial cells lining the proximal half of the villus by 24 h, and in epithelial cells along nearly the entire villus by 48 h. At no time did goblet cells contain CaBP. Serum calcium concentrations were significantly elevated in 2 h and maximal by 12 h (an increase of 3.6 mg/dl). Calcium accumulation by the intestinal mucosa in vitro was increased by 6 to 8 h and maximal (60% increase over controls) at 24 h. Phosphate accumulation by the intestinal mucosa in vitro was increased by 6 h and maximal (105% increase over controls) between 8 and 24 h. 1,25(OH)2D3 increased CaBP and calcium accumulation by 4 h, 2 h sooner than did 1αOHD3. 1,25(OH)2D3 decreased serum calcium levels and increased serum phosphate levels at 2 h unlike 1αOHD3. No difference in the effects of these compounds on alkaline phosphatase activity, RNA polymerase activity, and phosphate accumulation could be demonstrated. These results are consistent with the possibility that 1αOHD3 may not require conversion to 1,25(OH)2D3 for all of its biological effects.
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  • 18
    ISSN: 1432-0827
    Keywords: Perifusion ; Parathyroid hormone ; In vitro ; Calcium ; Beta regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary An in vitro perifusion system was used to study parathyroid hormone (PTH) secretion in response to calcium (Ca) and beta-adrenergic agents. Perifused parathyroid tissue responded to changes in Ca within the physiologic range during experiments up to 5 h. There was rapid secretory stimulation after exposure to low Ca, with the maximum response being observed at 20 min. Normal bovine glands showed a Ca-independent nonsuppressible component of PTH release at concentrations of Ca above physiologic. 1-isoproterenol produced rapid stimulation of PTH release, the response being blocked by a beta antagonist. The maximum secretory response to either low Ca (0.5 mM) or 1-isoproterenol (10−5 M) was enhanced when the two stimuli were applied simultaneously. The response to isoproterenol was blocked by raising Ca to 2.5 mM. Although d,l-propranolol (10−4 M) caused mild suppression of PTH release at a Ca of 1.25 mM, it did not cause additional suppression at 2.5 mM Ca nor did it decrease the response to 0.5 mM Ca stimulation. The secretory response of the gland to low Ca was sustained at a level more than double the baseline rate. The response to isoproterenol was more transient, with a return to or toward baseline secretion within 60 min. These results suggest that beta agonists and low Ca have separate but related mechanisms for stimulating PTH release and may affect different pools of hormone. The perifusion system described is a relatively simple technique for assessing the kinetics and interactions of various stimulators of PTH secretion.
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  • 19
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    Calcified tissue international 32 (1980), S. 29-44 
    ISSN: 1432-0827
    Keywords: Rabbit ; Dentin ; Calcium ; Sulfur ; Periodicity ; Circadian ; Ultradian
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary We have identified a variety of biological rhythms involved in the apposition and mineralization of dentin in the rabbit incisor. Animals were injected during the day or night with lead acetate at 2-week intervals—to provide biological time markers in forming dentin—and transverse undecalcified sections of the lower incisors were prepared for electron microprobe analysis. The positions of the lead markers were identified, and the continuous distribution of calcium and sulfur was measured at 1 µm intervals between the markers. In thin sections stained with hematoxylin after decalcification, the widths of a series of structural increments (bands) were measured with an ocular micrometer. Fourier analysis of the data revealed spectra of structural and compositional rhythms with a range of periodicities which extended from a matter of hours [ultradian (〈24 h)] to days [infradian (〉24 h) and circadian (approximately 24 h)]. The structural and compositional rhythms appeared to be independent to the extent that they did not necessarily have the same periods, or amplitudes. Nor were there simple phase relationships between all of the rhythms. At some times, Ca and S fluctuations are inversely proportional (180° out of phase), but in other cases they are directly proportional or out of phase by varying degrees other than 180°. The analyses thus suggest that calcium and sulfur deposition (representing mineral and glycosaminoglycan deposition, respectively) are not simply inversely proportional, and that the hematoxylin-stained structural increments did not solely reflect differences in the distribution of the mineral components in dentin.
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  • 20
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    Calcified tissue international 34 (1982), S. 253-257 
    ISSN: 1432-0827
    Keywords: Prednisolone ; Calcium ; Bone ; Corticoid osteopenia ; Vitamin D metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Adult male rats were fed a diet containing 0.15% calcium, 0.3% phosphorus, and either 100, 50, or 20 mg of prednisolone per kg of diet. All these levels of prednisolone led to osteopenia, decreased intestinal absorption of calcium, slightly lower serum calcium and phosphorus, and a decreased level of serum 1,25-dihydroxyvitamin D3. Exogenous parenteral 1,25-dihydroxyvitamin D3 corrected steroid-induced changes in serum calcium and phosphorus, but could not completely correct the low intestinal calcium transport; nor did it prevent the development of osteopenia. The prednisolone-induced osteopenia seems at least in part to be caused by impaired intestinal calcium transport. The impaired calcium transport may be the result of low levels of 1,25-dihydroxyvitamin D3 and a direct effect of presnisolone on the intestine.
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    Calcified tissue international 36 (1984), S. 596-603 
    ISSN: 1432-0827
    Keywords: Calcium ; Ameloblasts ; X-ray microanalysis ; Transport ; Frozen
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    Topics: Biology , Medicine , Physics
    Notes: Summary Energy dispersive X-ray microanalysis was applied to freeze-dried blocks of enamel organ tissue to determine levels of calcium in various celular regions. The tissue blocks were dissected free from adjacent forming enamel following injection of cobalt or fluoride ions, both of which temporarily inhibit enamel mineralization. In all control and experimental specimens there was an increasing gradient of calcium from the stratum intermedium cells to the distal ends of the ameloblasts. Calcium levels were significantly reduced near the distal ends of the ameloblasts following cobalt or fluoride injection as compared with controls. It is suggested that evidence of an intercellular buildup of calcium near the distal ends of the ameloblast supports a controlling function of these cells. The changes in calcium levels are correlated with alterations in mineralization known to occur in the adjacent enamel of the model systems employed.
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  • 22
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    Calcified tissue international 33 (1981), S. 477-484 
    ISSN: 1432-0827
    Keywords: 1,25-(OH)2-D ; Calcium ; Phosphorus ; Sex ; Age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Dietary phosphate deprivation in women, but not men, is accompanied by a fall in plasma PO4 and a rise in plasma 1,25-(OH)2-vitamin D concentrations. In contrast, young male rats exhibit a fall in plasma PO4 and a rise in plasma 1,25-(OH)2-D concentrations in response to PO4 deprivation. To evaluate whether age and sex influence basal plasma 1,25-(OH)2-D levels and their regulation by PO4 deprivation, plasma 1,25-(OH)2-D, PO4, and Ca levels were measured in male and female rats ranging in age from 6 weeks to 6 months while they were eating normal or low PO4 diets for 1 to 16 days. Similar observations were also made in 6-week-old castrated male and female rats, males replaced with testosterone, and females replaced with estradiol. Basal plasma 1,25-(OH)2-D levels were higher in 6-week-old males (228±76 pmol/l) than in 6-week-old females (148±62 pmol/l;P〈0.01) and declined by age 11 weeks to stable levels averaging about 100 pmol/l without sex difference. Dietary PO4 deprivation resulted in a three-to fourfold increase in plasma 1,25-(OH)2-D concentrations regardless of age and sex, accompanied by a correlated rise in serum Ca concentrations. Castration of 6-week-old males and females eliminated the sex difference in basal plasma 1,25-(OH)2-D levels and appeared to enhance the elevation of plasma 1,25-(OH)2-D concentrations in response to PO4 deprivation in females. Although gonadal hormones may modify basal plasma 1,25-(OH)2-D levels, they are not required for the augmentation of plasma 1,25-(OH)2-D levels in response to PO4 deprivation.
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  • 23
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    Calcified tissue international 33 (1981), S. 575-581 
    ISSN: 1432-0827
    Keywords: Osteoporosis ; Vitamin D ; Bone mineral ; Estrogen ; Aging ; Thiazide ; Fluoride ; Calcium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Bone mineral content (BMC) was measured by125I photon absorptiometry every 3 months in 264 normal females (45–54 years) over a 2-year period together with serum samples for calcium, phosphate, magnesium, creatinine, alkaline phosphatases, potassium, and protein. A 48-h urinary calcium and creatinine measurement was obtained. The subjects were divided into 7 treatment groups and 3 placebo groups. Five of the treatments (thiazide, vitamin D3, fluoride + vitamin D3, fluoride, and 1αD3) were ineffective at the doses used; the annual loss of compact bone was 1.5–2.2% (-X=1.8%), similar to the loss seen with placebos. Estrogen and estrogen + thiazide, in contrast, produced a 1.34% annual increase of BMC. The subjects were divided into groups with low, medium, and high initial BMC. Also, individual regressions for bone change were calculated and the subjects were divided into groups of responders, maintainers, and losers (annual change of 〉0%, 0 to −1%, and 〉−1%, respectively). The initial BMC status did not consistently affect bone or biochemical responses to the therapeutic agents. Estrogen was effective even in subjects with high BMC, whereas the other agents did not inhibit bone loss even in subjects with low initial BMC. Virtually all subjects responded to estrogen positively; in contrast we could not identify a subset of “responders” with any of the other treatments. Time since menopause appeared to influence the bone changes, although it was not a significant effect given the sample size. Bone loss in groups not treated with estrogens was 2%/year at 20 months after menopause with a decline to 1.3%/year at 45 months post-menopause. There was no apparent decline in the bone response to estrogen during the first 4 years after menopause, and in fact bone response tended to increase with time.
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  • 24
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    Calcified tissue international 33 (1981), S. 485-488 
    ISSN: 1432-0827
    Keywords: 1,25-(OH)2-D ; Hypophysectomy ; Calcium ; Phosphorus
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    Topics: Biology , Medicine , Physics
    Notes: Summary The mechanism by which dietary phosphate deprivation elevates plasma 1,25-(OH)2-D levels is not known. To evaluate the role of the pituitary in regulating plasma 1,25-(OH)2-D concentrations, the responses of plasma 1,25-(OH)2-D to dietary phosphate deprivation and, separately, to dietary calcium deprivation were evaluated in intact and hypophysectomized male rats. Among intact and hypophysectomized rats eating normal diets, plasma 1,25-(OH)2-D levels averaged 228±76 and 148±62 pmol/1, respectively (P〈0.01). During dietary phosphate deprivation, plasma 1,25-(OH)2-D levels rose to 1160±260 in intact rats and fell to 90±26 pmol/l in hypophysectomized rats (P〈0.001). By contrast, during dietary calcium deprivation, plasma 1,25-(OH)2-D levels rose in both intact and hypophysectomized animals to 856±107 and 742±279 pmol/l, respectively (NS). In response to dietary phosphate deprivation, serum calcium concentrations rose as 1,25-(OH)2-D concentrations rose in intact rats but remained at control levels in hypophysectomized rats. These results support the hypothesis that a pituitary hormone acting either directly or indirectly on the kidney mediates the increase in plasma 1,25-(OH)2-D during dietary phosphate deprivation. The hypercalcemia that occurs in rats during dietary phosphate deprivation appears to depend on the elevation of plasma 1,25-(OH)2-D.
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  • 25
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    Calcified tissue international 30 (1980), S. 27-34 
    ISSN: 1432-0827
    Keywords: Ultrastructure ; Calcium ; Cartilage ; Vesicles
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    Topics: Biology , Medicine , Physics
    Notes: Summary The potassium pyroantimonate technique was utilized for the selective subcellular localization of calcium in the mandibular condylar cartilage of 1-day-old rats. Electron dense calcium pyroantimonate precipitates were localized principally in mitochondria and at the cell membrane of the chondrocytes. In addition, small intracellular vesicles 0.1–0.2µm in diameter were observed in proximity to the cell membrane of chondrocytes of the mid-hypertrophic zone. The results suggest that these vesicles were being extruded from the cell into the extracellular matrix. Energy-dispersive analysis by X-rays confirmed that calcium is the principal cation of the electron-dense precipitates.
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  • 26
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    Calcified tissue international 34 (1982), S. 43-48 
    ISSN: 1432-0827
    Keywords: Calcium ; Phosphate ; Phosphatidylserine ; Transport ; Mineralization
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    Topics: Biology , Medicine , Physics
    Notes: Summary Experiments were performed to study the effect of inorganic phosphate (Pi) on phosphatidylserine-mediated Ca2+ transport utilizing two- and three-compartment lipid-aqueous phase model systems. When the three-compartment model was used, the rate of Ca2+ transport from an aqueous donor compartment to an aqueous receiver compartment, separated by a nonaqueous phospholipid phase, was determined. This experiment showed that the rate of Ca2+ transport was proportional to the phosphatidylserine concentration and the pH. Pi modulated the rate of Ca2+ transport; even when the Pi concentration of the donor aqueous phase was low, there was a marked enhancement of transport. To determine whether the Pi-mediated rise in the Ca2+ transport rate was due to an increase in the uptake of Ca2+ into the lipid phase, or to an increase in the ability of the lipid phase to release Ca2+, a two-compartment model was used. It was found that the ability of the phosphatidylserine phase to take up Ca2+ increased as the Pi concentration of the aqueous donor phase was raised. With the increase in Ca2+ uptake there was a concomitant elevation in the rate of Ca2+ transport into an aqueous receiver phase. However, Pi did not stimulate Ca2+ release from the phosphatide. Thus it was concluded that Pi enhanced the interaction between Ca2+ and phosphatidylserine, possibly by forming a Ca-phospholipid-Pi complex. Once this interaction had taken place, Ca2+ release into the aqueous receiver compartment was independent of the Pi concentration.
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  • 27
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    Calcified tissue international 36 (1984), S. 77-82 
    ISSN: 1432-0827
    Keywords: Osteogenesis ; Diffusion chambers ; Alkaline phosphatase ; Calcium ; Phosphorus
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    Topics: Biology , Medicine , Physics
    Notes: Summary The alkaline phosphatase activity and the calcium and phosphorus content of osteogenic tissue formedin vivo following the implantation of diffusion chambers loaded with rabbit bone marrow cells is reported. (In this study the term osteogenic includes osteoblastic and chondroblastic.) Chambers examined 14–70 days after implantation revealed progressive accumulation of mineral. Alkaline phosphatase activity increased until day 30 and declined thereafter. The osteogenic potential of the marrow cells decreased with increasing weight (age) of the cell donor rabbit when measured either as the percentage of chambers containing osteogenic tissue or as the amount of calcium, phosphorus, or alkaline phosphatase activity within the chambers. The results confirm that measurements of these parameters in tissue formed by cells incubated in diffusion chambersin vivo may be used as a method for assay of osteogenesis.
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  • 28
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    Calcified tissue international 36 (1984), S. 269-273 
    ISSN: 1432-0827
    Keywords: Bone loss (osteopenia) ; Calcium ; Corticosteroids (glucocorticosteroids) ; Fluoride ; Vitamin D
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    Topics: Biology , Medicine , Physics
    Notes: Summary To evaluate the effect of prednisone and triple treatment (sodium fluoride, calcium, and vitamin D) on trabecular and cortical bone serial bone mineral content (BMC) measurements were made at a metaphyseal (BMCD) and diaphyseal (BMCP) site on the forearm on 31 consecutive and previously bone-healthy patients scheduled for at least 24 weeks high-dose prednisone treatment. The patients were randomized into two further treatment groups: group I (n=16) received prednisone plus triple treatment and group II (n=15) received only prednisone. The two groups were similar with regard to age, sex, prednisone dose, and initial BMC. During 24 weeks treatment, BMCD (partially representing trabecular bone) and BMCP (mainly representing cortical bone) fell significantly and similarly, demonstrating that there is no preventive effect on bone mineral loss on the triple regimen. The BMC fall after 12 weeks was significantly more pronounced for metaphyseal (partially trabecular) than for diaphyseal (cortical) bone, whereas the values did not differ significantly after 24 weeks; this indicates a greater sensitivity to the hormone treatment of trabecular bone. In the entire group, the fall in BMC correlated positively with individual prednisone dose, significant at the diaphyseal site (r=0.39,P〈0.05), but not at the metaphyseal site (r=0.31, P=0.08). It is concluded that corticosteroid-induced osteopenia is a diffuse bone disease which affects trabecular as well as cortical bone, suggesting that BMC measured on the forearm reflects changes in bone mineral at other locations.
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  • 29
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    Calcified tissue international 36 (1984), S. 392-400 
    ISSN: 1432-0827
    Keywords: Vitamin D ; Chick embryo ; Bone ; Calcium ; Phosphate
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    Topics: Biology , Medicine , Physics
    Notes: Summary Chick embryos were injected in the yolk sac at various ages with various doses of different vitamin D3 metabolites. Serum concentrations of total calcium and inorganic phosphate were determined 24 h after the injection and histological and electron microscopic studies of the tibiae were conducted 3–6 days after. Confirming previous results, the injection of 1,25(OH)2D3 was found to produce significant hypercalcemia and hypophosphatemia. The dose required to produce these effects decreased with age: 100 ng on the 9th day, 50 ng on the 11th, and 10 ng on the 15th. This finding is interpreted as resulting from the fact that the specialized cells in the chorionic epithelium which are considered to be involved in mineral resorption from the shell differentiate between the 11th and 13th days. Although no bone changes were observed in embryos injected before the 11th day, a rim of unmineralized trabeculae (osteoid) was observed at the periphery of the cortex of the tibial diaphysis in the embryos which had been injected after that age. Thus, in embryos injected on the 11th day with 100 ng 1,25(OH)2D3, the trabeculae formed between the 11th and 14th day remained unmineralized until the 15th or 16th day at which time they completed their mineralization. In the embryos injected on the 14th day, the alterations were more severe and could be produced with doses 10 times smaller than those required when the injections were made on the 11th day. At all ages, the doses that produced an osteoid rim also induced hypercalcemia and hypophosphatemia. The electron microscopical study of the osteoid trabeculae showed that osteoblasts and osteocytes had normal cytological characteristics and that the bone matrix did not present changes other than the reduction in mineral deposition. While the above findings do not exclude a direct action of 1,25(OH)2D3 on bone cells as the mechanism of osteoid formation, they do underline the importance of the humoral changes at least as partial determinants of this phenomenon. The activities of various vitamin D metabolites were compared using as parameter the threshold-dose required to produce a rim of unmineralized trabeculae in the tibia of 14–15 days embryos (T-D). The most active metabolite appeared to be 1,25(OH)2D3 (T-D: 10 ng); it was followed by 1,24,25(OH)3D3 (T-D: 100 ng) and 1,25,26(OH)3D3 (T-D: 100 ng). Vitamin D3 itself (T-D: 100 µg), 25(OH)D3 (T-D: 2.5µg) and 24,25(OH)2D3 (T-D: 5 µg) produced similar responses but only when administered in much larger doses.
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    Calcified tissue international 36 (1984), S. 702-710 
    ISSN: 1432-0827
    Keywords: Corticosteroids ; Cartilage ; Organ culture ; Calcium ; Matrix vesicles
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    Topics: Biology , Medicine , Physics
    Notes: Summary The present study examined the effects of various corticosteroid and noncorticosteroid hormones upon the ultrastructure of chondroprogenitor cells and chondroblasts in an organ-culture system of late fetal condylar cartilage. Corticosteroids, (triamcinolone acetonide, dexamethasone, corticosterone) at concentrations of 10−6–10−8M stimulated markedly a precocious formation of matrix vesicles by chondroblasts. This stimulation was accompanied by a significant accretion of calcium complexes intra- and extracellularly in both the chondroprogenitor cell population and chondroblastsin vitro, as well as in the newly induced matrix vesicles. Nonglucocorticoid steroids (progesterone, estradiol, testosterone, cortexolone) did not evoke similar effects. Progesterone and testosterone, however, seemed to adversely affect the ultrastructure of the cartilage cells, whereas estradiol appeared to have a favorable effect on the morphology of cultured condylar cartilage.
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    Calcified tissue international 34 (1982), S. 121-124 
    ISSN: 1432-0827
    Keywords: Bone ; Calcium ; Metabolism
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    Topics: Biology , Medicine , Physics
    Notes: Summary Bone Gla protein (BGP) was measured in the plasma by radioimmunoassay (RIA) during treatment of 59 patients with bone diseases including Paget's disease (N=9), primary hyperparathyroidism (N=25), chronic renal failure (N=20), and cancer involving bone (N=5). Plasma BGP was increased above normal in all patients. BGP decreased in the patients with Paget's disease following the acute and chronic administration of salmon calcitonin. Plasma BGP was higher in women then in men with primary hyperparathyroidism. Following parathyroidectomy, BGP decreased in both sexes but the decrease was significant in women only. Plasma BGP was increased in patients with renal osteodystrophy and did not change after hemodialysis. In the patients with bone cancer, plasma BGP decreased during treatment of the attendant hypercalcemia with salmon calcitonin. Although plasma BGP and serum alkaline phosphatase (AP) levels were generally correlated in these studies, there were examples of dissociation between the two. The measurement of plasma BGP appears to provide a specific index of bone metabolism that may in some circumstances be more sensitive than serum alkaline phosphatase measurement. However, further studies are necessary to establish the clinical value of plasma BGP measurement by RIA in the management of patients with bone diseases.
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  • 32
    ISSN: 1432-2048
    Keywords: Calcium ; Cation exchange ; Lycopersicon esculentum ; Rhythm ; diurnal Transport (calcium) ; Zea mays
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    Topics: Biology
    Notes: Abstract Tomato (Lycopersicon esculentum Mill. cv. Moneymaker) and maize (Zea mays L. cv. spec.) plants were supplied with 45Ca-labeled nutrient solutions for a period of 8 or 16 h in the dark, in the light, or in a light-dark régime. Plant parts were analyzed for 45Ca content. The partitioning of 45Ca between mature leaves and meristems was shown to be affected by the presence of light. The transport of 45Ca to meristems was higher in a dark period than in a comparable light period. Experiments with excised tomato shoots yielded similar distribution patterns of 45Ca over leaves and meristems, thus excluding root pressure as the main driving force for the enhanced import of 45Ca into the meristems in the dark. Results are discussed in terms of cation-exchange transport and competition between the various calcium sinks.
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  • 33
    ISSN: 1432-2048
    Keywords: Bryophyta ; Bud formation (moss) ; Calcium ; Chlorotetracycline ; Cytokinin ; Funaria
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    Topics: Biology
    Notes: Abstract We have investigated the changes in membrane-associated calcium that occur during cytokinin induced bud formation in Funaria hygrometrica Hedw. using the fluorescent Ca2+-chelate probe chlorotetracycline (CTC). In the target caulonema cells a localization of CTC fluorescent material becomes evident at the presumptive bud site 12 h after cytokinin treatment. By the time of the initial asymmetric division this region is four times as fluorescent as the entire caulonema cell. Bright CTC fluorescence remains localized in the dividing cells of the bud. To relate the changes in CTC fluorescence to changes in Ca2+ as opposed to membrane-density changes we employed the general membrane marker N-phenyl-1-naphthylamine (NPN). NPN fluorescence increases only 1.5 times in the initial bud cell. We conclude that the relative amount of Ca2+ per quantity of membrane increases in this localized area and is maintained throughout bud formation. We suggest that these increases in membrane-associated Ca2+ indicate a localized rise in intracellular free Ca2+ concentration brought about by cytokinin action.
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  • 34
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    Planta 152 (1981), S. 450-456 
    ISSN: 1432-2048
    Keywords: Calcium ; Cell elongation ; Gibberellin ; Lactuca ; pH and growth
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    Topics: Biology
    Notes: Abstract The relationship between calcium ions and gibberellic acid (GA3)-induced growth in the excised hypocotyl of lettuce (Lactuca sativa L.) was investigated. The short-term kinetics of growth responses were measured using a linear displacement transducer. Test solutions were added either as drops to the filter paper on which the hypocotyl stood (“non-flow-past”) or by switching solution flowing past the base of hypocotyl (“flow-past”), resulting in differences in growth behavior. Drops of CaCl2 added at a high concentration (10 mM) inhibited growth within a few minutes. This inhibition was reversed by ethylenediaminetetraacetic acid (EDTA). Drops of EDTA or ethyleneglycol-bis(2-aminoethylether)-tetraacetic acid caused a rapid increase in growth rate. Growth induced by EDTA was not further promoted by GA3. A continuous H2O flow resulted in growth rates comparable to those in response to GA3. Addition of CaCl2 to the flow-past medium inhibited growth and this inhibition was reversed by a decrease in CaCl2 concentration. The growth rate was found to be a function of CaCl2 concentration. When a constant CaCl2 concentration was maintained by the flow-past medium, a shift in pH from 5.5 to 4.25 had no obvious effect on hypocotyl elongation. Gibberellic acid was found to reverse the inhibitory effect of CaCl2, causing an increase in growth rate similar to that found previously when GA3 was added to hypocotyls grown in H2O under non-flow-past conditions. We propose that gibberellin controls extension growth in lettuce hypocotyl sections by regulating the uptake of Ca2+ by the hypocotyl cells.
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    European biophysics journal 9 (1982), S. 131-136 
    ISSN: 1432-1017
    Keywords: Chemotaxis ; Calcium ; Oscillation ; Dictyostelium ; Ionophore
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    Topics: Biology , Physics
    Notes: Abstract Migration of differentiated cells to a capillary containing cyclic AMP was enhanced in the presence of 1 mM CaCl2 and was virtually absent in the presence of 1 mM EGTA. Furthermore, the cells contracted and extended pseudopods to a capillary filled with the calcium ionophore A 23187. At short distances, migration to the tip of the capillary was observed. The ionophore also induced transient decreases of the optical density of suspended cells indicating changes of cell shape. These findings support the hypothesis that cyclic AMP-binding to cell surface receptors causes a local influx of calcium ions. These in turn lead to an increase of the cytosolic calcium concentration and subsequently to an activation of cell migration. Perturbing pulses of the ionophore induced permanent phase shifts of free-running light scattering oscillations. This result indicates that cytosolic calcium is an intrinsic component of the oscillatory system.
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  • 36
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    European journal of clinical pharmacology 18 (1980), S. 321-326 
    ISSN: 1432-1041
    Keywords: sotalol ; hypertension ; renal impairment ; chronic administration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten hypertensive patients with moderate to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.
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    European journal of clinical pharmacology 19 (1981), S. 19-24 
    ISSN: 1432-1041
    Keywords: hypertension ; guanfacine ; central antihypertensives ; withdrawal ; catecholamines
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 1. Guanfacine (2–6 mg/day) a centrally acting antihypertensive drug, was effective in controlling blood pressure in 5 essential hypertensives and lowered plasma noradrenaline and urinary catecholamine excretion. 2. Withdrawal of guanfacine by blind substitution of identical placebo tablets under observation in hospital led to a gradual recovery of blood pressure over 2–4 days. 3. Salivary flow, which was reduced on guanfacine, returned to pretreatment levels by 2 days after withdrawal and significantly exceeded control for the next two days. 4. Urinary catecholamine excretion returned to pretreatment levels by 3 days but did not exceed control levels during the period of study. 5. Plasma noradrenaline returned gradually to pretreatment levels, and by day 4 significantly exceeded them. 6. No patient experienced symptoms suggesting catecholamine excess although four out of five reported a headache from the second day onwards. 7. Guanfacine, a centrally acting drug which pharmacologically resembles clonidine, has a slow offset of hypotensive effect over 2–3 days. Symptoms or biochemical evidence of catecholamine excess were not encountered within 48 h of withdrawal, possibly reflecting the longer duration of action and plasma half-life of guanfacine.
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    European journal of clinical pharmacology 18 (1980), S. 225-229 
    ISSN: 1432-1041
    Keywords: metoprolol ; hypertension ; slow-release preparations ; maximal exercise power ; fatigue
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The treatment of hypertension with a single daily-dose of a beta-blocker gives rise to high peak-plasma concentrations 1.5 h after ingestion. After slow release-preparations of beta-blockers, the peak concentrations are half those produced by the conventional preparation at the same oral dose. A frequently occurring side-effect of beta-blocker therapy is fatigue. In this study the effect of a single dose of metoprolol 300 mg, 200 mg, 200 mg slow-release and a placebo on maximal exercise power was tested in 6 healthy subjects, 1.5 h and 24 h after ingestion. Maximal exercise power was significantly reduced 1.5 h after ingestion of metoprolol 300 mg and 200 mg. No change was found 1.5 h after 200 mg of a slow-release preparation. The possible reasons for reduced maximal exercise power are discussed. It is concluded that use of a beta-blocker for the treatment of hypertension in a single daily-dose regimen may be a reason to prefer a slow-release preparation.
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  • 39
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    European journal of clinical pharmacology 18 (1980), S. 399-401 
    ISSN: 1432-1041
    Keywords: prazosin ; hypertension ; central monoaminergic neurons ; monoamine metabolites
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six hypertensive patients were treated with prazosin up to a final dose of 3–4.5 mg/day. There was a significant reduction of blood pressure. The cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline, dopamine and serotonin were unchanged. This indicates that the antihypertensive effect is not mediated via central monoaminergic neurons as suggested by animal studies.
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    European journal of clinical pharmacology 18 (1980), S. 105-108 
    ISSN: 1432-1041
    Keywords: renin ; angiotensin ; aldosterone ; hypertension ; hypoaldosteronism ; pseudohypoaldosteronism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary There is increased activity of the renin, angiotensin, aldosterone (RAA) system in infancy and childhood. An inverse relationship between plasma renin, aldosterone and age has been demonstrated. In childhood hypertension due to renovascular disease or pyelonephritic scarring peripheral plasma renin is increased. Renal vein renin measurements in children with renal hypertension have proved valuable in predicting surgical curability of the underlying lesion. The upper limit of normal for the renal venous renin ratio in normotensive children without renal disease is 1.5. Pharmacological blockade of the RAA system has a place in diagnosis and treatment of hypertensive children. The plasma renin aldosterone profile is diagnostically useful in the investigation of salt-wasting disease and can easily distinguish between aldosterone biosynthetic defects and pseudohypoaldosteronism.
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    European journal of clinical pharmacology 18 (1980), S. 135-139 
    ISSN: 1432-1041
    Keywords: hypertension ; labetalol ; propranolol ; renal haemodynamics ; glomerular filtration rate ; blood pressure ; exercise ; renal blood flow
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of exercise on renal haemodynamics was examined in young patients with mild essential hypertension. Four groups of subjects were studied: 13 normotensive, healthy control subjects, and 15 untreated, 11 propranolol-treated, and 6 labetalol-treated patients. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured during four consecutive periods, a pre-exercise control period, two exercise periods with loads of 450 kpm/min and 600 kpm/min, respectively, and a post-exercise control period. In the untreated patients RPF and GFR were lower during exercise than in the normotensive control subjects, whereas no significant differences were found at rest. In the propranolol-treated patients the reduction in RPF and GFR during exercise was more pronounced than in the untreated hypertensives. In the labetalol-treated patients however, RPF and GFR were reduced only to the same degree as in the untreated hypertensives. The reduced renal blood flow in propranolol-treated patients may be attributed to a compensatory increase in sympathetic activity caused by an impaired cardiac response to exercise. The lack of reduction in renal blood flow during labetalol therapy could partly be related to alpha-adrenergic blockade in the renal vascular bed induced by labetalol, and partly to the smaller reduction in cardiac output during labetalol than during propranolol therapy.
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  • 42
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    European journal of clinical pharmacology 18 (1980), S. 231-235 
    ISSN: 1432-1041
    Keywords: molsidomine ; hypertension ; hypotension ; angina pectoris
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Molsidomine (M), a new long-lasting antianginal compound, was studied in 38 hypertensive patients to assess its antihypertensive properties. Six patients were selected for an acute, single dose comparative trial with placebo over 8 h after treatment. The remaining 32 patients were used in a 1 month trial to study the effect on BP of more prolonged treatment. Systolic, diastolic and mean BP were significantly reduced after a single dose of M 4 mg, and the effect lasted for about 8 h. M also inhibited the hypertensive response to isometric exercise in handgrip tests performed 1 and 8 h after M ingestion. A dose-related decrease in systolic and diastolic BP in the one month trial was also observed. In addition to its antianginal properties, M appears to possess an interesting effect on BP in mildly to moderately hypertensive patients. A fall in BP is also a valuable effect in coronary patients with augmented metabolic demands of the heart.
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  • 43
    ISSN: 1432-1041
    Keywords: hypertension ; nifedipine ; beta-adrenoceptor blockade ; hypotensive action ; adverse effects ; combination therapy
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effect of nifedipine (10–20 mg t.i.d.) given alone, or in combination with a beta-adrenoceptor blocking drug, was related to the observed plasma concentration during one dosage interval at steady-state (Pl-Nifss). The study was carried out as a within-patient comparison of treatment with nifedipine or placebo for 4 weeks. A highly significant reduction in blood pressure was obtained during monotherapy, as well as during combined treatment. The blood pressure reduction when nifedipine was added to beta-adrenoceptor blockade was of the same magnitude as that observed on nifedipine monotherapy. A considerable variation in Pl-Nifss was noted (range: 2–70 ng/ml). No significant correlation was found between the percentage reduction in blood pressure and Pl-Nifss in either of the two groups. There was a close relationship between Pl-Nifss and the concentration found 4 h after the morning dose. Side-effects were common during nifedipine monotherapy and were the reason for discontinuation of treatment in 4 of 18 patients. In contrast, none of the 9 patients on combined treatment dropped-out. In neither of the treatment groups was there any evidence for sodium retention and volume expansion during the first 4 weeks expressed as weight gain or signs of cardiac insufficiency. However, in 13 patients who continued on long-term treatment for 3–14 months, a definite need for concomitant diuretic therapy was found. The results indicate that nifedipine is effective in lowering blood pressure in patients with mild to moderate essential hypertension, either when given alone or in addition to beta-adrenoceptor blockade. It appears best tolerated as combination therapy. Long-term treatment requires addition of a diuretic. Pl-Nifss did not seem to be a major determinant of the magnitude of the hypotensive response.
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  • 44
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    European journal of clinical pharmacology 18 (1980), S. 375-382 
    ISSN: 1432-1041
    Keywords: calcium antagonist ; verapamil ; hypertension ; vasodilators ; plasma renin activity ; mode of action ; sodium balance ; fluid balance
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 12 in-patients with moderate uncomplicated hypertension, maintained on constant sodium intake for 15 days, single-blind oral administration of verapamil 80–160 mg t. i. d. for 10 days had a significant antihypertensive effect: in the supine position systolic blood pressure decreased from 177±5 to 150±3 mmHg, and diastolic pressure from 111±3 to 96±2 mmHg; standing values were similarly lowered from 171±7 to 143±4 mmHg, systolic, and from 118±4 to 97±2 mmHg, diastolic. The heart rate did not show any significant change (from 79±3 to 77±2 beats/min, supine, and from 92±3 to 87±3 beats/min, upright). The antihypertensive effect was uniform throughout the day, being similar 2, 3, 6 and 8 h after administration of a dose. Dynamic exercise (75–100 watts on a cycle-ergometer) caused identical increases in arterial pressure and heart rate on the last day of placebo and again on the last day with verapamil, but the peak levels of systolic pressure reached during exercise were lower after verapamil than with placebo, because of the lower blood pressure before exercise. Reduction of arterial pressure by verapamil was not accompanied by increased plasma renin activity, or by renal retention of sodium and water: there was a small increase in sodium excretion, at least during the first days of verapamil administration (from 107±15 to 113±15 mEq Na+/day), and a slight significant reduction in body weight (from 74.2±3.7 to 73.5±3.7 kg). It is concluded that oral administration of verapamil significantly lowers blood pressure without simultaneously inducing cardiac stimulation, renin secretion or salt and water retention.
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  • 45
    ISSN: 1432-1041
    Keywords: guanfacine ; methyldopa ; hypertension ; rebound hypertension ; withdrawal symptoms ; plasma noradrenaline
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine patients with essential hypertension completed a clinical trial designed to study the effects and side effects of administration and withdrawal of guanfacine (2 mg tds) and methyldopa (250 mg tds) on blood pressure, heart rate, and plasma noradrenaline. The study was of randomised doubleblind crossover design with two active therapy phases of eight weeks each, preceded by an initial 4 week placebo phase, separated by an intermediate 2 week placebo phase, and followed by a final 2 week placebo phase. Patients took bendrofluazide 5 mgs daily throughout the entire trial, during both active and placebo periods. Each patient was admitted to hospital at the end of the 8 week active treatment phases, so that the effects of drug withdrawal on blood pressure, heart rate, plasma noradrenaline and side reactions, could be closely observed and monitored. The main conclusions from analysis of the results were that: 1. The hypotensive efficacy of guanfacine and methyldopa was very similar in the doses used, each of the two drugs lowering the supine mean arterial pressure by about 15 mm Hg and the supine diastolic pressure by about 10 mm Hg. 2. The frequency of side effects was greater with guanfacine than with methyldopa. 3. There was no signficant early rebound phenomenon after withdrawal of either methyldopa or guanfacine. 4. There was tendency for the blood pressure to rise slowly and marginally above initial placebo values, 2 weeks after cessation of guanfacine treatment though this was not significant. It was however, accompanied by a significant increase in plasma noradrenaline at 2 weeks. This was not seen 2 weeks after cessation of methyldopa. There was no single incidence of worrying rebound hypertension or withdrawal symptoms either early or late in any patient following cessation of methyldopa or guanfacine.
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  • 46
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    European journal of clinical pharmacology 21 (1982), S. 287-291 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; hypertension ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined β-blocker and diuretic therapy (average supine blood pressure 178/103 mm Hg) the addition of tolmesoxide (300–900 mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 µg/ml compared to 2.97 µg/ml) and a significant increase in the time to reach peak plasma concentration (1.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.
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  • 47
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    European journal of clinical pharmacology 21 (1982), S. 363-367 
    ISSN: 1432-1041
    Keywords: labetalol ; clonidine ; hypertension ; dose titration ; bendrofluazide ; side effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effect of labetalol (L) was compared with that of clonidine (C) in a randomized cross-over study in 17 hypertensive outpatients on bendrofluazide (B). After treatment for two weeks with B (5 mg qd), either L (100 mg tid) or C (0.1 mg tid) was given and their doses were titrated at 2-weekly visits until normotension was achieved, or intolerable side-effects occurred. The treatment with B and L or C was then continued in a cross-over fashion for two 6-week periods, with 3 week diuretic washouts and subsequent dose-titration periods between the treatment periods. At the end of B, the supine blood pressure (BP) was 156/101, and at the end of B + L and B + C it was 136/91 (p〈0.001) and 137/91 (p〈0.001), respectively, pooling the data from both periods. At the end of B, the standing BP was 155/115, and at the end of B + L and B + C 134/100 (p〈0.001) and 139/106 (p〈0.001), respectively. The mean daily doses required were L 476mg and C 0.335 mg. On a weight basis, labetalol had about 1/1400 of the potency of clonidine. 12 patients complained of tiredness and dry mouth on clonidine and 2 patients of unsteadiness on labetalol. Labetalol caused a psoriasiform rash on the hands in one patient and limb weakness in one patient.
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  • 48
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    European journal of clinical pharmacology 22 (1982), S. 7-14 
    ISSN: 1432-1041
    Keywords: prazosin ; baroreflexes ; hypertension ; reflex tachycardia ; alpha adrenergic blockade ; dopamine-beta-hydroxylase
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prazosin is a post synaptic alpha adrenergic blocker effective in hypertension, whose hypotensive effect is unaccompanied by reflex tachycardia or hyperreninemia, nor by other evidence of increased sympathetic activity. We studied the baroreceptor reflex arc as a potential mediator of these effects. Twenty-two essential hypertensive men were treated with prazosin alone versus placebo, and experienced a blood pressure fall (from 114.8±3.6 down to 101.1±2.5 mm Hg,p〈0.005) unaccompanied by any change in heart rate, plasma renin activity, or several other indices of sympathetic nervous system activity (plasma dopamine-β-hydroxylase activity; urinary excretion of free catecholamines and vanillyl mandelic acid; allp〉0.1). Concomitant with the blood pressure fall, there was a significant depression of baroreflex arc sensitivity, from 11.4±2.0 ms/mmHg down to 6.6±1.9 ms/mmHg (p〈0.05), without an associated change in cardiac vagal inhibition (291.2±46.2 versus 300.3±19.2 ms,p〉0.1). Baroreflex arc sensitivity depression may in part explain the lack of reflex sympathetic outflow noted during prazosin treatment of hypertension.
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  • 49
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    European journal of clinical pharmacology 22 (1982), S. 197-201 
    ISSN: 1432-1041
    Keywords: hypertension ; oxprenolol ; indomethacin ; drug interaction ; hypotensive effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A double-blind, cross-over study in 16 patients with essential hypertension was carried out, to evaluate any possible interference by indomethacin, a known prostaglandin-synthetase inhibitor, with the antihypertensive effect of oxprenolol, a non-selective beta-adrenoceptor blocking agent. Both indomethacin and oxprenolol, as well as the two drugs combined, inhibited plasma renin activity; no change was found in urinary sodium excretion or body weight. Oxprenolol alone caused a highly significant decrease in the systolic (−10.4 mmHg,p〈0.001), diastolic (−7.4 mmHg,p〈0.001) and mean (−7.7 mmHg,p〈0.01) blood pressures, whereas indomethacin did not influence blood pressure. When the two drugs were given in combination, blood pressure decreased (systolic: −5.9 mmHg; diastolic: −4.0 mmHg; mean: −4.6 mmHg), but the changes induced in blood pressure were reduced by about 50% when compared with those in the oxprenolol alone period. The data show that indomethacin seems to interfere with the antihypertensive effect of oxprenolol, by an action which may be due to the inhibition of prostaglandin synthesis.
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  • 50
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    European journal of clinical pharmacology 20 (1981), S. 163-168 
    ISSN: 1432-1041
    Keywords: hypertension ; captopril ; cardiac output ; extracellular fluid volume ; renin
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of captopril 450 mg/day for 4 weeks on blood pressure, heart rate, cardiac output and extracellular fluid volume were compared in severe, often drug-resistant hypertension (n=23), mild to moderate hypertension associated with renal artery stenosis (n=10) and mild to moderate essential hypertension (n=20). Plasma renin in the three groups was 52±19, 58±17 and 20±4 µU/ml (mean ± SEM), respectively. Blood pressure fell by 18±4%, 21±2% and 18±1%. The pressure drop was mainly due to a fall in peripheral vascular resistance. Addition of the diuretic hydrochlorothiazide (25–100 mg/day) caused a further fall in resistance. Despite the vasodilator effect of captopril, reflex cardiostimulation and reactive fluid retention were not observed. In severe hypertension, captopril alone was more effective in lowering blood pressure than combined diuretic-betablocker-vasodilator therapy. Moreover, cardiac output in these patients was higher and resistance was lower after captopril than during combined treatment. Thus, captopril was capable of normalising the abnormal haemodynamic state in patients with essential hypertension, and in hypertension associated with renal artery stenosis. Despite marked differences in pre-treatment plasma renin, the effects of captopril on systemic haemodynamics were similar in all the patients.
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  • 51
    ISSN: 1432-1041
    Keywords: vasodilator ; hypertension ; haemodynamic effects ; renal plasma flow ; renal tubular function ; plasma renin activity ; aldosterone ; Ro 12-4713
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Selected cardiovascular and endocrine effects of the new oral vasodilator Ro 12-4713 have been evaluated in an acute single dose study. In five patients with essential hypertension, Ro 12-4713 caused a dose-dependent decrease in supine and upright blood pressure and an increase in heart rate. Initial effects occurred one to 2 h after drug ingestion and maximal effects were noted after five hours and persisted for at least 8 h. Blood pressure was normalized, and the antihypertensive and chronotropic effects persisted for 24 h after a dose of about 300 mg/1.73 m2. Plasma and urinary norepinephrine and plasma renin levels tended to be raised, whereas plasma and urinary epinephrine and plasma aldosterone did not change. Changes in supine heart rate were inversely correlated with changes in mean blood pressure (r=−0.60; P〈0.02), and positively with those in plasma norepinephrine (r=0.55; P〈0.05) and renin (r=0.62, P〈0.01); changes in supine plasma renin level were also inversely correlated with those in mean blood pressure (r=−0.65; P〈0.01), and positively with those in plasma norepinephrine (r=0.58; P〈0.05). 24 h-urinary sodium excretion was significantly (P〈0.001) decreased; it was positively correlated with mean blood pressure (r=0.51; P〈0.05) and inversely with supine plasma renin activity (r=−0.63; P〈0.01). In six normal subjects and six patients with essential hypertension, effective renal plasma flow and the renal clearance of sodium, potassium, calcium and uric acid were not significantly altered five hours after a dose of Ro 12-4713 of about 250 mg/1.73 m2; glomerular filtration rate tended to be slightly decreased, and filtration fraction was significantly (P〈0.05) reduced in the hypertensive patients. At the same time blood pressure was decreased and plasma norepinephrine (P〈0.01) and renin (ns) were slightly increased in both groups. Ro 12-4713 in a single oral dose of about 300 mg appeared to be a potent, long acting, hypotensive vasodilator.
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  • 52
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    European journal of clinical pharmacology 22 (1982), S. 495-499 
    ISSN: 1432-1041
    Keywords: hypertension ; cyclothiazide ; hydrochlorthiazide ; thiazide diuretics ; potassium-sparing diuretics ; saluretic effect ; hypokalaemia ; hyperuricaemia ; amiloride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive, saluretic and hypokalaemic effects of a small dose of cyclothiazide (2.5 mg daily) were compared with those of a conventional dose of an hydrochlorthiazide-amiloride hydrochloride combination (50+5 mg daily). Both preparations were given to 13 patients with mild (WHO I) hypertension in a cross-over manner for six weeks, with an intervening wash-out phase of three weeks. The antihypertensive efficacy of cyclothiazide was well comparable to that of the hydrochlorthiazide-amiloride combination, although cyclothiazide tended to inhibit renal sodium reabsorption less than the combination. Cyclothiazide tended to cause hypokalaemia, apparently due to increased potassium loss, but with the present dosage none of the 13 patients developed marked hypokalaemia (serum potassium less than 3.3 mmol/l). Both drugs led to a comparable increase in serum urate concentration. Neither of the preparations affected creatinine or free-water clearance. The results suggest that even in relatively small doses thiazides effectively decrease blood pressure, and combining thiazides with potassium-sparing diuretics is advantageous only in patients with marked hypokalaemia and its associated risks.
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  • 53
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    European journal of clinical pharmacology 26 (1984), S. 309-313 
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; therapeutic window ; steady state concentration ; pharmacokinetics ; cardiovascular effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 µg/kg to patients with essential hypertension (n=6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time — plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the antihypertensive effect was established. At a plasma clonidine concentration of 0.65±0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.
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  • 54
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    European journal of clinical pharmacology 26 (1984), S. 331-334 
    ISSN: 1432-1041
    Keywords: metoprolol ; oxprenolol ; hypertension ; beta-blockers ; HDL-cholesterol ; intrinsic sympathomimetic activity ; cardioselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of the present study was to evaluate whether a reduction in HDL-cholesterol is peculiar to non cardioselective beta blockers or whether it is also produced by cardioselective beta1-blockers. 16 patients with primary arterial hypertension on a balanced isocaloric diet were given oxprenolol 120 to 240 mg/day or metoprolol 100 to 200 mg/day in a random cross-over study. No significant change was observed after either treatment in fasting blood glucose, serum total cholesterol and triglycerides. HDL-cholesterol concentration was significantly decreased on metoprolol, from 41 to 36 mg/dl (p〈0.05), while oxprenolol did not affect it at all. The difference might depend on intrinsic sympathomimetic activity which is possessed by oxprenolol and which metoprolol lacks.
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  • 55
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    European journal of clinical pharmacology 26 (1984), S. 549-553 
    ISSN: 1432-1041
    Keywords: pafenolol ; hypertension ; antihypertensive therapy ; beta1-blocking agent ; exercise tests ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pafenolol, a new selective adrenergic beta1-blocking agent, has been tested for the first time in 6 hypertensive patients. After single oral doses of pafenolol 25 to 100 mg, there was a marked reduction in heart rate and systolic blood pressure during exercise tests. These effects were dose dependent. A significant positive correlation was found between the reduction in heart rate during exercise and the plasma level of pafenolol 5 hours after drug intake (correlation coefficient r=0.94). Side effects were mild and seemed to be dose dependent. It is concluded that this new beta1-blocking agent was effective in reducing blood pressure and was well tolerated.
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  • 56
    ISSN: 1432-1041
    Keywords: etozolin ; ozolinone ; furosemide ; hypertension ; renin ; catecholamines ; chronic renal failure ; steady state kinetics ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect on urinary electrolyte excretion, renin release and plasma norepinephrine of single oral doses of 400 mg etozolin (E) and of 40 mg furosemide (F) were studied in hypertensive patients with normal (n=6) and impaired kidney function (n=6). E caused a marked saluresis up to 24 hours, showing its long duration of action. F, however, displayed a brief, brisk peak diuresis, followed by a rebound from the 4th to the 24th hours. The brisk peak diuresis induced by F was associated with pronounced release of renin, almost twice that induced by E. In chronic renal failure the renin release in relation to the magnitude of the diuresis was increased, i.e. the sensitivity of these patients to changes in water homeostasis was increased. E and F stimulated the sympathetic system to roughly the same extent. Patients with essential hypertension had higher plasma levels of norepinephrine than hypertensive patients with chronic renal failure. In addition, hypertensive patients with normal renal function (n=4) and varying degrees of renal impairment (n=11) were also given 400 mg daily for 2 weeks. Effects on blood pressure and electrolyte homeostasis were monitored, as well as the plasma kinetics of metabolite I, ozolinone. At the end of the 2 week treatment E had significantly lowered systolic (−12 mm Hg) and diastolic (−9 mm Hg) blood pressure, and had produced a significant loss of body weight, without altering plasma electrolytes or blood chemistry. There was no accumulation of the effective metabolite ozolinone under conditions of severe impairment of kidney function. It is concluded that E can effectively control high blood pressure in patients with normal and impaired kidney function. Its effective metabolite ozolinone did not accumulate in chronic renal failure.
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  • 57
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    European journal of clinical pharmacology 27 (1984), S. 397-405 
    ISSN: 1432-1041
    Keywords: indapamide ; hypertension ; cardiovascular reflexes ; diuretic effect ; blood pressure variability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine elderly and 11 young hypertensives underwent continuous ambulatory monitoring of blood pressure (BP), assessment of cardiovascular reflexes and M-mode echocardiography as hospital in-patients prior to treatment with once-daily indapamide (2.5 mg). They were followed as out-patients for 4 months during which time casual BP was measured at monthly intervals. The patients were then readmitted to hospital and studied using the same protocol under similar standardised conditions. The results showed that indapamide reduced casual and ambulatory BP in both young and elderly although the most marked effect was seen on systolic BP. Assessment of cardiovascular reflexes indicates that at least part of the hypotensive action of indapamide is due to a diuretic effect. Treatment with indapamide has comparable results on both young and elderly.
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  • 58
    ISSN: 1432-1041
    Keywords: atenolol ; hypertension ; plasma renin activity ; pharmacokinetics ; pharmacodynamic effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To show whether repeated administration of atenolol for several days would influence its pharmacokinetic parameters and the extent and duration of the pharmacologic responses, the plasma level of atenolol and changes in heart rate, blood pressure and plasma renin activity were measured in 12 hypertensive patients at various times of day (9 a. m., 12 noon, 3 p. m. and 7 p. m.) after oral administration of the first dose of atenolol 100 mg, again during the 7th and 14th days of continued once-daily administration of the same dose, and finally during the three days following withdrawal of the drug. The peak plasma concentration of atenolol (about 600 ng/ml) was found 3 h after administration of the first dose, and measurable amounts (50–70 ng/ml) were found after 24 h. None of the pharmacokinetic characteristics were changed by administration of a single daily dose for two weeks. After withdrawal of the drug, detectable amounts of atenolol were found in plasma for at least 48 h. The first dose of atenolol caused prompt (3 h) and prolonged (up to 24 h) lowering of supine and standing systolic and diastolic blood pressures, slowing of supine and standing heart rate, reduction of the blood pressure and heart rate responses to dynamic exercise, and a decrease in plasma renin activity. The extent and time-course of all these responses were not influenced by repeated once-daily administration of the 100 mg dose for two weeks. Most of the effects continued during the withdrawal days, the lowering of blood pressure being somewhat more prolonged than the slowing of heart rate. It is concluded that a once-daily dose of atenolol 100 mg decreases blood pressure and heart rate throughout the following 24 h, without excessive daily fluctuation in its effects, and without signs of tolerance or accumulation.
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  • 59
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    European journal of clinical pharmacology 17 (1980), S. 239-241 
    ISSN: 1432-1041
    Keywords: timolol ; hypertension ; dose ranging ; double-blind trial
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nine previously untreated patients with mild-moderate hypertension were included in a dose-ranging double-blind trial to determine the effectiveness of daily versus thrice daily timolol administration. In 8 patients control of blood pressure was equally effective though with significantly lower heart rate achieved in the once daily group. One patient was not satisfactorily controlled on the daily regimen demonstrating that many but not all hypertensives can be controlled with daily administration of timolol.
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  • 60
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    European journal of clinical pharmacology 18 (1980), S. 391-394 
    ISSN: 1432-1041
    Keywords: propranolol ; hypertension ; beta-adrenergic blockade ; exercise heart rate ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of propranolol in 16 hypertensive patients was compared after the first oral dose of 80 mg and during chronic treatment with 80 mg bd. The degree of beta-adrenergic blockade was estimated by the reduction in maximal exercise heart rate. No significant change in plasma half-life occurred and there was no correlation between the mean steady-state propranolol concentration and beta-adrenergic blockade or antihypertensive effect. A linear relationship was observed between the decrease in blood pressure and the reduction in heart rate during maximal exercise. Therefore, the antihypertensive effect of propranolol can be explained by its peripheral beta-adrenergic blocking properties.
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  • 61
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    European journal of clinical pharmacology 19 (1981), S. 25-32 
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; baroreceptor reflex ; mode of action ; sympathetic activity ; urinary catecholamines
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acute studies of clonidine suggest that it lowers blood pressure by central enhancement of baroreflex sensitivity coupled with diminished evidence of sympathetic outflow, but longterm clonidine data have not been conclusive. We examined effects of one month of low dose clonidine (0.4 ± 0.15 mg/day) alone in 13 essential hypertensive men, assessing several biochemical indices of sympathetic function, as well as physiologic parameters, including baroreflex sensitivity, the cold pressor test, and the hypotensive response to alpha adrenergic blockade. Clonidine diminished mean arterial pressure (from 104±5 to 84±3 mmHg;p〈0.01), without associated changes in several biochemical parameters of sympathetic outflow (urinary excretion of catecholamines, metanephrines, and vanillylmandelic acid; allp〉0.1). Circulatory baroreflex function was not enhanced by clonidine, during either the amylnitrite test or the phenylephrine test, before or after parasympathetic blockade with atropine. The cold pressor test, an index of efferent sympathetic pressor function, was also unaltered. The enhanced mean arterial pressure response to phentolamine during clonidine therapy (from a fall of 14.8±4.3 to 39.4±5.2 mmHg,p〈0.01), suggested an increase in alpha adrenergic vascular tone, perhaps mediated by clonidine's alpha agonist properties in vascular smooth muscle. The antihypertensive mechanism of longterm low dose clonidine cannot reliably be ascribed either to baroreflex enhancement or to suppression of sympathetic outflow.
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  • 62
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    European journal of clinical pharmacology 19 (1981), S. 113-118 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; vasodilators ; hypertension ; side-effects ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and a diuretic. After a 50 mg oral dose mean (± SD) peak plasma concentration of T was 1.13±0.29 µg/ml−1 and occurred 0.79±0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37±0.09 µg/ml−1 at 1.92±1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78±0.77 h and 10.78±7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50–200 mg t. i. d. During in-patient administration of 600–900 mg T daily (n=6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n=4) was associated with a significant fall in mean systolic but not diastolic bp (lying −15/+1 mm Hg. standing −25/−8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean ± SD) significantly from 55±5/min to 66±8/min following 900–1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600–900 mg daily eventually necessitated drug withdrawal. In its present from T is not recommended for the treatment of hypertension.
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  • 63
    ISSN: 1432-1041
    Keywords: carteolol ; hydrochlorthiazide ; amiloride ; hypertension ; double-blind clinical trial
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effect of carteolol, a new β-blocking agent, added to basal diuretic treatment (hydrochlorthiazide 50 mg and amiloride 5 mg) has been assessed in a controlled trial in 17 patients with mild-to-moderate hypertension. The trial was divided into 4 stages: 1) run-in period with no antihypertensive treatment, 2) diuretic period (the diuretic being continued as basal treatment during the two following periods), 3) carteolol titration period, and 4) double-blind cross-over period comparing carteolol with placebo, which lasted 2 times 4 weeks. Although the diuretic effectively reduced the blood pressure, 17 of the 20 patients originally studied still had an elevated diastolic blood pressure (≧ 95 mmHg) after the diuretic period, thus fulfilling the inclusion criteria for the study. During the titration period carteolol 5 to 20 mg b. i. d. significantly reduced the elevated blood pressure. The blood pressure was reduced to normal in all 17 patients, although in two patients this occurred only during the double-blind period. During the double-blind period, the dose of carteolol was used which had given a satisfactory response during the titration period. The blood pressure in the 14 patients who completed the trial remained low both with carteolol and placebo during the double-blind stage, and was only slightly lower with carteolol than with placebo. This is probably due to a “carry-over” effect. Three patients discontinued the trial due to side effects (1 urticaria, 1 insomnia and 1 nausea) while on carteolol. There was no other difference between carteolol and placebo in the number or severity of side effects.
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  • 64
    ISSN: 1432-1041
    Keywords: beta-blocker ; hypertension ; clonidine ; plasma catecholamines ; metoprolol ; propranolol ; blood pressure responses ; isometric work ; dynamic work
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of metropolol (beta1-selective), propranolol (nonselective) and clonidine (central alpha-stimulant) on plasma norepinephrine, blood pressure and heart rate were assessed at rest, during isometric work and dynamic exercise in 15 patients with moderate hypertension. Metroprolol resulted in a lower diastolic blood pressure during isometric and dynamic exercise than propranolol, which was paralleled by a lower plasma norepinephrine level during dynamic work; both beta-adrenergic blocking compounds resulted in a lower heart rate in all test situations than that obtained with clonidine; clonidine produced similar control of diastolic blood pressure to that obtained with the beta-adrenergic blocking agents, but did not clearly attenuate the systolic blood pressure response to dynamic exercise. Plasma norepinephrine concentrations tended to be lowest following clonidine, especially during dynamic work. The findings support the hypothesis that the central action of clonidine inhibits peripheral release of norepinephrine, but is insufficient to attenuate cardiac stimulation by physical exercise. The fact that propranolol caused higher plasma norepinephrine concentrations than metoprolol during exercise may explain the difference in the blood pressure responses during exercise.
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  • 65
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    European journal of clinical pharmacology 21 (1982), S. 445-449 
    ISSN: 1432-1041
    Keywords: pindolol ; hypertension ; retard formulation ; plasma levels ; side effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 36 out of 52 patients with essential hypertension, whose blood pressure was not normalized with pindolol 15 mg per day, were treated with 30 mg per day for four to six weeks. Pindolol was administered in random order, either as 15 mg twice daily or as one 30 mg retard tablet once daily. Blood pressure was lowered from mean pretreatment levels of 174/111 mmHg to 149/98 mmHg by 15 mg b.d., and to 145/97 mmHg by 30 mg retard. In five patients diurnal variations in blood pressure and plasma pindolol levels were determined. At all times during the day blood pressure was at least as well controlled by 30 mg retard as by 15 mg b.d. Plasma concentration maxima were similar with both forms, but a higher concentration was maintained for a longer time after the retard tablet. Pindolol 30 mg was well tolerated and the incidence of side effects was lower than during treatment with 15 mg b.d. Thus, patients requiring high doses of pindolol for control of hypertension can safely and conveniently be treated with a single tablet of 30 mg pindolol retard.
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  • 66
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    European journal of clinical pharmacology 21 (1982), S. 473-477 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; vasodilators ; heart failure ; haemodynamics ; hypertension ; sulphoxide
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effect of Tolmesoxide, a new sulphoxide chemically dissimilar from other vasodilators, was investigated in eight patients with chronic heart failure subsequent to ischaemic heart disease and/or hypertension. Tolmesoxide significantly increased the cardiac output and reduced the indices of systemic vascular resistance, the mean pulmonary arterial pressure and left ventricular filling pressure in most patients studied. These changes were observed both as acute and chronic effects. No significant effect on the mean arterial pressure, heart rate or myocardial oxygen supply/demand was observed. Tolmesoxide appeared to be therapeutically potent by both intravenous and oral routes.
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  • 67
    ISSN: 1432-1041
    Keywords: vasodilator ; hypertension ; antihypertensive treatment ; catecholamines ; renin ; aldosterone ; blood volume
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive efficacy and endocrine profile of the new antihypertensive agent, Ro 12-4713, were evaluated in 23 patients (17 men and 6 women) with moderate to severe arterial hypertension. Following addition of Ro 12-4713 to pre-existing therapy with diuretics and beta-blockers or sympatholytics, blood pressure in most of the patients was normalized within one month by a daily dose of 60 to 120 mg. Heart rate was only slightly increased. Orthostatic hypotension was not observed. Weight gain or oedema formation occurred in 14 patients within the first four weeks, but could be controlled satisfactorily by intensified diuretic therapy. Increased hair growth occurred in most of the patients. After a mean duration of treatment of 2.8 months, plasma volume and plasma and urine sodium were unaltered, and plasma potassium was slightly decreased. Plasma renin activity was doubled, whereas plasma aldosterone concentrations were unaltered. Plasma norepinephrine levels were high before and increased only slightly during chronic Ro 12-4713 treatment, whereas urinary norepinephrine excretion was unchanged. Plasma and urinary epinephrine were unaltered by Ro 12-4713. Ro 12-4713 appears to be a potent vasodilator for the combination treatment of hypertension in men.
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  • 68
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    European journal of clinical pharmacology 22 (1982), S. 285-288 
    ISSN: 1432-1041
    Keywords: hypertension ; plasma adrenaline ; plasma noradrenaline ; isoprenaline response ; noradrenaline response ; salivation ; parasympathetic nervous system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Parameters of the autonomic nervous system were studied in normotensive subjects (NT; standing blood pressure (BP)≤125/85 mmHg) and in subjects with borderline hypertension (BHT; 140/90≤standing BP〈60/100 mmHg). No differences in plasma noradrenaline and adrenaline levels were found between NT and BHT subjects, neither at rest nor during exercise at 75% of maximum work capacity. The dose of noradrenaline required to increase systolic BP by 10 mmHg was significantly higher in NT than in BHT subjects (5.13±0.42 vs 3.50±0.57 µg · min−1). No difference between NT and BHT subjects was found in the dose of isoprenaline required to increase heart rate by 20 beats · min−1 (1.21±0.12 vs 1.09±0.11 µg · min−1). Resting salivary flow was significantly lower in BHT than in NT subjects (0.39±0.06 vs 0.98±0.06 g · min−1), suggesting decreased parasympathetic activity in the former group. The enhanced pressor effect of noradrenaline, together with the decreased parasympathetic activity, could explain the elevated blood pressure and heart rate in subjects with borderline hypertension.
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  • 69
    ISSN: 1432-1041
    Keywords: bopindolol ; hypertension ; beta-blocker ; blood pressure ; plasma renin ; plasma catecholamines
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bopindolol (LT 31-200), a new, long-acting, non-selective beta-blocker, was given as monotherapy to 13 patients, 12 with essential hypertension and 1 with renovascular hypertension. After a placebo period of 4–6 weeks, bopindolol was given once daily, starting with 1 mg and subsequently increasing at two-weekly intervals to 2 and 4 mg once daily until a diastolic blood pressure⩽90 mmHg was achieved. The effective dose was continued for 12 weeks. In 10 patients plasma levels of renin, noradrenaline, adrenaline and cholesterol were measured during placebo and after 3 months of therapy. Blood pressure and heart rate were lowered significantly during bopindolol treatment. The mean effective dose was 2.2 mg per day. In 10/13 patients a diastolic blood pressure⩽90 mmHg was achieved. Side effects were minimal. Changes in plasma noradrenaline and adrenaline were small and not significant, but renin and cholesterol were significantly reduced. Thus, LT 31-200 is an effective and well tolerated beta-blocker when given in a once daily dosage.
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  • 70
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    European journal of clinical pharmacology 20 (1981), S. 335-338 
    ISSN: 1432-1041
    Keywords: atenolol ; atherosclerosis ; hypertension ; serum lipoproteins
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum lipoproteins were determined in 15 patients before and during antihypertensive treatment with atenolol 0.1–0.2 g/day for a mean of 8 months. The mean blood pressure fell from 171/103 to 154/93 mm Hg (p〈0.05). Significant lipoprotein changes were an increase in very low density triglycerides (VLDL-TG) from 1.21±0.95 (SD) to 1.62±1.24 mmol/l (p〈0.01) and in low density (LDL) TG from 0.46±0.12 to 0.51±0.12 mmol/l (p〈0.05). Together, these TG increases resulted in development of hypertriglyceridaemia in 7/15 patients during atenolol treatment. No effect on whole serum cholesterol or on the high density lipoprotein cholesterol concentrations were found. Thus, some patients on long term treatment with atenolol seem to receive the benefit of normotension at the cost of hypertriglyceridaemia. This may have practical implications, since hypertriglyceridaemia constitutes an important risk factor for atherosclerosis.
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  • 71
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    European journal of clinical pharmacology 20 (1981), S. 347-349 
    ISSN: 1432-1041
    Keywords: reserpine ; syrosingopine ; prolactin secretion ; hypertension
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 mild hypertensive women, reserpine induced a significant increase in mean plasma PRL, both under basal conditions (from 6.6±0.9 to 17.9±2.9 ng/ml), and on repeated determinations during the day. In contrast to reserpine, the administration of syrosingopine, a synthetic compound derived from reserpine, to the same subjects was not followed by a significant change in prolactin level. Beyond their pharmacological interest, these results are of clinical importance when considering that rauwolfia alkaloids are used for long term treatment, and that an increase in PRL levels is important in pathology, both in relation to the function of the hypophyseogonadal axis and in view of its possible facilitation of the growth and development of mammary cancer.
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  • 72
    ISSN: 1432-1041
    Keywords: hypertension ; nifedipine ; beta-adrenoceptor blockade ; long-term treatment ; adverse effects ; propranolol ; timolol ; metoprolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effect of nifedipine during long-term therapy was investigated in 5 patients receiving nifedipine as the sole drug and in 10 patients who had nifedipine in combination with a beta-adrenoceptor blocking drug. Nifedipine monotherapy was problematic because of side-effects and development of resistance to therapy after a few months. In patients who received the combined therapy significant and stable blood pressure reductions were maintained during the whole observation period (12–33 months). However, the occurrence of peripheral oedema in 4 of the patients necessitated the addition of a thiazide diuretic. It is concluded that nifedipine is not a first choice drug for the long-term treatment of arterial hypertension. When given in addition to a beta-blocker it is well tolerated and powerful but fluid retention may occur and if not counteracted by a diuretic it will limit the antihypertensive potential of the drug.
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  • 73
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    European journal of clinical pharmacology 23 (1982), S. 197-201 
    ISSN: 1432-1041
    Keywords: nifedipine ; hypertension ; low dose ; plasma concentration ; acute and long-term treatment
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute and long-term hypotensive effects of low doses of nifedipine, and the correlation between the fall in the blood pressure (BP) and the plasma nifedipine concentration, were investigated in patients with essential hypertension. The oral administration of nifedipine 5 mg rapidly decreased BP from 163±22/101±10 to 127±12/82±9 mmHg (mean±SD; p〈0.001), and increased heart rate from 72±8 to 76±6 beats/min (p〈0.05), plasma renin activity rose from 1.2±0.6 to 1.4±0.8 ng/ml/h (p〈0.05), and plasma nifedipine concentration was 75.6±22.0 ng/ml 30 min after administration (n=7). The nifedipine concentration was significantly correlated both with the fall in BP (r=0.410, p〈0.02, n=31) and the rise in the heart rate (r=0.412, p〈0.02, n=31). Treatment with nifedipine 5 mg t.d.s. alone or in combination either with propranolol 10 mg t.d.s., or thiazide 1 tablet daily, or propranolol and thiazide, controlled BP in 36 patients during the 22 week study period. During the long-term nifedipine therapy, the plasma nifedipine level was significantly correlated with the fall in systolic (r=0.577, p〈0.01, n=20) and diastolic (r=0.595, p〈0.01, n=20) BP. It was concluded that the plasma nifedipine concentration could be correlated with the fall in BP, and that low doses of nifedipine, either as monotherapy or in combination, were effective in the acute and long-term treatment of patients with essential hypertension.
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  • 74
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    European journal of clinical pharmacology 23 (1982), S. 215-220 
    ISSN: 1432-1041
    Keywords: hypertension ; muzolimine ; mild renal functional impairment ; diuretic treatment ; body sodium ; catecholamines ; cardiovascular pressor responsiveness
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eighteen patients with mild impairment of renal function (glomerular filtration rate 65±5 ml/min: m±SEM) and hypertension (168/105±6/3 mmHg) were shown on average to have abnormally increased cardiovascular pressor responsiveness to infused norepinephrine (NE; p〈0.05), whereas plasma and urinary NE, exchangeable body sodium and blood-volume did not differ significantly from normal. A slightly increased pressor responsiveness to angiotensin II was associated with a tendency to low plasma renin activity (PRA). Compared to placebo conditions, treatment with the loop-diuretic muzolimine in a mean dose of 35±2 mg/day for six weeks decreased blood-pressure and exchangeable sodium (p〈0.05), and NE pressor responsiveness was restored to normal values, whilst plasma and urinary NE were not significantly changed. This was consistent with improvement of the initially abnormal relationship between NE levels and NE responsiveness factors. In contrast, the pressor dose of angiotensin II and PRA were increased to an approximatively similar extent during muzolimine treatment. These observations suggest that removal of body sodium and a decrease in NE reactivity without an equivalent increase in sympathetic nervous activity may be important complementary factors in the antihypertensive mechanisms of diuretic treatment in patients with mild renal functional impairment.
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  • 75
    ISSN: 1432-1041
    Keywords: prizidilol ; vasodilator ; hypertension ; beta blocker ; plasma renin ; aldosterone ; catecholamines ; acetylator type
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prizidilol is a new antihypertensive agent reported to possess combined precapillary vasodilator and betareceptor-blocking properties. To clarify the profile of the acute effects of prizidilol in man, a variable dose study was performed in 8 patients with benign essential hypertension. Blood pressure, heart rate, plasma renin activity, aldosterone, plasma and urinary catecholamines and electrolytes were determined at short intervals before and up to 23 h after oral administration of placebo and prizidilol 150, 300 and 600 mg. The 4 studies were performed at weekly intervals according to a Latin square design. Prizidilol produced dose-dependent decreases in supine and upright blood pressure, with an initial change after about 2 h and maximal effects from 4 to 8 h after drug ingestion. Following a high dose of prizidilol, supine mean blood pressure (average 128 mmHg prior to treatment) was normalised (〈107 mmHg) from 3 to 7 h and was still below predose levels 23 h after ingestion. The only reported side effects were postural dizziness in 2 cases (corresponding to a fall in systolic upright blood pressure to 〈95 mmHg) and headache in one case. A biphasic variation in heart rate and plasma renin activity, with an early drop and a subsequent tendency to a slight rise, was observed after an intermediate or high dose of prizidilol. Plasma norepinephrine levels were increased by a high dose of prizidilol, while plasma epinephrine, aldosterone and plasma and urinary electrolytes were not consistently changed. Prizidilol in a single oral dose appeared to be a potent antihypertensive agent. The profile of heart rate and plasma renin point to early dominance of beta-blockade followed by appearance of the concomitant vasodilator properties of prizidilol.
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  • 76
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    European journal of clinical pharmacology 26 (1984), S. 315-323 
    ISSN: 1432-1041
    Keywords: captopril ; hypertension ; glomerular filtration ; para-aminohippuric acid ; renal function ; severe drug reaction ; nephrotic syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of captopril up to 450 mg/day on blood pressure and renal function were investigated during sustained treatment of 10 patients whose severe hypertension had not responded to previous therapy. All the patients were kept on diuretics and most of them on β-blockers, too. A control determination of glomerular filtration rate (GFR) and para-aminohippuric acid clearance (CPAH) was performed during the prior treatment. The effect of the addition (or substitution) of captopril were assessed after an average of 25 days (short-term) and 26 weeks (long-term). Short-term treatment produced a 15.5% decrease in mean blood pressure and interindividually variable effects on renal function. On average GFR was somewhat lower and CPAH slightly higher than the control values (not significant). This pattern is quite similar to the effects of most other antihypertensive drugs. On long-term therapy GFR rose by a mean of 9% (NS) and CPAH by 17% (p〈0.02). However, in a patient who developed a captopril-induced nephrotic syndrome, GFR dropped to 56% and CPAH to 50% of the control values. In another patient a transient rise in serum creatinine accompanied a severe drug reaction.
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  • 77
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    European journal of clinical pharmacology 17 (1980), S. 329-332 
    ISSN: 1432-1041
    Keywords: reserpine ; hydrochlorothiazide ; pituitary hormones ; gonadal hormones ; hypertension ; serum concentration ; antihypertensive therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sex histories and serum samples were obtained from 27 hypertensive men before and after 3 months of therapy with either 100 mg of hydrochlorothiazide or 0.25 mg of reserpine daily. Sera were analyzed for testosterone, dihydrotestosterone, estradiol, luteinizing hormone and prolactin. Both drugs effectively lowered blood pressure. The incidence of impaired sexual performance was low and insignificantly different in the two treatment groups. There were no significant changes in serum hormone concentrations as a result of drug therapy.
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  • 78
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    European journal of clinical pharmacology 17 (1980), S. 409-413 
    ISSN: 1432-1041
    Keywords: penbutolol ; hypertension ; propranolol ; double-blind crossover comparison ; blood pressure ; heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Penbutolol is a potent long-acting non-cardioselective beta-adrenergic blocker with partial agonist activity. A double-blind cross-over comparison of penbutolol given in a single daily dose and propranolol given twice daily in the treatment of ambulant patients with moderate hypertension is described. Fourteen patients completed the study and were treated with each drug for 12 weeks. Penbutolol in daily doses of 20–120 mg and propranolol in daily doses of 80–400 mg produced similar significant reductions in both supine and erect blood pressure. Penbutolol did not reduce heart rate to the same extent as propranolol, in equivalent doses. Penbutolol appears to produce adequate control of moderate hypertension when administered once a day, and this effect appears to be equivalent to divided doses of propranolol. No serious adverse effects were reported, although one patient receiving penbutolol experienced severe eye pains at a dose of 40 mg which resolved on crossing over to treatment with propranolol.
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  • 79
    ISSN: 1432-1041
    Keywords: papaverine ; propranolol ; pindolol ; hypertension ; isoprenaline ; haemodynamic effects ; blood pressure
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of two β-adrenoceptor antagonists, propranolol and pindolol, on the haemodynamic effects of papaverine, isoprenaline and noradrenaline was investigated in 9 male patients with first degree essential hypertension. Propranolol and pindolol were given according to a doubleblind, crossover scheme. Heart rate and blood pressure were measured before and after each treatment. Propranolol 670 µg/kg i. v. reduced the supine and standing systolic blood pressures by 2.3% and 1.6%, respectively. Similarly, the intravenous administration of pindolol 35 µg/kg reduced supine and standing systolic blood pressure by 5.5% and 8.3% respectively (clinically insignificant). Neither drug affected diastolic blood pressure. Following propranolol, there were moderate reductions in supine and standing heart rates, respectively by 24% and 20% (p〈0.001). Similarly, but to a lesser extent, pindolol reduced supine and standing heart rate by 12% and 17% (p〈0.001). The effects of papaverine, which, at 1.5 mg/kg i. v. reduced systolic blood pressure by 5–10% and increased heart rate by 8–15%, were not significantly influenced by the β-blockers. The blood pressure and heart rate responses to isoprenaline, on the other hand, were attenuated or inhibited by both β-blockers. While the β-blockers inhibited the β-adrenoceptor component of noradrenaline, the pressor component of noradrenaline, which is mediated through the α-adrenoceptors, was not influenced by propranolol, but was inhibited after pindolol. It is concluded that pindolol differs qualitatively from propranolol in that it inhibited both the α-and β-adrenoceptor effects of noradrenaline.
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  • 80
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    European journal of clinical pharmacology 19 (1981), S. 395-401 
    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; hypertension ; combination fixed ratio ; serum potassium ; long term treatment
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The combination of sotalol and hydrochlorothiazide in a fixed ratio of 6.4:1 was evaluated in thirty patients with uncomplicated hypertension. In the first part of the study, once daily administration of an optimal dose of the combination was significantly more effective than either hydrochlorothiazide or sotalol alone in lowering both the supine and standing systolic and diastolic blood pressure. Blood pressure was still controlled 24 h after the previous dose. Serum potassium fell by 0.37 mEq/l from the mean pretreatment value after treatment with the combination, but it still remained within the normal range. In the second part of the study the long term effect of the combination on blood pressure, heart rate and biochemical parameters was studied in twenty patients. Supine and standing blood pressure fell by 28.7/15.3 mmHg and 29.5/17.6 mmHg, respectively (p〈0.001). Serum potassium was 3.98±0.07 mEq/l after twelve months of therapy; potassium supplements were not administered. Like serum potassium, the other biochemical parameters remained within the normal range. The combination was well tolerated on long term use, and only one patient withdrew from the study.
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  • 81
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    European journal of clinical pharmacology 17 (1980), S. 321-328 
    ISSN: 1432-1041
    Keywords: metoprolol ; hypertension ; pharmacokinetics ; plasma renin ; blood pressure effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eleven patients were treated for essential hypertension with metoprolol (Selokén®) for more than three months. The time course of changes in blood pressure, pulse rate and plasma renin activity was studied during treatment with an oral maintenance dose of 100 mg twice daily. Significant decreases in pulse rate, diastolic blood pressure and plasma renin activity were observed even after the first dose. The plasma concentration of metoprolol reached equilibrium after the second dose. After the third dose there was no further significant change in blood pressure. There was a significant correlation (p〈0.001) between the initial (after three doses) and final (after 〉90days) effect of metoprolol on blood pressure (r=0.86 and 0.91 for systolic and diastolic blood pressure change, respectively).
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    European journal of clinical pharmacology 21 (1982), S. 263-267 
    ISSN: 1432-1041
    Keywords: hypertension ; spironolactone ; hypotensive action ; peripheral circulation ; plethysmography ; handgrip test ; cold pressure test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Since there is only scanty, indirect information about the mechanism of the hypotensive effect of spironolactone, 9 patients with essential hypertension were studied according to a randomised double-blind, cross-over protocol. Spironolactone 100mg b.i.d. and placebo were each given for one month and the following parameters were studied: blood pressure, heart rate, response to cold pressure and hand-grip tests, as well as blood flow in the calf and finger vessels. Flow in the calf and fingers representing muscle and skin arteries, respectively, was measured semicontinuously with an ECG-triggered venous occlusion plethysmograph. After spironolactone there was a significant decrease in the systolic and diastolic blood pressures in the supine, sitting and standing positions; the sitting systolic and diastolic blood pressure decreased by (mean ± SE) 27±4mm Hg (p〈0.001) and 11±4mm Hg (p〈0.02), respectively. No orthostatic response was observed. Heart rate remained unchanged. Blood flow through muscle and skin vessels increased in 6 out of 9 patients, and in these patients calculated vascular resistance in these areas decreased. Spironolactone did not significantly change the response of systemic blood pressure to the handgrip and cold pressure tests. The present data confirm the hypotensive properties of spironolactone and show that this effect is associated with dilatation of muscle and skin arteries in many but not in all the patients. The data do not support the hypothesis that spironolactone decreases the responsiveness of systemic blood pressure to orthosympathetic stimulation.
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  • 83
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    European journal of clinical pharmacology 20 (1981), S. 1-8 
    ISSN: 1432-1041
    Keywords: hypertension ; captopril ; angiotensin ; renin ; aldosterone ; catecholamines ; prostaglandins ; kininase II ; hypotensive action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute hypotensive effect of captopril 25 mg was investigated in 26 hypertensive patients (11 with essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril led to an increase in plasma renin activity, active and total plasma renin concentration and angiotensin I, a decrease in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E2 and F2* and no change in plasma (nor)adrenaline, dopamine and inactive renin concentration. The hypotensive effect of captopril was related to the changes in plasma angiotensin II level and inversely to the change in prostaglandin E2; the correlation coefficients were low, respectively 0.61 and −0.44. It is likely that the acute hypotensive effect of captopril to some extent is related to changes in plasma angiotensin II and in prostaglandins E2 and F2*. There is no evidence for a role of the adrenergic systems in the hypotensive response.
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  • 84
    ISSN: 1432-1041
    Keywords: hypertension ; indapamide ; pindolol ; plasma renin activity ; plasma aldosterone concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide (2.5 mg daily) and pindolol (10 mg daily) on blood pressure, heart rate, plasma renin activity and plasma aldosterone concentration. There were four randomised test phases of eight weeks each during which patients received indapamide alone, pindolol alone, indapamide plus pindolol and no active treatment (placebo). Blood pressure and heart rate were measured every two weeks. Supine mean arterial pressure fell from 117 mm Hg in the placebo phase to 111 mm Hg in the indapamide phase, 106 mm Hg in the pindolol phase and 103 mm Hg in the combined indapamide plus pindolol phase. Factorial analysis confirmed that the hypotensive effects of the two drugs were additive, without evidence of potentiation or antagonism. Indapamide caused significant reductions in plasma potassium and chloride, and increases in plasma bicarbonate and urate concentrations; it also caused increases in plasma renin activity and aldosterone concentration. These changes are similar to those observed with thiazide diuretics.
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  • 85
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    European journal of clinical pharmacology 22 (1982), S. 487-489 
    ISSN: 1432-1041
    Keywords: nadolol ; hypertension ; effective dose range ; compliance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An open, observer-blind, therapeutic titration trial was carried out in 28 patients with mild or moderate essential hypertension to determine the effective dose range of nadolol given once a day. 11 patients became normotensive (supine diastolic blood pressure 90 mm Hg or below) with 80 mg, 4 with 120 mg and 1 with 160 mg. The largest step in the reduction of blood pressure was achieved with the first dose step of 80 mg, and only a small, non-significant further decrease was obtained with higher dose levels. Thus, nadolol, unlike propranolol, has a narrow effective dose range, and this should permit a brief dose adjustment period, which would be important in improving patient compliance.
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  • 86
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    European journal of clinical pharmacology 23 (1982), S. 93-97 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; vasodilator ; hypertension ; pharmacokinetics ; haemodynamics ; plasma renin activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic response and pharmacokinetics of single dose oral tolmesoxide were studied at various dose levels in 4 patients with severe hypertension. There was a reproducible fall in mean arterial pressure from baseline of 24.2% and a rise in heart rate of 37.6% following administration of tolmesoxide. The onset of antihypertensive action occurred within 1 h, with a peak effect at 3 h after dosing. The mean duration of action was up to 12.0 h. Tolmesoxide had a mean half-life of 3.0 h. It was rapidly absorbed with a mean peak plasma level occurring at 1.0 h. Plasma levels correlated well with the doses administered. Side-effects included mild nausea, facial flushing and postural symptoms.
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  • 87
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    European journal of clinical pharmacology 20 (1981), S. 399-405 
    ISSN: 1432-1041
    Keywords: alpha-adrenergic blocker ; hypertension ; blood pressure ; pulse rate ; noradrenaline ; plasma renin activity ; plasma aldosterone ; dopamine-beta-hydroxylase ; E-643
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To determine whether E-643, a new α-blocking agent, would reduce the blood pressure, regardless of the posture, a 1 mg dose was given 3 times daily for 7 consecutive days, to 8 male and 7 female inpatients, aged 37–73 years, with essential hypertension. Blood pressure and pulse rate were measured daily in the supine, sitting and standing positions. Before and after the treatment with E-643, plasma levels of noradrenaline, adrenaline, dopamine-β-hydroxylase, renin and aldosterone were determined, samples being obtained with the subjects recumbent and after standing upright for 60 min. A significant reduction in the systolic and diastolic blood pressures was evident in the supine (172±31/100±12 → 151±28/89±14 mmHg), sitting (158±22/101±11 → 138±28/89±15 mmHg) and standing (153±32/103±21 → 129±31/89±20 mmHg) positions. The reduction in blood pressure remained unchanged throughout the period of administration of E-643. Pulse rate was not affected when the subjects were supine (67±10 → 69±10 beats/min), but was increased in the sitting (68±10 → 73±9 beats/min) and standing (73±10 → 81±11 beats/min) positions. The increased pulse rate tended to decline during continued administration of E-643. Treatment with E-643 produced no significant change in plasma levels of adrenaline, noradrenaline, dopamine-β-hydroxylase, renin and aldosterone. The antihypertensive effect of treatment was more prominent in the patients with higher levels of plasma catecholamines and dopamine-β-hydroxylase, and was less prominent in those with higher plasma renin and aldosterone. Two patients had temporary bouts of dizziness and visual disturbances, but there were no subjective complaints during treatment.
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  • 88
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    European journal of clinical pharmacology 20 (1981), S. 407-411 
    ISSN: 1432-1041
    Keywords: chlorthalidone ; hypertension ; dose response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The dose response curve for 25, 50, 75 and 100 mg doses of chlorthalidone was studied in double blind fashion over an 8 week period in patients who presented with untreated mild hypertension. One hundred and thirty four patients completed this multicentre, family practice study. After 2 week's medication, a decline in blood pressure was noted in all dosage groups and this was maximal by 4 weeks. At 8 weeks all doses of chlorthalidone induced a significant reduction in both systolic and diastolic blood pressures (mean −18 and −10 mmHg respectively). Amongst the 4 dosage groups, no differences in response were noted resulting in a flat dose response curve. During the study, mean blood urea and serum uric acid rose whilst serum potassium fell, the urea and potassium being least affected in the 25 mg dosage group. As the dosage of chlorthalidone increased, so the tendency for abnormal laboratory values increased. Unwanted effects sought during the study were relatively few in number. No clear dose response relationship was evident although the positive responses in the 25 mg dosage group were less than in the higher dosages. These results suggest that 25 mg chlorthalidone is the optimum dosage for initiation of therapy in patients with mild to moderate hypertension. This dosage is associated with less adverse biochemical changes and unwanted effects than the higher dosages studied.
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  • 89
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    European journal of clinical pharmacology 20 (1981), S. 453-457 
    ISSN: 1432-1041
    Keywords: diuretics ; trichlormethiazide ; hypertension ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of trichlormethiazide (TCZ) was studied in twelve patients after a single 4 mg dose. Seven patients had normal renal function with creatinine clearances greater than 90 ml/min. Five patients had compromised renal function with creatinine clearances averaging 48±29 ml/min. The TCZ plasma half life and area under the plasma concentration-time curve (AUC) were significantly greater in patients with impaired function, compared to patients with normal renal function. There were no significant differences between the two patient groups in terms of either rate of drug absorption or total urinary recovery of unchanged drug. Furthermore, there was no correlation between peak drug levels or AUC and renal excretion of water or electrolytes.
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  • 90
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    European journal of clinical pharmacology 21 (1981), S. 1-8 
    ISSN: 1432-1041
    Keywords: hypertension ; combination therapy ; population survey ; drug treatment ; prescription patterns ; population incidence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a cross-sectional study, antihypertensive drug treatment was studied in a representative population sample of people aged 30–64 years, using a combination of postal survey, personal interview, clinical assessment and drug prescriptions. 11% of the men and 16% of the women were currently taking antihypertensives; 54% of patients used one, 38% used two, and 8% used three or more preparations. Men used slightly more drugs than women. Diuretics were used by 62% and betablockers by 49% of the sample population. Fixed combinations of thiazides and potassium-sparing agents formed 70% of all diuretic preparations used. Only 12% of the patients used fixed antihypertensive combinations, of which over half were diuretic-reserpine-vasodilator combinations; women and older patients used them most often. The most common freely combined preparations were diuretics and betablockers, which formed almost half of all two-drug combinations, and were also present in 70% of all triple combinations. Adequate control of blood pressure (DBP 〈100 mmHg) was achieved by slightly under 50% of the patients, the BP of women being more adequately controlled than that of men. Differences in BP control were found between the different drugs and combinations. Antihypertensive combination therapy is important in successful treatment, but we still cannot be sure whether fixed combination preparations or, as in this study, free combinations of marketed preparations are better alternatives for treatment.
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  • 91
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    European journal of clinical pharmacology 21 (1981), S. 87-92 
    ISSN: 1432-1041
    Keywords: hypertension ; metoprolol ; sotalol ; comparison ; plasma levels ; serum uric acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 28 patients, aged 35–62 years, with uncomplicated hypertension, entered a double-blind, crossover study, in which the effects of single daily doses of sotalol and metoprolol were compared. Both drugs exerted a clinically useful anti-hypertensive effect as monotherapy, or in combination with a thiazide diuretic. No significant difference in hypotensive effects was noted between the two beta-blocking agents, when the dose was titrated to an optimal clinical effect. Treatment with sotalol and metoprolol was associated with a clinically insignificant increase in serum uric acid concentration. The side-effects observed were few, and in only two cases was therapy discontinued. We regard both sotalol and metoprolol as useful anti-hypertensive drugs.
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  • 92
    ISSN: 1432-1041
    Keywords: frusemide ; saralasin ; hypertension ; reninangiotensin ; sodium ; diet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The use of tests of the renin-angiotensin system for predicting antihypertensive responses to frusemide combined with dietary sodium deprivation was evaluated in eighteen patients with severe hypertension. No relationship could be shown between changes in blood pressure induced by the angiotensin analogue, saralasin, and the short-term or long-term therapeutic effects of diuretic- and diet-induced sodium depletion. Mean values for saralasin response and initial plasma renin activity in eight patients whose blood pressure was adequately controlled by therapeutic sodium depletion were closely similar to those obtained in the remaining ten patients, who proved refractory to this treatment.
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  • 93
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    European journal of clinical pharmacology 21 (1982), S. 457-460 
    ISSN: 1432-1041
    Keywords: hypertension ; propranolol ; hydralazine ; labetalol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomised cross-over trial the combination labetalol/hydrochlorothiazide was compared with the combination of propranolol/hydralazine/hydrochlorothiazide in 34 uncomplicated hypertensive patients, who were not satisfactorily controlled with hydrochlorothiazide 50 mg alone. The elevated diastolic pressure (D.P.) in 27 patients responded satisfactorily to the labetalol schedule and in 28 patients to the propranolol/hydralazine schedule. No difference was found in the rate of decrease of D.P., nor in the disappearance of hypertension — related complaints. Although the duration of the washout between treatments was at least one month, treatment was significantly more efficacious during the second period. Labetalol pre-treatment especially seemed to enhance the effect of subsequent propranolol/hydralazine administration. Side effects due to therapy were rare and were not related to any particular treatment. The median daily dose of labetalol in responders was 600 mg and that of propranolol/hydralazine 120/60 mg (in both therapies hydrochlorothiazide 50 mg was given in addition). Patients showed a slight preference for the labetaol medication. It is concluded that labetalol/hydrochlorothiazide and propranolol/hydralazine/hydrochlorothiazide are equally satisfactory in the treatment of uncomplicated hypertension.
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  • 94
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    European journal of clinical pharmacology 22 (1982), S. 203-206 
    ISSN: 1432-1041
    Keywords: hypertension ; ticrynafen ; hydrochlorothiazide ; renal impairment ; uricosuria ; diuretic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of ticrynafen in the treatment of hypertension in patients with moderate renal impairment was compared with that of hydrochlorothiazide in a randomised, double-blind crossover trial in eleven subjects with renal insufficiency. Significant reductions in blood pressure occurred with both treatments, with the maximum responses occurring at different time intervals and to different degrees in individual patients. Thus, although ticrynafen caused a significant reduction in blood pressure in this group of hypertensive patients with renal insufficiency, it was not consistently different from that which could be achieved with hydrochlorothiazide. Ticrynafen also significantly reduced the serum uric acid concentration, compared with a significant rise with hydrochlorothiazide. No major biochemical abnormalities or side-effects were encountered in any subject. Thus, in these patients with renal insufficiency, ticrynafen still demonstrated a uricosuric effect as well as a useful anti-hypertensive action.
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  • 95
    ISSN: 1432-1041
    Keywords: labetalol ; chlorthalidone ; hypertension ; fixed combination ; antihypertensive therapy ; side effects ; multicentre study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a multicentre, double-blind, crossover, placebo-controlled study, the antihypertensive effect of labetalol 100 mg and chlorthalidone 10 mg, given alone or in combination, has been assessed in 32 hypertensive patients. The combination had a greater effect in reducing blood pressure than did its separate components. This was particularly evident after exercise. Heart rate increased during chlorthalidone therapy, decreased during labetalol therapy, and a summation effect was observed during treatment with the combination. In most cases additivity was observed, as no interaction between the single components was observed, except for heart rate after exercise, and for diastolic blood pressure in the upright position. No interaction was observed either in the biochemical indices or in the clinical side-effects.
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  • 96
    ISSN: 1432-1041
    Keywords: beta-blocking drugs ; insulin sensitivity ; pancreatic beta-cell function ; hypertension ; propranolol ; atenolol ; insulin secretion ; plasma GIP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of two beta-blocking drugs on endogenous insulin secretion and insulin sensitivity were investigated in a double blind cross-over study in 13 hypertensive patients. The patients were randomly allocated to each of three 2-week treatment periods with propranolol 80 mg b.i.d., atenolol 50 mg b.i.d. and placebo b.i.d. Endogenous insulin secretion was assessed by measuring serum insulin and C-peptide before and 6 min after iv administration of glucagon; insulin sensitivity was determined by measuring insulin binding to erythrocytes, and as the glucose disappearance rate (KITT) after i.v. insulin. Fasting concentrations of serum free fatty acids (S-FFA) and plasma gastric inhibitory polypeptide (P-GIP) were also recorded during the three study periods. Both propranolol and atenolol reduced blood pressure, heart rate and S-FFA concentrations compared to placebo, and all patients showed measurable plasma concentrations of propranolol and atenolol. The results can be considered representative, therefore, of clinical beta-blockade. The two drugs did not significantly influence the fasting blood glucose level. There was an increase in fasting and glucagon-stimulated serum C-peptide concentration during propranolol therapy compared with placebo (p=0.037 and p=0.030, respectively), although this was not reflected by a significant change in serum insulin. Propranolol and atenolol did not significantly influence insulin binding to erythrocytes, but they clearly reduced the glucose disappearance rate KITT was compared to placebo (p=0.0036 and p=0.0003, respectively). The findings support the view that beta-blocking drugs can influence glucose metabolism by mechanisms other than inhibition of endogenous insulin secretion.
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  • 97
    ISSN: 1432-1041
    Keywords: acetylator phenotype ; hydralazine response ; hypertension ; blood pressure control ; lupus syndrome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The role of acetylator phenotype in determining the response to hydralazine when it was added to diuretic and β-blocker at doses not exceeding 200 mg daily was examined in 57 hypertensive patients. 81% of rapid acetylators needed 200 mg hydralazine daily compared to 38% of slow acetylators (p〈0.01). Despite higher doses of hydralazine the blood pressure was controlled in only 27% of rapid acetylators compared to 65% of slow acetylators (p〈0.02). The relation of acetylator phenotype to blood pressure response was statistically independent of initial blood pressure, age, sex, body weight and serum creatinine (p〈0.005). Current recommendations on hydralazine dosage are unsatisfactory for the 40% of hypertensive patients who are rapid acetylators. We suggest measurement of the acetylator phenotype in patients who respond incompletely to 200 mg hydralazine daily. About 70% of these patients will be rapid acetylators in whom the dose of hydralazine can be increased safely.
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  • 98
    ISSN: 1432-1041
    Keywords: Tobanum® ; beta-blocker ; chloranolol ; hypertension ; angina pectoris ; arrhythmia ; detection methods
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The incidence of side-effects on administration of chloranolol (Tobanum®), a beta-adrenergic receptor blocking drug, to 2066 patients with hypertension, angina pectoris or arrhythmias was measured by three different methods. In 600 patients in an efficacy trial (Group 1) both spontaneously reported complaints and objective signs were tabulated. A side effect — directed method, utilising a questionnaire containing a list of possible side-effects was also used, with the questionnaire being completed by the physician. 35 questions referred to anticipated and other side-effects. The trial was performed in two groups: in 537 patients a placebo was also given (Group 2), and in another set of 929 patients (Group 3) the questionnaire inquiry was performed uncontrolled, without placebo. All three groups were comparable in their distribution of sexes, ages and diagnoses, the mean daily dose of chloranolol its use alone or in combination, and in a similar duration of treatment. 55% of all patients received chloranolol therapy for a period of more than 3 months. The ratio of in- and outpatients was 1:5. The side-effect incidence was independent of the age and sex of the patients and of the dose of chloranolol. The incidence was also unaffected whether chloranolol was used alone or in combination. The number of side-effects differed markedly between the three groups, their ratio was 1:10:24 in Groups 1, 2 and 3. Two-thirds of the side-effects subsided spontaneously within 1 month of their onset. The duration of the side-effects varied according to their character: cardiorespiratory side-effects were of the shortest duration and those affecting the central nervous system were the most enduring. The appreciable differences in incidence could be attributed to the methods of collection of the data. It has been stated that placebo controlled trials using a detailed questionnaire are the most suitable for estimating the incidence of side-effects; recording side-effects spontaneously reported by patients are insufficiently sensitive, and uncontrolled trials using a questionnaire have been shown to be too sensitive. The revealed incidence of side effects leading to interruption of treatment is less affected by the method chosen. In 100 patients (4.8%) therapy had to be suspended because of the side-effects of chloranolol (Group 1: 1%, Group 2: 6.20%, Group 3: 6.6%). Comparison of the incidence of cessation of therapy due to side-effects did not show an appreciable difference between the various beta-adrenergic receptor blocking agents, including chloranolol.
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  • 99
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    European journal of clinical pharmacology 26 (1984), S. 1-6 
    ISSN: 1432-1041
    Keywords: hypertension ; beta-blockers ; propranolol ; metoprolol ; labetalol ; exercise ; heart rate ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double blind, within patient investigation of twenty-four patients (nineteen males and five females) with a mean age of 46.3 years (SD 10.9 years) with mild to moderate essential hypertension a comparison between equipotent beta-blocking doses of propranolol, metoprolol and labetalol was carried out. Blood pressure and pulse rate were measured in lying, sitting and standing positions and before, during and after isometric and dynamic exercise. Peak expiratory flow was recorded before and during dynamic exercise. All the active treatments were better than placebo in reducing blood pressure and heart rate. Comparing the effects of treatment, labetalol lowered sitting diastolic pressure significantly more than propranolol and standing diastolic pressure than both propranolol and metoprolol. Metoprolol and propranolol were more effective in reducing heart rate. Propranolol significantly reduced peak flow rate compared to labetalol. During the exercise, both isometric and dynamic, the heart rate and the blood pressure, both systolic and diastolic, of the treated patients were lower than those on placebo. There was little difference between the drugs in the influence on blood pressure, but metoprolol and propranolol were significantly more effective than labetalol in lowering the heart rate.
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  • 100
    ISSN: 1432-1041
    Keywords: alpha-methyldopa ; propranolol ; hypertension ; side effects ; blood pressure control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A multicentre study of 6–10 weeks duration was performed in 60 ambulant hypertensive patients aged over 60 years to compare the efficacy of methyldopa and propranolol with particular reference to the occurrence of cold extremities and sleep disturbances. Blood pressure was effectively controlled by both drugs being reduced from a mean of 180/108 mmHg to 161/93 with methyldopa and 180/108 to 162/94 with propranolol. More patients treated with methyldopa (74%) achieved the target diastolic blood pressure of 95 mmHg or below compared with those treated with propranolol (58%). Side effects were more frequent in the propranolol group necessitating the withdrawal of four patients from the study. Only one patient on methyldopa was withdrawn. The incidence of cold extremities was significantly greater with propranolol. The occurrence of sleep disturbances was similar in both groups. In this group of elderly patients methyldopa was better tolerated than propranolol.
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