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  • Articles  (86)
  • adverse effects  (51)
  • Bone  (35)
  • Springer  (86)
  • American Chemical Society
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  • Oxford University Press
  • 2005-2009
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  • Articles  (86)
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  • Springer  (86)
  • American Chemical Society
  • Annual Reviews
  • Elsevier
  • Oxford University Press
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  • 2005-2009
  • 1990-1994  (64)
  • 1980-1984  (22)
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  • 1
    Electronic Resource
    Electronic Resource
    A new semiautomatic method for quantitative static and dynamic bone histology (1982)
    Springer
    Calcified tissue international 34 (1982), S. 439-448 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Histomorphometry ; Osteocytes ; Bone dynamics ; Histology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary A new semiautomatic technique combining advantages of the manual and fully automatic methods is described for obtaining quantitative static and dynamic histologic data of bone. The hardware consists of a photomicroscope, digitizing platen, digitizer, plotter/printer, floppy disc drive, and computer. The microscope is equipped with a drawing tube through which the image of the digitizing platen is projected over the optical field. The investigator selects and traces all histologic structures to be measured by moving a cursor on the digitizing platen which is visible by its projection over the histologic field. The results on accuracy and static and dynamic precision of this method show that static and dynamic parameters of bone are obtained with a degree of error (〈20%) well within the acceptable range for biologic measurements. Comparison of this method with the grid technique according to Merz and Schenck showed that for almost all micromorphometric parameters comparable absolute data are obtained. Due to the higher precision of our method, however, the number of optical fields evaluated in obtaining these comparable data could be reduced to 25% of the number of fields evaluated by the Merz and Schenck technique. The time requirements for quantitative evaluation of a histologic slide of bone by our technique are 40–50 min; 20–25 min is needed for quantitative evaluation of osteocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411282
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  • 2
    Electronic Resource
    Electronic Resource
    Quantitative bone histology in 84 normal American subjects (1982)
    Springer
    Calcified tissue international 34 (1982), S. 449-455 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Histomorphometry ; Normal values ; Bone biopsies ; Sampling error
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Quantitative bone histology was done in undecalcified sections of iliac crest bone specimens obtained from 84 normal American individuals. Samples were obtained within 12 h after death in a vertical and horizontal manner from both the right and left iliac crests. In addition to the determination of normal values of micromorphometric parameters of bone in these healthy American subjects, the following studies were carried out: (a) comparison of variance of micromorphometric parameters of bone obtained from the right versus left iliac bone (40 pairs), (b) comparison of micromorphometric parameters of bone obtained in a vertical versus horizontal manner (12 pairs), (c) evaluation of variance with increasing distance from the compact zone in bone samples obtained in a vertical manner (44 pairs), (d) analysis of variation between bone samples obtained more anteriorly versus posteriorly along the iliac crest (N=40), (e) comparison of differences in micromorphometric parameters obtained from age-matched men versus premenopausal women (N=12), and (f) plotting of histograms for assessment of distribution of micromorphometric parameters. The results show that histomorphometric data of bone cannot be easily compared when different techniques are employed for obtaining bone samples. Sampling variations are kept smaller when bone specimens are obtained in a vertical manner. Anterior/posterior variation does not cause major sampling error. If ranges of variation are taken into account, quantitative bone histology is a valuable tool for assessment of bone structure and bone cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411283
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  • 3
    Electronic Resource
    Electronic Resource
    Growth hormone involvement in the regulation of tartrate-resistant acid phosphatase-positive cells that are active in cartilage and bone resorption (1993)
    Springer
    Calcified tissue international 52 (1993), S. 216-221 
    Details
    ISSN: 1432-0827
    Keywords: Growth hormone ; Resorption ; Bone ; Cartilage ; Tartrate-resistant acid phosphatase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Young male Sprague-Dawley rats (5–7 weeks old, 80–120 g) were hypophysectomized (HX) and maintained on thyroxin and dexamethasone replacement therapies. Ten days after surgery, some HX rats received a single injection of human growth hormone (hGH), and others five daily injections of hGH. Tartrate-resistant acid phosphatase (TRAP) histochemistry was employed in order to evaluate the number of cells of resorptive potential in the metaphyseal bone of the proximal tibiae of HX rats and was compared with normal rats and HX rats that further received hGH replacement therapy. In normal rats, two populations of TRAP-positive cells were identified: multinuclear cells, which showed histological characteristics of osteoclasts, and small mononuclear cells, the number of which was overwhelming when compared with the number of TRAP-positive multinuclear cells. Both populations were reduced in the HX rat, but more so the mononuclear cells, which were assumed to represent the precursor pool of mature osteoclasts and chondroclasts (P〈0.005). Five daily injections of hGH to HX rats brought about a significant increase in the number of TRAP-positive multinuclear cells, the number of nuclei of these cells, and the number of mononuclear TRAP-positive cells, throughout the metaphyseal bone (P〈0.05). A single injection of hGH increased only the number of TRAP-positive multinuclear cells in the trabecula/bone marrow interface (P〈0.05), indicating a very rapid fusion of precursor cells into mature osteoclasts in that particular location. It was concluded that GH depletion caused a major reduction in the number of cells presenting resorption capacity and that a short hGH replacement regimen resulted in a gradual restoration of these cells n the metaphyseal bone of the proximal tibia of the HX rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00298722
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  • 4
    Electronic Resource
    Electronic Resource
    Vitamin K-induced changes in markers for osteoblast activity and urinary calcium loss (1993)
    Springer
    Calcified tissue international 53 (1993), S. 81-85 
    Details
    ISSN: 1432-0827
    Keywords: Vitamin K ; Osteocalcin ; γ-carboxyglutamic acid ; Bone ; Calcium excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The objective of this study was to identify subjects in whom vitamin K has an effect on markers for calcium and bone metabolism and to detect hitherto-unnoticed correlations between vitamin K-induced changes in these markers. Participants in our studies were apparently healthy women, in whom we measured serum-immunoreactive osteocalcin (irOC) before and after adsorption to hydroxylapatite; total serum alkaline phosphatase (T-AP) and bonespecific alkaline phosphatase (B-AP); and fasting urinary calcium and creatinine. We describe a trial among 145 women who were treated with vitamin K (1 mg/day) for 2 weeks, and a prospective placebo-controlled trial among two groups each of 70 postmenopausal women with a treatment period of 3 months. It turned out that in elderly women vitamin K induced increased levels of serum irOC with a high affinity for hydroxylapatite (irOCbound), whereas that with low affinity (irOCfree) remained unaffected. In placebo-treated women the ratio irOCfree/irOCbound shifted from 0.38 to 0.65 around the 50th year of age. This shift was not found in vitamin K-treated women. After 3 months of treatment the vitamin K-induced changes in irOCbound were correlated with changes in B-AP, whereas irOCfree was correlated to urinary calcium excretion. In fast losers of urinary calcium vitamin K induced a 30% decrease of calcium excretion. The hypothesis is put forward that irOCbound may be a marker for bone formation, that serum irOCfree may be a marker for bone resorption, and that the serum irOCfree/irOCbound ratio may become a marker for skeletal remodeling. It is concluded that vitamin K administration may help to reduce urinary calcium loss in postmenopausal women, notably in the fast losers of calcium. The ratio irOCfree/irOCbound provides more information than total irOC and may become a practical marker for bone metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01321883
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  • 5
    Electronic Resource
    Electronic Resource
    Mechanical properties, bone mineral content, and bone composition (collagen, osteocalcin, IGF-I) of the rat femur: Influence of ovariectomy and nandrolone decanoate (anabolic steroid) treatment (1993)
    Springer
    Calcified tissue international 53 (1993), S. 269-277 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Nandrolone decanoate ; Ovariectomy ; Bone mechanics ; IGF-I ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Nandrolone decanoate (ND) is an anabolic steroid with a positive effect on bone mass in osteoporotic patients. The mechanism of action, (i.e., reduction of bone resorption and/or Stimulation of bone formation), the ultimate effect on mechanical properties, and the most effective dosage are not yet clear. To address these issues, dose-related effects of the long-term effect of ND on Serum and bone biochemistry, bone mineral content, and bone mechanical properties in ovariectomized (OVX) rats (12 weeks old at the Start of the experiment) were Studied for 6 months. The results were compared with those obtained in agematched, intact, and OVX rats. OVX caused in the femur a significant increase in net periosteal bone formation and net endosteal bone resorption of bone collagen content and torsional strength, and of Serum alkaline phosphatase, osteocalcin, and insulin-like growth factor-I (IGF-I) levels, whereas cortical bone density and calcium/creatinine and phosphorus/creatinine in 24-hour urine were Significantly reduced. Treatment of OVX rats with 1 mg ND/14 days resulted in a Significant increase in periosteal bone formation, femur length, cortical and trabecular bone mineral content and density, torsion stiffness and Strength, and bone IGF-I content, and a decrease in Serum osteocalcin, urinary calcium/creatinine levels, and bone collagen content compared with OVX controls. The higher ND dosage of 2.5 mg/14 days did not improve the results. ND treatment did not reverse all changes induced by OVX to the level of the intact controls. These results indicate that ND acts as an antiresorptive drug and as a bone formation Stimulating drug. Furthermore, the increased bone mass and bone mineral density is associated with improved bone Strength and stiffness and the presence of an increased amount of IGF-I. IGF-I is a growth factor considered to play a role in the maintenance of normal skeletal balance by a paracrine or autocrine mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01320913
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  • 6
    Electronic Resource
    Electronic Resource
    Iron distribution in thalassemic bone by energy-loss spectroscopy and electron spectroscopic imaging (1993)
    Springer
    Calcified tissue international 53 (1993), S. 29-37 
    Details
    ISSN: 1432-0827
    Keywords: Iron ; Bone ; Osteoblasts ; Ferritin ; Electron energy loss spectroscopy ; Electron spectroscopic imaging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Iron overload occurs frequently in thalassemia as a consequence of regular blood transfusions, and iron has been found to accumulate in bone, but skeletal toxicity of iron is not clearly established. In this study, bone biopsies of thalassemic patients were investigated by light (n = 6) and electron microscopy (n = 8) in order to analyze iron distribution and possible iron-associated cellular lesions. Sections (5 μm thick) were used for histomorphometry and iron histochemistry. Ultrathin sections were examined with an energy filtering transmission electron microscope. Iron was identified by electron energy loss spectroscopy (EELS), and iron distribution was visualized by electron spectroscopic imaging (ESI) associated with computer-assisted treatment (two-window method). This study shows that EELS allows the detection of 4500–9000 iron atoms, and that computer-assisted image processing is essential to eliminate background and to obtain the net distribution of an element by ESI. This study shows also that stainable iron was present along trabecular surfaces, mineralizing surfaces, and on cement lines in the biopsies of all patients. Moreover, iron was detected by EELS in small granules (diffusely distributed or condensed in large clusters), in osteoid tissue, and in the cytoplasm of bone cells, but not in the mineralized matrix. The shape and size (9–13 nm) of these granules were similar to those reported for ferritin. As for iron toxicity, all patients had osteoid volume and thickness and osteoblast surface in the normal range. Stainable iron surfaces did not correlate with osteoblast surfaces, plasma ferritin concentrations, or the duration of transfusion therapy. Numerous osteoblasts contained damaged mitochondria, and impaired osteoblast activity can therefore not be excluded.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01352012
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  • 7
    Electronic Resource
    Electronic Resource
    Skeletal demineralization in Turner's syndrome (1982)
    Springer
    Calcified tissue international 34 (1982), S. 519-522 
    Details
    ISSN: 1432-0827
    Keywords: Turner's syndrome ; Ovarian dysgenesis ; Osteoporosis ; Bone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The bone mineral status of 17 girls with Turner's syndrome was evaluated by single photon absorptiometry. Bone mineral content (BMC) was 25.4% below that predicted by normalization for age, sex, height, weight, and bone width. Only 25% of this demineralization could be attributed to delayed skeletal maturation. Bones of girls who received estrogen replacement therapy were less demineralized than those of the others. The bone mineral deficit became less pronounced with advancing age. It could not be determined if the apparent effect of estrogens was related to age or if the apparent improvement with age was really due to an effect of estrogen treatment. For 8 subjects followed longitudinally there was no significant change in the BMC deficit.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411296
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  • 8
    Electronic Resource
    Electronic Resource
    Distribution of fluoride in cortical bone of human rib (1993)
    Springer
    Calcified tissue international 52 (1993), S. 278-282 
    Details
    ISSN: 1432-0827
    Keywords: Fluoride ; Bone ; Human ; Aging ; Sex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary We describe a detailed study of fluoride distribution with age in the human cortical rib bone. Human ribs were obtained from 110 subjects (M:68,F;42) aged 20–93 years. The fluoride distribution from the periosteal to endosteal surfaces of the ribs was determined by sampling each specimen using an abrasive micro-sampling technique, and the samples were analyzed using the fluoride electrode, as described by Weatherell et al. [1]. The concentration of fluoride was highest in the periosteal region, decreased gradually towards the interior of the tissue where the concentration of fluoride tended toward the plateau, and then rose again towards the endosteal surface. Patterns of fluoride distribution changed with age, and the difference between periosteal and endosteal fluoride levels increased with age. Although average fluoride concentrations increased with age in both sexes, there was a significant difference between males and females at the age of about 55 years (P〈0.05).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00296652
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  • 9
    Electronic Resource
    Electronic Resource
    Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans (1993)
    Springer
    Calcified tissue international 53 (1993), S. 21-25 
    Details
    ISSN: 1432-0827
    Keywords: Omeprazole ; Bone ; Resorption ; Inhibition ; Human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Omeprazole is an inhibitor of gastric H+, K+-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H+-ATPase which is different from the gastric H+, K+-ATPase,in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2 blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01352010
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  • 10
    Electronic Resource
    Electronic Resource
    Plasma proteins in human cortical bone: Enrichment ofα 2 HS-glycoprotein,α 1 acid-glycoprotein, and IgE (1982)
    Springer
    Calcified tissue international 34 (1982), S. 229-231 
    Details
    ISSN: 1432-0827
    Keywords: Plasma proteins ; IgE ; IgD ; α 1Acid-glycoprotein ; Bone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Human cortical bones were extracted with EDTA, and the residue after EDTA extraction was digested with bacterial collagenase. Ten plasma proteins were identified and quantitated in the EDTA extracts. Three of them—IgE, IgD, andα 1acid-glycoprotein—had not previously been described in bone or dentine. Five plasma proteins identified in collagenase digests are albumin, IgG, IgA, IgE, andα 1acid-glycoprotein. IgE,α 1acid-glycoprotein, andα 2HS-glycoprotein were found to be concentrated in the bone more than other plasma proteins by factors between 11 and 525. The identification of plasma proteins was facilitated by the addition of polyethylene glycol in agarose gel. The presence of plasma proteins both in EDTA extracts and in collagenase digests suggests their structural role in bone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411242
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  • 11
    Electronic Resource
    Electronic Resource
    Effect of 1,25-dihydroxyvitamin D3 on osteopenia induced by prednisolone in adult rats (1982)
    Springer
    Calcified tissue international 34 (1982), S. 253-257 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411246
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  • 12
    Electronic Resource
    Electronic Resource
    Role of vitamin D in maternal skeletal changes during pregnancy and lactation: A histomorphometric study (1982)
    Springer
    Calcified tissue international 34 (1982), S. 245-252 
    Details
    ISSN: 1432-0827
    Keywords: Vitamin D ; Vitamin D deficiency ; Bone ; Pregnancy ; Lactation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The effect of vitamin D on bone changes during the reproductive cycle in female rats has been investigated. One group of female rats was maintained on a vitamin D-deficient diet and another group on a vitamin D-replete diet from weaning. Both groups were mated with normal males and changes in their bones were determined histomorphometrically during pregnancy, lactation, and after weaning. All vitamin D-deficient rats had bone changes typical of rickets. Pregnancy caused significant reductions in mineralized tissue of trabecular and cortical bone in the vitamin D-deficient rats. Lactation caused further significant reductions in mineralized tissues of cortical and trabecular bone in both the vitamin D-deficient and vitamin D-replete animals, with the greatest changes seen at weaning. Some restoration of mineralized tissues occurred following weaning. There was an increase in tetracycline-labeled bone surface in the vitamin D-replete animals during lactation, likely due to an increase in bone formation rates. In the vitamin D-deficient animals during lactation, there was a decrease in tetracyclinelabeled bone surface, likely due to severely depressed bone mineralization. These results indicate that the mobilization of calcium from bone to maintain pregnancy and lactation occurs by a mechanism independent of vitamin D.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411245
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  • 13
    Electronic Resource
    Electronic Resource
    Osteogenesis in osteopetrotic mice (1982)
    Springer
    Calcified tissue international 34 (1982), S. 37-42 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Osteopetrosis ; Osteoclast
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Ectopic bone arising in grafts of compatible normal intact bone marrow in microphthalmic osteopetrotic recipients was examined in the light microscope and was found to be unaffected by the deficiency that curtails resorption of primitive woven bone in osteopetrotic animals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411206
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  • 14
    Electronic Resource
    Electronic Resource
    Effects of vitamin D metabolites and analogs on bone collagen synthesis in vitro (1982)
    Springer
    Calcified tissue international 34 (1982), S. 103-110 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Collagen ; Vitamin D metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The effects of selected vitamin D3 metabolites and analogs on bone collagen synthesis in vitro were examined in organ cultures of neonatal mouse calvarial bone. The incorporation of [3H]proline into the collagenase-digestible fraction of newly synthesized protein was progressively inhibited by 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) (10−12 M to 10−7 M) in 24-h cultures, and incorporation into noncollagen protein was also blunted at the higher doses employed. The synthetic analog 1α-hydroxyvitamin D3 (1α-OHD3) was almost 300-fold less potent an inhibitor of collagen synthesis than was 1α,25(OH)2D3, and the natural metabolites 25-hydroxyvitamin D3 (25OHD3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3), 1000-fold less potent, although the dose-response curve for each of these compounds was not parallel with that for 1α,25(OH)2D3. The 24S,25(OH)2D3 enantiomer was four-fold less potent than 24R,25-(OH)2D3 or 25OHD3, and vitamin D3 showed less than 2% the activity of 25OHD3. The responses were unaffected by the substitution of 0.4% bovine albumin for 5% horse serum in the medium, and no stimulation of collagen synthesis was observed in response to 25-hydroxylated metabolites between 2×10−14 and 2×10−6 M or in cultures treated for up to 96 h with 24R,25(OH)2D3 (2×10−10M). The overall results emphasize the similarity of the structural requirements for the inhibition of matrix synthesis and the stimulation of resorption by active vitamin D metabolites in bone. In addition, these studies support the importance of the 1-hydroxyl function to the biologic activity of vitamin D in the skeleton.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411216
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  • 15
    Electronic Resource
    Electronic Resource
    Serum 1,25-dihydroxyvitamin D levels in subjects with X-linked hypophosphatemic rickets and osteomalacia (1982)
    Springer
    Calcified tissue international 34 (1982), S. 125-130 
    Details
    ISSN: 1432-0827
    Keywords: X-Linked hypophosphatemic rickets ; Osteomalacia ; 1,25-Dihydroxyvitamin D ; Bone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary In order to determine whether a defect in vitamin D metabolism might play a role in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia (XLH), we compared the serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level in 52 normal subjects and 37 patients with XLH. In untreated patients, adults were found to have values similar to age-matched controls, while youths had values similar to growth-rate-matched controls but significantly lower than the levels of age-matched controls who were growing at a normal rate. In contrast, treated XLH patients of all ages had serum levels significantly lower than both controls and untreated XLH patients. Further, the serum levels of 1,25(OH)2D in these treated patients had a significant inverse linear correlation with serum 25-(OH)D concentrations. We propose that subjects with XLH have serum 1,25(OH)2D levels within appropriate age- and growth-rate-matched normal ranges. However, in the presence of hypophosphatemia, we would have anticipated elevated levels of 1,25(OH)2D; viewed in this light the serum 1,25(OH)2D levels are inadequate, suggesting the presence of a relative deficiency of this active vitamin D metabolite.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411222
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  • 16
    Electronic Resource
    Electronic Resource
    Blood:Bone disequilibrium. V. Effects of a diphosphonate (EHDP) on phosphate fluxes in rat calvaria (1982)
    Springer
    Calcified tissue international 34 (1982), S. 145-148 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Diphosphonate ; Phosphate fluxes ; Solubility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Calvaria taken from rats (normal or thyroparathyroidectomized) given a diphosphonate (EHDP 10 mg/kg daily for 7 days) were placed in special Ussing chambers for the measurement of phosphate fluxes to and from bone. When compared with appropriate controls, the experimental calvaria showed a marked decrease in influx, K, a significant increase in the projected equilibrium concentration, E/K, where E is the efflux and a significnant increase in the calcium concentration in the medium. It is concluded that this large increase in passive “solubility” is caused by the diphosphonate's ability to stabilize the small amount of regulator phase (brushite or brushite-apatite mixture) present in bone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02411225
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  • 17
    Electronic Resource
    Electronic Resource
    Parathyroid hormone and calcitonin interactions in bone: Irradiation-induced inhibition of escape in vitro (1982)
    Springer
    Calcified tissue international 34 (1982), S. 197-203 
    Details
    ISSN: 1432-0827
    Keywords: Parathyroid hormone ; Calcitonin ; Bone ; Escape ; Irradiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Calcitonin (CT) inhibits hormonally stimulated bone resorption only transiently in vitro. This phenomenon has been termed “escape,” but the mechanism for the effect is not understood. One possible explanation is that bone cell differentiation and recruitment of specific precursor cells, in response to stimulators of resorption, lead to the appearance of osteoclasts that are unresponsive to CT. To test this hypothesis, cell proliferation in neonatal mouse calvaria in organ culture was inhibited by irradiation from a cobalt-60 source. At a dose of 6000 R, [3H]thymidine incorporation into intact calvaria was inhibited approximately 90%. Irradiation had no effect on the resorptive response to 0.1 U/ml parathyroid hormone (PTH). However, irradiation induced a dose-dependent inhibition of the escape response which was maximal at 6000 R. A dose of 6000 R did not affect the binding of125I-salmon CT to calvaria and decreased PTH stimulation of cyclic AMP release from bone without affecting the cyclic AMP response to CT. Although irradiation caused a dose-dependent inhibition of DNA synthesis, the dose-response curves for that effect and inhibition of escape were not superimposable. A morphologic study of hormonally treated calvaria demonstrated that irradiation prevented the early increase in number of osteoclasts in PTH-treated calvaria that had been observed previously in unirradiated bones. Autoradiography showed that irradiation also prevented the PTH-stimulated recruitment of newly divided mononuclear cell precursors into osteoclasts. This may be correlated with the effect of irradiation to prevent the loss of responsiveness to CT in the presence of PTH.
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    URL: http://dx.doi.org/10.1007/BF02411233
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    Changes in plasma bone GLA protein during treatment of bone disease (1982)
    Springer
    Calcified tissue international 34 (1982), S. 121-124 
    Details
    ISSN: 1432-0827
    Keywords: Bone ; Calcium ; Metabolism
    Source: Springer Online Journal Archives 1860-2000
    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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    URL: http://dx.doi.org/10.1007/BF02411221
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    Tensile properties of antler bone (1982)
    Springer
    Calcified tissue international 34 (1982), S. 301-305 
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    ISSN: 1432-0827
    Keywords: Antler ; Bone ; Collagen ; Tension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The tensile deformation characteristics of compact bone from deer antler were measured in both the “dry” and “wet” states and compared with published values for bovine compact bone. The tensile strength in the wet state (108±5.1 MN/m2) was comparable to the value for bovine compact bone tested at the same strain rate. The modulus value was very low: 7.5±0.9 GN/m2. The work to fracture was comparatively high, about 3 times that for bovine compact bone. Fractographic examination revealed fibrillar and osteonal shear for samples fractured in the dry state. In the samples tested in the wet state, some regions exhibited pull-out of lamellar segments from within a Haversian system. The results are explained in terms of the higher collagen content and lesser degree of mineralization in the antler.
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    URL: http://dx.doi.org/10.1007/BF02411255
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    The effects of long-term immobilization on the histomorphology of human cortical bone (1982)
    Springer
    Calcified tissue international 34 (1982), S. 337-342 
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    ISSN: 1432-0827
    Keywords: Bone ; Histomorphology ; Immobilization ; Quadriplegia ; Multiple sclerosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The cortical bone histomorphometrics, total visible osteon density, and mean osteonal cross-sectional area were determined for the major long bones and sixth ribs of two individuals with neurological deficit. One was a multiple sclerosis patient who had been in a wheelchair for 15 years. The other was a quadriplegic as a result of poliomyelitis. Statistically significant differences in osteon densities occurred only in the case of the quadriplegic. Nevertheless, in that subject, the total visible osteon densities for bones of the right arm were not statistically different from those of their age-matched (control) radii. Medical history records revealed that there had been partial use of this limb. These results support the belief that mechanical stress is an important factor in the maintenance of normal cortical bone remodeling. In addition, since there were subnormal osteon densities and normal mean osteonal cross-sectional areas, immobilization appears to be characterized by reduced activation frequency with a normal amount of bone turnover per BMU.
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    URL: http://dx.doi.org/10.1007/BF02411264
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  • 21
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    Activation of serum complement inhibits collagen synthesis in fetal rat bone in organ culture (1982)
    Springer
    Calcified tissue international 34 (1982), S. 370-375 
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    ISSN: 1432-0827
    Keywords: Complement ; Bone ; Collagen ; Prostaglandins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Activation of rabbit serum complement caused a marked reduction in collagen synthesis but a much smaller change in noncollagen protein synthesis in fetal rat calvaria maintained in organ culture. In the periosteum of the fetal rat calvarium, both collagen and noncollagen protein synthesis were reduced, whereas in the central bone, presumably enriched in osteoblasts, only collagen synthesis was inhibited. This large decrease in bone collagen synthesis could not be attributed to enhanced degradation of newly synthesized collagen or its release into the culture medium. Activation of complement also stimulated the production of PGE in fetal rat calvaria. Antagonists of prostaglandin cyclooxygenase decreased prostaglandin synthesis but did not restore collagen synthesis in complement-treated bones, suggesting that complement decreases osteoblast collagen synthesis by a mechanism largely independent of prostaglandin production.
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    URL: http://dx.doi.org/10.1007/BF02411270
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    Occurrence of actin-like protein in extracellular matrix vesicles (1982)
    Springer
    Calcified tissue international 34 (1982), S. 376-381 
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    ISSN: 1432-0827
    Keywords: Matrix vesicles ; Bone ; Actin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Preliminary indications of the occurrence of actin and myosin in crude matrix vesicle preparations have been reported previously. In the present study extracellular matrix vesicles from rat alveolar bone were isolated. They were further purified by a sucrose density gradient. SDS-polyacrylamide gel electrophoresis of the purified vesicles revealed the presence of a polypeptide with a molecular weight of 43 K daltons and with electrophoretic mobility identical to that of blood platelet actin. The limited proteolysis of both 43 K dalton vesicular polypeptide and actin byStaphylococcus aureus-V8-protease revealed three fragments with identical electrophoretic mobility. In addition, the vesicular preparations inhibited the activity of DNase I, a property typical of actin monomers. Filamentous material extracted from matrix vesicles showed ultrastructural features of F-actin. Reaction of this material with heavy meromyosin resulted in arrowhead formation, which is characteristic of acto-heavy meromyosin. The occurrence of actin in extracellular matrix vesicles may account for their budding from the osteoblastic plasma membrane, their possible motility in the matrix, and maintenance of the spherical shape.
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    URL: http://dx.doi.org/10.1007/BF02411271
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    Abnormal skeletal response to parathyroid hormone in dogs with chronic uremia (1982)
    Springer
    Calcified tissue international 34 (1982), S. 403-407 
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    ISSN: 1432-0827
    Keywords: Cyclic AMP ; Parathyroid hormone ; Bone ; Chronic uremia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The release of cyclic AMP from bone in response to stimulation with PTH 1–34 was examined in 20 dogs with long-term chronic renal failure (CRF) produced by unilateral nephrectomy and contralateral partial renal artery ligation. After 9 to 15 months of uremia, the tibiae were removed and perfused in vitro. Seven dogs with CRF served as controls, 7 dogs with CRF were treated with 24,25(OH)2D3 — 2.5 µg per day, and 6 CRF dogs underwent thyroparathyroidectomy (TPTX) 42 h before they were sacrificed. The release of cyclic AMP from bone in response to PTH 1–34 in the CRF dogs was severely reduced compared to the response observed in 7 dogs with normal renal function (net accumulation of cyclic AMP release 86±8.5 versus 426±59.0 pmol/30 min). Long-term treatment of uremic dogs with 24,25(OH)2D3 had no effect on the release of cyclic AMP by bone. However, the release of cyclic AMP was restored to normal levels in the CRF dogs that underwent thyroparathyroidectomy. All CRF dogs had secondary hyperparathyroidism and the fact that TPTX returned the cyclic AMP response to normal values suggests that desensitization to PTH of the adenylate cyclase system of bone exists in chronic uremia.
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    URL: http://dx.doi.org/10.1007/BF02411275
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    A mathematical model for fluoride uptake by the skeleton (1993)
    Springer
    Calcified tissue international 52 (1993), S. 130-138 
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    ISSN: 1432-0827
    Keywords: Fluoride ; Bone ; Osteoporosis ; Bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary A mathematical model was developed that prediets fluoride accumulation and clearance from the skeleton based upon fluoride bioavailability, bone remodeling rate, and the fluoride binding characteristics of bone. It was assumed that fluoride binds to bone in a nonlinear fashion such that a smaller percentage of fluoride is bound to bone if fluoride intake is increased to high levels. Bone resorption rate was assumed to be proportional to the solubility of hydroxyfluorapatite which is inversely related to bone fluoride content. The predictions made by the model compared favorably with experimental results from fluoride uptake and clearance studies. Parametric studies done using the model showed the following: (1) fluoride can be cleared from the skeleton by bone remodeling, but fluoride clearance takes over four times longer than does fluoride uptake; and (2) fluoride uptake by the skeleton was positively associated with bone remodeling rate. However, the concentration of fluoride in newly formed bone does not decrease with reduced remodeling rates and surpasses 10,000 ppm for intakes of fluoride greater than 9 mg/day. For osteoporosis, daily dose and duration of fluoride treatment should be selected to avoid reaching a toxic cumulative bone fluoride content.
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    URL: http://dx.doi.org/10.1007/BF00308322
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    The effects of diet, age, and sex on the mineral content of primate bones (1993)
    Springer
    Calcified tissue international 52 (1993), S. 399-405 
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    ISSN: 1432-0827
    Keywords: Rhesus monkey ; Bone ; Diet ; Age ; Sex ; Bone mineral
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The effect of diet, age, and sex on the mineral content of primate bones was determined for free-ranging rhesus monkeys (Macaca mulatta) from the Caribbean Primate Research Center. Monkeys in this study were of known age and sex and had been provided with either a low protein (15%) or a high protein (25%) diet for most of their lives. Instrumental neutron activation analysis was used to assess bone mineral content. Results showed that diet had no significant effect on the bulk mineral composition of Ca, Mg, Br, and Cl in the bones. Of the minerals analyzed, only Na and Mn showed significant diet-related effects. The bone Ca content was found to be lower in females than in males when controlled for age. Finally, Ca content was found to be higher in young adults, lower at middle age, and higher in old age in both male and female monkeys. In conclusion, this study has shown that increasing protein content in the diet does not change the bulk mineral content of primate bones. The nondietary effect that Ca content of monkey bones is lower during middle age has not been previously reported.
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    URL: http://dx.doi.org/10.1007/BF00310206
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    Histomorphometry of iliac crest trabecular bone in adult male baboons in captivity (1993)
    Springer
    Calcified tissue international 52 (1993), S. 447-454 
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    ISSN: 1432-0827
    Keywords: Iliac crest ; Bone ; Histomorphometry ; Baboon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Dat in the literature on bone histomorphometry in the baboon are scant. This study provides data from analysis of trabecular bone of the iliac crest of 16 adult male chacma baboons (Papio ursinus) in captivity. Five animals were young adults judging by the presence of growth cartilage in the iliac crest biopsy. Bone volume resembled that in humans, but trabeculae were thinner and more closely spaced. Bone turnover appeared somewhat lower than in humans. Coupling of resorption and formation was excellent as judged by cellular and kinetic variables; erosion surface was an unreliable indicator of ongoing coupling. The similarities between human and baboon trabecular bone make the baboon suited for the study of microstructure and bone turnover of trabecular bone with relevance to humans.
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    URL: http://dx.doi.org/10.1007/BF00571335
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    Osteoclastic resorption of Ca-P biomaterials implanted in rabbit bone (1993)
    Springer
    Calcified tissue international 53 (1993), S. 348-356 
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    ISSN: 1432-0827
    Keywords: Osteoclast ; Giant multinucleated cell ; Biomaterials ; Ceramics ; Morphometry ; Bone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The nature of the multinucleated cells involved in the resorption processes occurring inside macroporous calcium-phosphate biomaterials grafted into rabbit bone was studied using light microscopy, histomorphometric analysis, enzymatic detection of tartrate-resistant acid phosphatase (TRAP) activity, scanning, and electron microscopy. Samples were taken at days 7, 14, and 21 after implantation. As early as day 7, osteogenesis and resorption were observed at the surface of the biomaterials, inside the macropores. Resorption of both newly formed bone and calcium-phosphate biomaterials was associated with two types of multinucleated cells. Giant multinucleated cells were found only at the surface of the biomaterials; they showed a large number of nuclei, were TRAP negative, developed no ruffled border, and contained numerous vacuoles with large accumulation of mineral crystals from the biomaterials. Osteoclasts exhibited TRAP positivity and well-defined ruffled border. They were observed at the surface of both newly formed bone and biomaterials, around the implant, and inside the macropores. In contact with the biomaterials, infoldings of their ruffled border were observed between the mineral crystals, deeply inside the microporosity. The microporosity of the biomaterials (i.e., the noncrystalline spaces inside the biomaterials) increased underneath this type of cell as compared with underneath giant cells or to the depth of the biomaterials. These observations demonstrate that macroporous calcium-phosphate biomaterials implanted in bone elicit osteogenesis and the recruitment of a double multinucleated cell population having resorbing activity: giant multinucleated cells that resorb biomaterials and osteoclasts that resorb newly formed bone and biomaterials.
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    URL: http://dx.doi.org/10.1007/BF01351842
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    Osteocyte death and hip fracture (1993)
    Springer
    Calcified tissue international 53 (1993), S. S113 
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    ISSN: 1432-0827
    Keywords: Bone ; Osteocyte ; Femoral neck fractures
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary The viability of osteocytes can be demonstrated in sawn decalcified sections of bone by their lactate dehydrogenase activity. In the cancellous bone of the femoral head, the proportion of lacunae containing viable osteocytes decreased from 88 ± 7% (mean ± SD) at 10–29 years to 58 ±12% (P 〈 0.001) by 70–89 years. Viability in the second lumbar vertebra was 88 ± 3% in subjects aged 25–90 years and did not decrease with age. Mean osteocyte viability in the femoral head of 21 hip fracture patients aged 72–94 years was 58 ± 21%, similar to controls of a similar age, though there was greater variation and, in five patients, osteocyte viability was less than 25%. In hip, fracture patients, microfracture callus incidence correlated positively with osteocyte viability, with little or no fracture callus observed if the bone viability was low. Ultimate compressive strength did not correlate with osteocyte viability. In the femoral head there is gradual, age-related reduction in osteocyte viability that can be more pronounced in hip fracture. Osteocyte death may affect bone quality by impairing repair of fatigue damage.
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    URL: http://dx.doi.org/10.1007/BF01673417
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    The effects of two centrally-acting anti-hypertensive drugs on the quality of life (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 397-400 
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    ISSN: 1432-1041
    Keywords: Antihypertensive therapy ; Quality of life ; centrally-acting drugs ; clinical trials ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The objectives of this study were to compare the effects of two centrally-acting antihypertensive drugs on measures of quality of life in a three-month double-blind trial of hypertensive patients randomized to methyldopa (n=79) or rilmenidine (n=78). We studied men and women aged over 21 y attending eight hospital out-patient clinics in the United Kingdom. They had average diastolic blood pressures between 95 and 110 mm Hg and systolic pressures below 210 mm Hg after a 4-week placebo run-in period. The doses ranged from 1 to 2 mg daily of rilmenidine and 500 mg to 1 g of methyldopa. Hydrochlorothiazide (25 mg daily) was added after 8 weeks when the diastolic blood pressure remained at 90 mm Hg or more in 29% of patients on rilmenidine and 35% of those on methyldopa. Quality of life was assessed from self-completed questionnaires using standardized instruments. Both drugs reduced blood pressure, but at the end of the trial the fall in the methyldopa group (19.3/13.0 mm Hg) was significantly greater than in the rilmenidine group (13.2/10.0 mm Hg). Ten patients in the methyldopa group withdrew from the trial compared with three in the rilmenidine group, primarily because of adverse effects. In both groups there was a significant increase in the overall reporting of adverse effects. Reports of dry mouth increased on both drugs, and sleepiness on rilmenidine but not methyldopa. There was no significant difference between the drugs in the overall reporting of adverse effects or of individual adverse effects. Psychological well-being tended to improve on rilmenidine, but was adversely affected by methyldopa, with increases in reports of depression and cognitive impairment. However, at the end of the trial there were no significant differences in overall psychological well-being between the two groups.
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    URL: http://dx.doi.org/10.1007/BF00626358
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    Morphine-sparing effect of diclofenac in cancer pain (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 1-5 
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    ISSN: 1432-1041
    Keywords: Morphine ; Diclofenac ; Cancer pain ; analgesia ; patient-controlled-analgesia ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effectiveness of diclofenac 50 mg t.i.d. as additive treatment to parenteral patient-controlled administration therapy (PCAT) with morphine in cancer pain has been investigated in a double-blind study. In the fifteen patients who completed the study, morphine i.v. was titrated to optimal pain relief over 5 days. The mean total morphine consumption was significantly reduced during diclofenac administration (82.8 mg morphine per day) compared to placebo (95.0 mg morphine per day). The reduction in mean morphine consumption during active treatment with diclofenac was independent of the initial dose of self-titrated morphine. Pain, self-assessed according to VAS, tended to be lower during the diclofenac period, although the difference did not reach statistical significance. No adverse events were recorded among the 15 patients who completed the study. The present findings show that a non-steroidal anti-inflammatory agent, such as diclofenac, has a morphine-sparing effect in morphine-treated patients with cancer pain.
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    Systemic and renal haemodynamic effects of angiotensin converting enzyme inhibition by zabicipril in young and in old normal men (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 35-39 
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    ISSN: 1432-1041
    Keywords: Zabicipril ; Haemodynamics ; ACE-inhibition ; renal plasma flow ; glomerular filtration rate ; normal males ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Zabicipril is a recently introduced angiotensin converting enzyme (ACE) inhibitor, which has been observed in experimental animals to increase diuresis, natriuresis, glomerular filtration rate (GFR) and renal plasma flow (RPF). We have investigated the acute effects of zabicipril on systemic and renal haemodynamics in two groups of 8 sodium-replete normal men, aged 23 to 30 y and 65 to 74 y. Zabicipril 0.5 mg, 1 mg or 2.5 mg and a placebo were administered orally, at one week intervals, in a random order and in a double blind fashion. Haemodynamic measurements were performed at base line and every hour for 4 hours after intake of drug or placebo. Cardiac output (Q) was measured by Doppler echography, and RPF and GFR by the constant infusion technique using I123 iodohippurate and Cr51 EDTA, respectively. In the young men zabicipril did not affect Q, heart rate (HR), systemic arterial pressure (AP) or GFR, but it did increase RPF at the 4th hour after the highest dose (from 540 to 653 ml · min−1 · m−2). In the old men zabicipril had similar actions, but the effect of the highest dose on RPF (from 355 to 415 ml · min−1 · m−2) was less marked than in the young men. In the young and old men the inhibition of ACE peaked at about of 90% or more from the 2th to the 4th hour after the highest dose of zabicipril. We conclude that, in normal men, zabicipril increases the renal fraction of cardiac output in the absence of a concomitant change in systemic haemodynamics. This specific effect of zabicipril on the kidney may be less important with advancing age.
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    URL: http://dx.doi.org/10.1007/BF00315277
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    Effect of ampicillin on mefloquine pharmacokinetics in thai males (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 631-633 
    Details
    ISSN: 1432-1041
    Keywords: Mefloquine ; ampicillin ; Thai subjects ; pharmacokinetics ; enterohepatic recycling ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml−1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 μg·ml−1 day). These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.
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    URL: http://dx.doi.org/10.1007/BF00279985
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    Dose-dependent uricosuric effect of ambroxol (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 237-241 
    Details
    ISSN: 1432-1041
    Keywords: Ambroxol ; Uricosuric effect ; uric acid clearance ; creatinine clearance ; hypoxanthine ; diurnal rhythm ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ambroxol is known to promote bronchial secretion and is used as an expectorant. Previous studies had suggested that high doses of ambroxol could reduce the plasma uric acid concentration. The present study was undertaken to confirm this finding, to determine its dose-response relationship and to identify the underlying mechanism of action. Using a placebo-controlled, double-blind parallel group design, 48 healthy male volunteers were randomly allocated to receive placebo b.d. and ambroxol 125 mg b.d., 250 mg b.d. or 500 mg b.d. (12 subjects per group). The subjects were hospitalised during a dietary run-in period of 3 days (Days -3 to -1) and a treatment period of 5 days (Days 1 to 5). On Day -1 (baseline) and Days 1 to 5, all urine was collected and blood samples were taken for the analysis of uric acid, creatinine, xanthine and ambroxol. The measurements were repeated four days after treatment had closed. Steady state plasma concentrations of ambroxol (trough levels) were reached after 2 or 3 days and were linearly related to dose. Ambroxol induced a significant, dose-dependent, reduction in plasma uric acid (250 mg b.d. about 20%; and at 500 mg b.d. about 30%). The diurnally fluctuating uric acid clearance was dose dependently increased and there was no notable effect on creatinine clearance. Plasma hypoxanthine levels were not affected by ambroxol. No severe adverse events were reported and no drug induced changes in the clinical laboratory values were observed. It is concluded that ambroxol has an uricosuric action following oral administration of higher doses (250 mg-500 mg b.d.) and it is well tolerated.
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    URL: http://dx.doi.org/10.1007/BF00271364
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    Acute haemodynamic effects and pharmacokinetics of ramipril in patients with heart failure (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 241-246 
    Details
    ISSN: 1432-1041
    Keywords: Heart failure ; haemodynamics ; ramipril ; ACE-activity ; ACE-inhibitor ; plasma levels ; urine levels ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; −59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng·ml−1. The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.
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    Ambulatory blood pressure monitoring in elderly hypertensives treated with the new calcium antagonist, nilvadipine (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 255-257 
    Details
    ISSN: 1432-1041
    Keywords: Nilvadipine ; Hypertension ; elderly patient ; circadian rhythm ; ambulatory blood pressure monitoring (ABPM) ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary. A newly developed calcium antagonist, nilvadipine, was administered to 7 hypertensive patients aged 75.6 y. Nilvadipine 4 mg b.d. decreased the average 24-h blood pressure significantly from 169/89 mm Hg to 152/81 mm Hg after 7 to 14 days without any change in the pulse rate. The circadian patterns of blood pressure and pulse rate were not affected by nilvadipine. Although the present study was a preliminary one done over a short period in a small number of patients, the results suggest that nilvadipine exerts an antihypertensive effect without altering the circadian pattern or the variability of blood pressure in elderly hypertensive patients.
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    Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 263-265 
    Details
    ISSN: 1432-1041
    Keywords: Metformin ; Glibenclamide ; NIDDM ; lipoproteins ; C-peptide ; diabetes mellitus ; adverse effects ; serum lipids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary. Twenty-two NIDDM patients completed an open randomized cross-over study comparing metformin and glibenclamide over 1 year. The drugs had an equivalent effect on glycaemic control, but, in contrast to glibenclamide, metformin reduced body weight. Neither drug affected triglycerides, total-and LDL-cholesterol or C-peptide. Metformin caused a slight elevation of HDL-cholesterol (P 〈 0.05). No serious adverse effects were observed. The results show that oral hypoglycaemic agents are not associated with undesirable effects on lipids and lipoproteins.
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    URL: http://dx.doi.org/10.1007/BF00315441
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    Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 259-261 
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    ISSN: 1432-1041
    Keywords: Cushing's disease ; Mitotane ; o,p'-DDD ; long term treatment ; plasma monitoring ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary. Mitotane (o,p'-DDD) can be used for the treatment of various adrenocortical diseases such as Cushing's syndrome, but the usual doses of 6–8 g per day are often associated with severe adverse effects. This paper reports the results of much lower doses of o,p'-DDD (0.5–2 g per day) in two patients with Cushing's disease over periods of 8 and 5 years, respectively, under concomitant monitoring of the plasma levels of the parent drug and its major metabolite, o,p'-DDE. It became apparent that o,p'-DDD and o,p'-DDE have a strong tendency to accumulate in the body due to their high lipophilicity. As a consequence, changes in dose regimens had long lag times before they were reflected in plasma levels and once an increase or decrease had started one had to be careful not to cause overshoot. Steady state plasma levels of o,p'-DDD between 5–10 μg/ml appeared sufficient to induce and to maintain remission of the disease, which was accompanied with normal cortisol levels in plasma and urine. DDD-levels below 5 μg/ml for several weeks may lead to relapses, whereas DDD-levels over 10 μg/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 μg/ml in plasma.
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    Buccal versus intravenous nitroglyerin in unstable angina pectoris (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 5-9 
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    ISSN: 1432-1041
    Keywords: Unstable angina pectoris ; Buccal nitroglycerin ; intravenous nitroglycerin ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical syndrome of unstable angina includes patients with the first onset of angina, change in a previous stable pattern or the development of chest pain at rest. Administration of intravenous nitroglycerin is established therapy in unstable angina. Buccal nitroglycerin has been introduced as an alternative means of administering nitroglycerin, which provides relief of anginal pain within 2 to 3 min and a sustained effect for 3 to 5 h. Twenty-nine patients admitted to the coronary care unit due to unstable angina were randomized to receive treatment with nitroglycerin i.v. for 24 h or buccal nitroglycerin every 4 h. Therapy was titrated according to haemodynamic effects. The mean dose of buccal nitroglycerin was 4.42 mg versus 0.45 ug·kg−1·min−1 in the intravenous group. The efficacy of treatment was similar in the two groups. Buccal nitroglycerin appeared to cause fewer adverse effects, especially less haemodynamic intolerance and headache, although the differences were not significant. Repeated administration of buccal nitroglycerin appears to be a safe and well tolerated alternative to high-dose i.v. nitroglycerin treatment in unstable angina pectoris.
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  • 39
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    Relationship between renal function and disposition of oral cefixime (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 579-583 
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    ISSN: 1432-1041
    Keywords: Cefixime ; renal failure ; pharmacokinetics ; volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC. There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulte in uraemic patients, has antibacterial activity. In normal subjects, the peak serum level (Cmax) was 2.50 μg·ml−1 at 2.83 h (tmax); the apparent elimination half-life (t1/2) was 3.73 h; the apparent total body clearance (CL·f−1) was 154 ml·min−1, the mean renal clearance (CLR) was 39.1 ml·min−1 and the apparent fraction of the dose recovered in 24 h urine was 0.22. In uraemic patients, Cmax and tmax were slightly increased and t1/2 was increased to 12–14 h in patients with an endogenous creatinine clearance below 20 ml·min−1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CLR and creatinine clearance (CLCR). The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.
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  • 40
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    Pharmacokinetics and pharmacodynamics of quinaprilat after low dose quinapril in patients with terminal renal failure (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. S53 
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    ISSN: 1432-1041
    Keywords: Quinapril ; Renal failure ; quinaprilat ; haemodialysis ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of the ACE inhibitor quinaprilat have been studied in six chronic haemodialysis (HD) patients and in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after a single oral dose of 2.5 mg quinapril. Mean tmax and Cmax values (SEM) for quinaprilat in interdialytic HD patients were 4.0 (0) h and 84 (8.4) ng · ml−1 respectively, and they did not differ significantly from those in CAPD patients (4.7 (0.7) h and 64 (5.7) ng · ml−1). Elimination half lives were 30 (10.1) h (HD) and 34 (7.3) h (CAPD). Cmax, tmax, t/12, and AUC were increased and CL was decreased compared to data reported previously after giving 2.5 mg to healthy subjects. Peritoneal clearance was calculated as 0.1 (0.1) ml · min−1, thus less than 0.5 % of the dose were removed within 24 h by CAPD. ACE activity was suppressed by more than 93 % between 4 and 24 h postdose (P 〈 0.001). It decreased in both groups with increasing plasma quinaprilat levels. Angiotensin II concentration compared to baseline was significantly decreased at 4 hours (−30.4±10 %) and 24 h (−30±9.9 %) (P 〈 0.05,n=11), while active plasma renin concentration was still significantly increased at 48 h postdose (+60.2±14.5 %,P 〈 0.01). Mean arterial pressure 24 h postdose was significantly (P 〈 0.05) decreased in HD (−12 mm Hg) and CAPD patients (− 20 mm Hg). Only two patients reported unwanted effects (fatigue, dizziness, nausea, and weakness). In conclusion, due to its long lasting effect on ACE activity and on blood pressure in terminal renal failure a starting dose of quinapril 2.5 mg o. d. may be used in hypertensive HD and CAPD patients.
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  • 41
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    Pharmacokinetics of ibuprofen in febrile children (1991)
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    European journal of clinical pharmacology 40 (1991), S. 427-428 
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    ISSN: 1432-1041
    Keywords: Ibuprofen ; children ; fever ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC. The maximum observed serum concentrations of ibuprofen ranged from 17–42 μm·ml−1 at 5 mg·kg−1 and 25–53 μm·ml−1 at 10 mg·kg−1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean tmax, oral clearance and elimination half life were 1.1 h, 1.2 ml·min−1·kg−1, and 1.6 h, respectively in patients at 5 mg·kg−1 doses; the corresponding values were 1.2 h, 1.4 ml·min−1·kg−1, and 1.6 h in those receiving 10 mg·kg−1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients. These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.
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  • 42
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    Double-blind, placebo controlled comparison of paracetamol and paracetamol plus codeine — a quantitative evaluation by laser induced pain (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 241-247 
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    ISSN: 1432-1041
    Keywords: Paracetamol codeine ; Experimental pain ; laser ; evoked potential ; threshold ; hypoalgesia ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The aim of the present double-blind, placebo controlled, three-way cross over study was to evaluate the analgesic efficacy of single oral doses of paracetamol 1.0 g and paracetamol 1.0 g plus codeine 60 mg. Pain threshold and brain evoked potentials to laser stimulation were determined hourly for 6 h in 12 healthy volunteers. Pain threshold was significantly elevated compared to placebo 1 and 2 h after paracetamol ingestion. Paracetamol 1.0 g plus codeine 60 mg was superior to placebo 1 to 6 h after medication. Only at 1 and 2 h after ingestion the combined drug was better than paracetamol. The evoked potentials were significantly depressed compared to placebo 2 and 4 h after paracetamol. The combination of paracetamol and codeine was superior to placebo 1 to 6 h after ingestion. The potentials showed no difference between the two active drugs. The total analgesic effect (approximation of area under the time-efficacy curve), showed that the combined drug was superior to plain paracetamol. A higher incidence of adverse effects in 10 of the 12 subjects was observed after ingestion of the combined drug compared to plain paracetamol (1 of 12). Paracetamol appears to exert part of its action by a cental effect. There was at least 1 h between the peak plasma concentration of paracetamol and the peak hypoalgesia.
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    Correlation between pharmacokinetics and clinical effects of ergotamine in patients suffering from migraine (1982)
    Springer
    European journal of clinical pharmacology 21 (1982), S. 397-402 
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    ISSN: 1432-1041
    Keywords: ergotamine ; migraine ; radioimmunoassay ; clinical effects ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headachefree state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6h. Their mean plasma levels at 30 min (0.33ng/ml) and 1h (0.40ng/ml) were significantly higher than those (0.06 and 0.08ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11ng/ml) responders appeared later (at 3h) than in good responders (at 1h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20ng/ml or more is achieved within 1 hour after oral or rectal administration.
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    Long-term therapy of arterial hypertension with nifedipine given alone or in combination with a beta-adrenoceptor blocking agent (1982)
    Springer
    European journal of clinical pharmacology 22 (1982), S. 101-103 
    Details
    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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    Kinetics of cholinesterase inhibition by eptastigmine in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 83-84 
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    ISSN: 1432-1041
    Keywords: Eptastigmine ; cholinesterase inhibitor ; Alzheimer's disease ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00280116
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  • 46
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    Pharmacokinetic investigation of oral and IV dihydroergotamine in healthy subjects (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 597-602 
    Details
    ISSN: 1432-1041
    Keywords: Dihydroergotamine mesilate ; pharmacokinetics ; urinary excretion ; prolonged half-life ; deep compartment ; RIA ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized crossover trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz=33 l/kg) and a high plasma clearance (CLP=2l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8′-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.
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  • 47
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    Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 107-112 
    Details
    ISSN: 1432-1041
    Keywords: Metformin ; Diabetes mellitus ; noninsulin-dependent ; secondary failure to sulphonylureas ; combined therapy ; glucose homoeostasis ; plasma lipids ; blood pressure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin. At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose −4.1 mmol·l−1; glycosylated haemoglobin A1 decrease −1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These postive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile 〈10 mmol·l−1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile 〉10 mmol·l−1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (−21.6 U/day). Metformin was well tolerated by all diabetics. Combining metforming with insulin in obese, insulin-treated and poorly controlled diabetics may represent a safe strategy to achieve better glycaemic control with a reduction in certain metabolic risk factors associated with the increased incidence of cardiovascular disease in diabetes mellitus.
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    Pharmacokinetic study and effects on growth hormone secretion in healthy volunteers of the new somatostatin analogue BIM 23014 (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 73-77 
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    ISSN: 1432-1041
    Keywords: BIM 23014 ; Somatostatin analogue ; growth hormone ; GHRH test ; OGTT ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics and the effects of BIM 23014 (BIM), a new, long-acting octapeptide somatostatin analogue, on basal and stimulated GH secretion in normal men. BIM 250 μg sc significantly reduced a GHRH-induced increase in plasma GH. The continuous sc administration of BIM for 24 h dramatically blunted spontaneous GH secretion; 2000 and 3000 μg daily reduced GH secretion to a greater extent than 1000 μg daily. During these experiments a significant negative correlation (r−0.66) was found between plasma GH and BIM levels. Acute sc administration of 1000 μg BIM significantly reduced the rise in plasma GH observed in the second part of the oral glucose tolerance test. Plasma BIM levels peaked around 30 min, and the elimination half life was 90 min. Plasma BIM levels were below 1 ng/ml 6 h after the injection of 1000 μg BIM, and at that time GH started to rise again. We conclude that BIM 23014 250 to 1000 μg sc is able to reduce the plasma GH response to GHRH or to the fall in glucose following an oral glucose tolerance test; a constant infusion of BIM, in doses 1000 μg daily, dramatically suppresses spontaneous GH secretion; 2000 μg/day by chronic subcutaneous infusion was the most effective dose of BIM in the suppression of GH secretion, and was associated only with minor adverse effects.
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    Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 113-116 
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    ISSN: 1432-1041
    Keywords: Repaglinide ; Glibenclamide ; Diabetes mellitus ; oral hypoglycaemic agent ; Phase II study ; metabolic control ; non-insulin-dependent diabetes ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have evaluated the effects of repaglinide, a new non-sulphonylurea oral hypoglycaemic agent that has a stimulatory effect on insulin secretion. Forty-four patients with NIDDM, already treated with a sulphonylurea, took part in an open, randomised, group comparison study of 12 weeks duration, during which they received either repaglinide or glibenclamide twice daily. While glibenclamide had a greater effect on fasting blood glucose (10.4 to 8.6 mmol·l−1), repaglinide significantly lowered postprandial blood glucose (13.8 to 12.2 mmol· l−1). Glycosylated haemoglobin remained unchanged in both groups, and serum fructosamine showed a tendency to fall. With both treatments total cholesterol was significantly decreased after 12 weeks, while HDL-cholesterol and triglycerides did not change. Fasting plasma insulin in the repaglinide group decreased from 80 (median value) to 67 pmol·l−1; it did not change in the glibenclamide group. Two patients in the repaglinide group did not complete the study, one for personal reasons, and one because of a rise in blood glucose. No abnormal findings attributable to repaglinide were observed in clinical and laboratory examinations, and no hypoglycaemic symptoms caused by it were observed.
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    Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 129-134 
    Details
    ISSN: 1432-1041
    Keywords: Nitrendipine ; Hypertension ; pharmacokinetics ; renal function ; hypertensive crisis ; pharmacodynamics ; blood pressure ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nitrendipine solution 5 mg·ml−1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (≥110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance 〈5 ml·min−1) and 10 were at the predialysis stage (endogenous creatinine clearance 5–20 ml·min−1). The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy. After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups. The mean maximum plasma concentration was 14.8 μg·1−1 in the study population as a whole, with comparable means in the dialysis (17.3 μg·1−1) and non-dialysis (12.4 μg·1−1) groups. The nitrendipine solution proved to be effective in lowering acutely elevated blood pressure in patients with advanced renal failure and renal hypertension, and was well tolerated. The pharmacokinetics was not affected by renal impairment or by dialysis.
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    Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 141-145 
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    ISSN: 1432-1041
    Keywords: Platelet activating ; Factor RP 48740 ; platelet aggregation ; PAF-antagonist ; dose-response relationship ; adverse effects ; pharmacokinetics ; dose-response relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and exvivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg·l−1. There were no clinical or biological adverse reactions to RP 48740 during the study.
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    Dose-proportionality of eltoprazine (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 485-488 
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    ISSN: 1432-1041
    Keywords: Eltoprazine ; pharmacokinetic ; serenics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eltoprazine. HCl belongs to a new class of psychotropic drug, the serenics. The dose-proportionality and pharmacokinetics of eltoprazine HCl has been investigated after single oral doses of 5, 10, 20 mg (18 subjects) and 30 mg (12 subjects) in a partly randomized, cross-over design. Eltoprazine was well tolerated and there were no relevant changes in safety parameters. All subjects showed irregular plasma-concentration-time profiles, some subjects demonstrating secondary peaks. The mean half-life was calculated to be about 6.5 h. The renal excretion of eltoprazine was characterized by net tubular secretion. AUC, peak plasma concentrations and the amount excreted unchanged in the urine were linearly related to the dose. Renal clearance and t1/2 were independent of dose. Thus, eltoprazine HCl was well tolerated orally and exhibited a linear pharmacokinetic profile.
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    Use of pentoxifylline as an inhibitor of free radical generation in peripheral vascular disease (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 511-515 
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    ISSN: 1432-1041
    Keywords: Pentoxifylline ; Free radical generation ; peripheral vascular disease ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of an infusion of pentoxifylline 1 g as an inhibitor of free radical generation have been determined in a double-blind placebo-controlled study. Leucocyte-derived free radical generation (by the superoxide dismutase-inhibitable reduction of ferricytochrome), the release of reactive oxygen metabolites (as plasma oxidant activity), unfractionated leucocyte and erythrocyte filterability rates (using a constant-flow positive-pressure system), plasma viscosity, and plasma fibrinogen concentration have been measured in two matched groups of 10 patients with Stage II peripheral vascular disease, before and after treatment. Transcutaneous oxygen pressure (PtcO2) during treadmill exercise to stress leg circulation was also measured. Leucocyte-derived free radicals were generated during peripheral ischaemia. Pentoxifylline inhibited their generation, blocked the release of reactive oxygen metabolites, and reduced impairment of the filterability rate of unfractionated leucocytes. The improvements were accompanied by significant shortening of the half-time of recovery of transcutaneous oxygen pressure, indicating that ischaemic damage had been contained.
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    Electrophysiological effects of intravenous rilmenidine in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 537-540 
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    ISSN: 1432-1041
    Keywords: Rilmenidine ; α-adrenoceptors ; clonidine ; cardiac electrophysiology ; cardiac rhythm ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten patients (44 y), 6 with the Wolff-Parkinson-White syndrome, and none with hypertensive disease, underwent electrophysiological studies before and after intravenous infusion of a single dose of 1 mg rilmenidine administered over 15 min. The regimen produced a mean plasma rilmenidine concentration of 3.16 ng·ml−1 at the end of the infusion. There was no significant change in sinus cycle length, PR interval, QRS, QT duration or in PA, AH and HV intervals. Estimated sinoatrial conduction time and corrected sinus node recovery time did not significantly change. In one patient, however, an abnormal pause was noted after termination of rapid atrial pacing. The right atrial effective refractory period decreased from 209 to 194 ms. There was no significant change in the anterograde and retrograde block cycle length or in the refractoriness of the nodal, ventricular and accessory pathways. The cycle length of induced reciprocating tachycardia decreased slightly from 374 to 351 ms. No patient exhibited an abnormal response to the carotid sinus massage. The findings indicate that intravenous administration of 1 mg rilmenidine exerts modest effects on the electrophysiological parameters of the human heart.
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    Renal and hormonal effects and tolerance of an ANP analogue in healthy man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 547-554 
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    ISSN: 1432-1041
    Keywords: Atrial natriuretic peptide ; P-ANP ; Hormonal effects ; Angiotensin II ; aldosterone ; arginine vasopressin ; PgE2 ; cGMP ; renal plasma flow ; urinary sodium excretion ; healthy volunteers ; blood pressure ; renal tubular function ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of an analogue of atrial natriuretic peptide (P-ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by the lithium clearance technique, and plasma levels of sodium and water homeostatic hormones, has been studied in 40 healthy males. Placebo or P-ANP 0.3, 1.5, or 3.0 μg·kg−1 bwt were given as an intravenous bolus injection to different groups. P-ANP did not cause any immediate change in GFR or RPF, but significant dose-dependent increases in filtration fraction, urinary flow rate and urinary excretion rate of sodium were detected during the first 30 min after administration. Proximal absolute and fractional tubular reabsorption and distal absolute tubular reabsorption of sodium did not change after injection of P-ANP, while the distal fractional reabsorption of sodium was reduced in a dose dependent manner during the first 30 min. Plasma angiotensin II and aldosterone were significantly increased 30 and 150 min after dosage, whereas plasma atrial natriuretic peptide, plasma arginine vasopressin, and urinary excretion of prostaglandin E2 were unchanged. Cyclic guanosine monophosphate both in plasma and urine were increased in a dose-dependent manner. P-ANP cause a significant reduction in diastolic blood pressure and an increase in pulse rate. Two subjects had vasovagal syncope 30–60 min after injection of P-ANP. It is concluded that P-ANP has natriuretic, diuretic and hypotensive properties in healthy man.
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    Cyclic hormonal replacement therapy after the menopause: Transdermal versus oral treatment (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 555-559 
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    ISSN: 1432-1041
    Keywords: menopause — oestradiol ; conjugated oestrogens ; transdermal delivery ; postmenopausal women ; medroxyprogesterone ; acetate ; plasma lipids ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open, randomized, comparative, between-patient trial, 45 postmenopausal women were treated for 4 months with cyclical transdermal oestradiol 0.05 mg per day or oral conjugated equine oestrogens 0.625 mg per day, in both cases, plus, medroxyprogesterone acetate 10 mg per day on the last 8 days of each cycle. Similar relief from postmenopausal symptoms was obtained with both treatments. Post-treatment histological evaluation of the endometrium did not reveal neoplastic or hyperplastic change in any patient. Early follicular-phase plasma oestradiol levels were observed only after transdermal oestradiol. There was a significant reduction in serum total cholesterol and LDL cholesterol in both treatment groups, with no difference between treatments, whereas serum triglyceride levels were decreased only by transdermal oestradiol. Plasma calcium and phosphorus fell significantly and serum intact parathyroid hormone rose significantly, with no difference between the therapies. No significant changes were observed in clotting factors. Transdermal oestradiol appears to be an effective and safe hormonal replacement therapy, and this route of administration may be responsible for the more useful action of the drug on serum lipids and plasma oestradiol levels.
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    Inhibition of sucrose- and starch-induced glycaemic and hormonal responses by the α-glucosidase inhibitor emiglitate (BAY o 1248) in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 561-567 
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    ISSN: 1432-1041
    Keywords: Emiglitate (BAY o 1248) ; sucrose ; starch ; postprandial hyperglycaemia ; glucosidase inhibitor ; blood glucose ; serum insulin ; serum GIP ; breath hydrogen ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorbable deoxynojirimycin derivative emiglitate (BAY o 1248) is a potent competitive inhibitor of small intestinal α-glucosidases in man. In two similar randomized, placebo-controlled, double blind investigations, the efficacy, duration of action and tolerability of single doses of 10, 20 and 40 mg emiglitate have been assessed in healthy male volunteers after repeated sucrose or maize-starch loads at 08.00, 12.00 and 17.00 h. Even at the lowest dose used, emiglitate almost abolished the glycaemic (−88%) and hormonal responses after the first sucrose meal, simultaneously evoking significant hydrogen evolution (mean peak H2-concentration 〉100 ppm), which was not related to the dose, and which induced unacceptable symptoms of carbohydrate malabsorption, i.e. at the dosages tested, the inhibition of glycaemic and hormonal responses was at the expense of intolerable gastrointestinal adverse effects. Flattening of postprandial responses of blood glucose, serum insulin and gastric inhibitory polypeptide was still apparent after a second sucrose load 4 h later, demonstrating long-lasting inhibition of α-glucosidase activity. After starch, the dose dependency of inhibition emerged more clearly than after sucrose, i.e. the reduction was less pronounced. However, emiglitate led to significant reduction of the glycaemic and hormonal rises after both the first and second starch meals. Symptoms of carbohydrate malabsorption were absent after 10 mg and were negligible with 20 mg or 40 mg emiglitate. Breath hydrogen concentration increased gradually, indicating slight but significant carbohydrate malabsorption after the highest dose of the α-glucosidase inhibitor. The results show that a single morning dose of 20–40 mg emiglitate might be useful in the control of postprandial hyperglycaemia after breakfast and lunch. This dose of the inhibitor was effective after either both 50 g starch or 50 g sucrose as the substrate, but was only tolerable after the starch meal.
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    Pharmacokinetics of paroxetine in patients with cirrhosis (1991)
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    European journal of clinical pharmacology 41 (1991), S. 351-354 
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    ISSN: 1432-1041
    Keywords: Paroxetine ; Cirrhosis ; pharmacokinetics ; multiple-dose study ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20–30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg. Dose-corrected, trough drug concentration at steady state (CSS min) and dose-corrected AUC24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng · ml−1 per mg paroxetine and 89 vs 43 h (ng) · ml−1 per mg paroxetine]. The elimination t1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.
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    Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 429-434 
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    ISSN: 1432-1041
    Keywords: Ticlopidine ; Platelet aggregation ; Anti-aggregating drugs ; Pharmacodynamics ; plasma levels ; intracellular drug ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 normal volunteers given single oral doses of 250, 500 and 1000 mg ticlopidine (T), the peak plasma level of unchanged drug was reached after about 2 h. There was no correlation between the plasma T level and its inhibitory effect on platelet function, expressed as % inhibition of ADP-induced aggregation. By means of HPLC and GC/MS significant concentrations of T were demonstrated in washed red cells, platelets and neutrophils, with a marked difference in the time course of the appearance of cell-associated drug. The time course of platelet-associated T very accurately fitted that of the antiaggregatory activity. After subacute oral administration (250 mg b. d. for 7 days), the maximum effect on platelet function was observed after 3 to 4 days, when a significant concentration of platelet-associated T had been reached. The pharmacological effect persisted as long as drug was detectable in platelet. An in vitro study strongly suggested that the antiaggregating effect was retained by treated washed platelets but not by treated plasma. It is suggested that the platelet compartment represents the pharmacological target of T via a specific uptake system.
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    The effects of repeated doses of clomipramine and alprazolam on physiological, psychomotor and cognitive functions in normal subjects (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 355-362 
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    ISSN: 1432-1041
    Keywords: Clomipramine ; alprazolam ; psychomotor performance ; cognitive effects ; adverse effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10. The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam. Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam. It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.
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    The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous, intramuscular, and subcutaneous injection (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 399-403 
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    ISSN: 1432-1041
    Keywords: Lisuride ; pharmacokinetics ; prolactin concentrations ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 μg lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min−1·kg−1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.
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    Cadralazine versus prazosin as second-step treatment in hypertensive patients on beta-blockers: a randomized multicentre study (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 461-465 
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    ISSN: 1432-1041
    Keywords: Cadralazine ; hypertension ; prazosin ; metoprolol ; combined therapy ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A randomized multicentre between-patient study comparison has been made of the efficacy and tolerability of cadralazine and prazosin, both administered for 6 weeks to hypertensive patients with a supine diastolic blood pressure (DBP) ≥ 95 mm Hg whilst on a beta-adrenoceptor-blocker. The doses of the beta-adrenoceptor-blocker (metoprolol SR 200 mg once daily) and cadralazine (10 mg once daily) were held constant during the study, while prazosin was individually titrated from 0.5 mg to a maximum of 2 mg tds. 108 patients (50 m and 58 f; mean age 54 y) were enrolled in 12 centres. Twelve patients withdrew due to adverse effects or poor efficacy (5 patients on prazosin and 7 on cadralazine). Both treatments induced a similar significant reduction in systolic blood pressure (SBP) and DBP, allowing normalization of BP in 58% of subjects on cadralazine and 55% on prazosin. Heart Rate (hR) increased significantly from 67 to 72 beats · min−1 in those on cadralazine and from 65 to 69 beats · min−1 on prazosin. Body weight was unchanged. Adverse effects were mild and typical of vasodilators, such as headache, flushing and dizziness. Physician evaluation of drug efficacy was not different between drugs, and cadralazine was rated better in terms of tolerability. Thus, in this multicentre study, cadralazine in the fixed dose of 10 mg once daily, as a second-step antihypertensive treatment in patients not satisfactorily controlled by a beta-adrenoceptor-blocker, was as effective and showed a similar side effect profile to prazosin given three times daily.
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    Pharmacodynamics and pharmacokinetics of eptastigmine in elderly subjects (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 373-376 
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    ISSN: 1432-1041
    Keywords: Eptastigmine ; Cholinesterase inhibition ; Elderly subjects ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eptastigmine is a new cholinesterase inhibitor, which may be potentially useful for the symptomatic treatment of Alzheimer's disease. A preliminary evaluation of its pharmacodynamic and pharmacokinetic profiles in the elderly has now been made in 6 healthy subjects (63–84 years of age) given 30 mg eptastigmine as a single oral dose. Blood was collected prior to and 1, 2, 3, 4, 6, 8, and 12 h after eptastigmine administration for measurement of cholinesterase inhibition in plasma and red blood cells and the plasma drug concentrations. The maximum plasma cholinesterase inhibition was 17%, which was reached 2.7 h after treatment. In red cells the maximum inhibition of the enzyme was 29% after 3.8 h. The estimated half-time of cholinesterase recovery was 12.4 h in plasma and 13.6 h in red blood cells. The peak plasma concentration of eptastigmine of 0.86 ng·ml−1 was reached after 1.4 h. Following absorption the drug was rapidly distributed into tissues (t1/2α = 0.44 h) and then eliminated with a half-life of 12.1 h. The drug was well tolerated in all but one subject, who showed bradycardia with hypertension and nausea for about 2 h after the dose. The results indicate that oral administration of eptastigmine to elderly subjects produces long lasting inhibition of cholinesterase activity in plasma and in red blood cells.
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    Racemic therapeutics — ethical and regulatory aspects (1991)
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    European journal of clinical pharmacology 41 (1991), S. 89-93 
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    ISSN: 1432-1041
    Keywords: Racemates therapeutics ; ethical aspects ; isomers ; adverse effects ; chirality drug stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Racemic therapeutics are fixed ratio mixtures of stereoisomers to be regarded biologically as different compounds. Usually only one of the isomers fully contributes to the therapeutics action, and the other is often classifiable as “isomeric ballast”. Due to differences in turnover and pharmacokinetics, the proportion of enantiomers (1:1 in the racemate) continuously changes in plasma. The implications of the neglect of stereoselectivity for various levels in the investigation of racemic drugs are discussed and summarized in Table 2. The fact is that clinical investigators, Ethical Committees and regulatory authorities have for decades accepted invalid pharmacokinetic data on some 25% of therapeutics. That those racemates remain in use make the benefit of and necessity for kinetics generally questionable. Exposure of patients to the “isomeric ballast” present in about 50% of the most commonly used drugs will probably containe for many decades. As a result of a change in attitude of the regulatory authorities, however, for new drugs the choice in future between the racemic therapeutic or the single isomeric ballast-free drug will largely be based on a critical evaluation of the chiral characteristics with regard to their therapeutic, toxicological and pharmacokinetic aspects.
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    Pharmacokinetics and β-blocking effects of transdermal timolol (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 493-495 
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    ISSN: 1432-1041
    Keywords: Timolol ; β-adrenoceptor antagonist ; transdermal ; percutaneous absorption ; skin ; pharmacokinetics ; bioavailability ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic profiles of transdermal timolol 6 and 24 mg (as 5 and 20% w/v patches) was studied in four healthy young volunteers. To assess its bioavailability, the pharmacokinetics of an IV infusion of timolol maleate 5 mg was also determined in the same subjects. When the 20% (w/v) timolol patch was applied, the mean bioavailability was 74.4%. Plasma timolol concentrations were below the detection limit when a 5% patch was applied to the same skin area in all four subjects, except for one in whom the bioavailability was 23.6%. Weak erythema developed at the application site in all of the volunteers after application of the 20% (w/v) patch. However, erythema did not develop in any volunteer when the 5% patch was applied. The β-blocking effect was determined by exercise testing. Similar plasma levels generated similar changes in exercise-induced heart rate after the transdermal and intravenous administration of timolol.
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    Enalapril versus atenolol in the treatment of hypertensive smokers (1993)
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    European journal of clinical pharmacology 44 (1993), S. 13-17 
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    ISSN: 1432-1041
    Keywords: Enalapril ; Atenolol ; Hypertension ; cigarette smoking ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A randomised crossover study has been done to compare the antihypertensive efficacy of enalapril and atenolol in 45 smoking, hypertensive men. Treatment was started with enalapril 20 mg/d or atenolol 50 mg/d and, if necessary, the doses were doubled after 4 weeks to achieve a sitting diastolic blood pressure ≤ 95 mm Hg, after which hydrochlorothiazide was added, if necessary. Both drugs lowered blood pressure significantly. However, enalapril was more efficient in lowering both systolic and diastolic blood pressure; the mean difference was significant after both 4 and 8 weeks in the sitting systolic (11.6 mm Hg and 7.9 mm Hg) and diastolic (3.3 mm Hg and 3.0 mm Hg) pressures and in the erect systolic pressures (8.2 mm Hg and 7.2 mm Hg), and after 8 weeks in the supine systolic pressure, too (8.9 mm Hg). The effect on enalapril was especially marked in moderate (〈20 cigarettes/day) smokers. The need for diuretics was also significantly less in the enalapril group. It appears that angiotensin-converting enzyme inhibitors may be superior to β-adrenoceptor blockers in the treatment of hypertensive smoking patients.
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    Lack of effect of omeprazole treatment on steady-state plasma levels of metoprolol (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 61-65 
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    ISSN: 1432-1041
    Keywords: Omeprazole ; substituted benzimidazole ; metoprolol ; interaction ; cytochrome P450 ; debrisoquine hydroxylase ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomised double-blind crossover study, seven healthy males were concomitantly given metoprolol 100 mg o. d. as a controlled release formulation, and omeprazole 40 mg o. d. or placebo, for 8 days. Plasma levels of the R- and S-enantiomers of metoprolol were determined on the 8th day of each treatment. The subjects were also characterised by their metabolic capacity to hydroxylate debrisoquine. Concomitant omeprazole treatment had no significant influence on the steady-state plasma levels of the two enantiomers of metoprolol. All subjects were characterised by extensive debrisoquine hydroxylation, i.e. extensive metoprolol metabolism. As metoprolol is metabolised to a great extent by debrisoquine hydroxylase (IID6), it is concluded that concomitant omeprazole treatment will probably have a negligible influence on the metabolism of the relatively large number of drugs mainly metabolised by this isoenzyme of the cytochrome P450 family.
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    Pharmacological activity and safety of trandolapril (RU 44570) in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 149-153 
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    ISSN: 1432-1041
    Keywords: Trandolapril ; ACE inhibition ; pharmacodynamics ; duration ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacological activity and safety of the new angiotensin converting enzyme (ACE) inhibitor trandolapril (RU 44570) has been evaluated in ten healthy male volunteers given 2 mg once daily for seven days. Assessment criteria included evaluation of plasma ACE and renin activity and aldosterone levels in the supine and standing positions, monitoring of blood pressure, heart rate and electrocardiogram, routine blood and urine laboratory tests, and evaluation of adverse effects. Plasma ACE activity (both in the supine and standing positions) was significantly lower after the first dose and was almost completely suppressed after 7 days of treatment. Plasma renin activity with the subjects in both positions was significantly increased at the end of treatment. Plasma aldosterone did not vary significantly, except for an increase in the standing position after 7 days of washout. No significant changes occurred in blood pressure, heart rate, electrocardiogram, blood or urine laboratory tests. No adverse effects were reported, in particular, no orthostatic hypotension, cough or episodes of bronchospasm occurred. It is concluded that oral trandolapril 2 mg o.d. is an effective and long-lasting ACE inhibitor with a good safety profile on repeated dosing. Further studies are warranted to investigate its therapeutic application as well as its safety profile after long-term administration.
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    In-patient major depression: is rolipram as effective as amitriptyline? (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 127-129 
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    ISSN: 1432-1041
    Keywords: Rolipram ; amitriptyline ; depression ; adverse effects ; efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antidepressant efficacy and adverse-effects of rolipram (a dialkoxyphenyl-2-pyrrolidone) were compared to those of amitriptyline in the treatment of depressive illness requiring hospital admission in a double-blind study. Fifty patients meeting DSM-III criteria for Major Depression whose scores on the Hamilton Rating Scale for Depression (HRSD) remained above 17 after 5 to 7 days on placebo were randomly allocated to either treatment. The rate of recovery in those patients treated by amitriptyline was substantially greater than in those patients treated by rolipram. Twice as many patients dropped out of treatment by rolipram because of lack of efficacy or adverse-effects compared with patients treated by amitriptyline. Rolipram produced fewer adverse-effects attributable to cholinergic blockade, but more nausea. We conclude that amitriptyline is more effective than rolipram in the treatment of depressed hospital in-patients.
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    Comparison of postpartum pain treatments using a sequential trial design: II. Naproxen versus paracetamol (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 539-542 
    Details
    ISSN: 1432-1041
    Keywords: Naproxen ; paracetamol ; pain ; sequential trial ; adverse effects ; uterine cramping ; episiotomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of naproxen and paracetamol in relieving uterine cramps has been compared in a sequential trial. The treatments did not differ significantly in a two-sided test in 56 patients. A corresponding fixed sample test would have required 140 patients to obtain the same significance level and power. In addition to uterine pain, the effect on episiotomy pain was also estimated at the termination of the trial. Again, there seemed to be no difference between naproxen and paracetamol.
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    URL: http://dx.doi.org/10.1007/BF00279965
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    Treatment of insomnia with two benzodiazepines: a double-blind crossover study (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 137-140 
    Details
    ISSN: 1432-1041
    Keywords: Oxazepam ; Nitrzepam ; Insomnia ; long term treatment ; adverse effects ; sleep quality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty-eight patients (12M, 16F) with insomnia were treated with nitrazepam 5 mg/d and oxazepam 25 mg/d, each for 11 days, in a double-blind crossover comparison with placebo. Half the patients received nitrazepam in the first drug period, and oxazepam in the second and the other half followed the contrary sequence. Both nitrazepam and oxazepam were found to be effective in inducing sleep and increasing sleep quality. No effects on dreaming or adverse effects were found. Nitrazepam did influence the frequency of awakening, but only in the second drug period. In the first period it reduced self-waking. It is concluded that both nitrazepam and oxazepam were effective in inducing sleep and in improving sleep quality.
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    URL: http://dx.doi.org/10.1007/BF00265906
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  • 72
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    Time course of the anti-oedematous effect of O-(β-hydroxyethyl)-rutosides in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 625-627 
    Details
    ISSN: 1432-1041
    Keywords: O-(β-hydroxyethyl)-rutosides ; leg oedema ; healthy subjects ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary O-(β-hydroxyethyl)-rutosides (HR) is used for the treatment of disorders of the venous and microcirculatory systems. In order to evaluate the time course of its activity, the effect of HR on a provocation model of orthostatic oedema in healthy volunteers was used. After a 2 week placebo run-in period, 16 healthy volunteers were randomized to HR (2 tablets of 500 mg/day) of placebo for a further 3 weeks, in a double-blind parallel design. Oedema was provoked by standing motionless for 1 h, with measurement of leg volume before and afterwards. The procedure was undertaken at entry to the study and then weekly during the entire 5 week period. There were no significant differences in the extent of oedema produced by the orthostatic challenge during the 2 week run-in period or in the subjects who continued on placebo (∼90 arbitrary units i.e. ∼48 ml). During the 3 week treatment with HR, however, there was a progressive reduction (−1.1, −5.9, and −7.6 arbitrary units after 1, 2, and 3 weeks, respectively) in the volume of induced oedema, which was significant after 2 and 3 weeks of treatment compared to the placebo group.
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  • 73
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    Nimodipine in migraine: clinical efficacy and endocrinological effects (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 69-71 
    Details
    ISSN: 1432-1041
    Keywords: Migraine ; nimodipine ; propranolol ; prolactin ; luteinizing hormone ; growth hormone ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum prolactin is increased during chronic flunarizine treatment of patients suffering from migraine. In order to clarify the role of calcium in control of the secretion of anterior pituitary hormones, a study has now been made of the effects of chronic nimodipine and propranolol treatment of migraine patients on prolactin (PRL), luteinizing hormone (LH) and growth hormone (GH) levels. 11 patients were treated with nimodipine and 8 with propranolol for four months. A statistically significant reduction in the frequency of the attacks was demonstrated in both groups. No significant change was found in the hormones levels during nimodipine treatment.
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    URL: http://dx.doi.org/10.1007/BF00280110
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  • 74
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    Pharmacokinetic profile and tolerability of pimobendan in patients with terminal renal insufficiency (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 107-111 
    Details
    ISSN: 1432-1041
    Keywords: Pimobendan ; pharmacokinetics ; tolerability ; renal impairment ; adverse effects ; haemodynamic actions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of an i.v. bolus of pimobendan (P) 2.5 mg and 5.0 mg, its tolerability and the effect on heart rate and blood pressure have been studied in 12 subjects (42–70 y) suffering from severe terminal renal impairment. Plasma level data were compared with those obtained in a previous investigation in healthy volunteers. Pharmacokinetics were dose linear and were comparable to those in healthy subjects. No adjustment of the dose of P is necessary in patients with severe renal impairment. Tolerability of P, observed by means of blood pressure monitoring, clinical chemistry tests, electrocardiography and subjective judgement resulted in 4 complaints out of 12 patients: three suffered from orthostatic problems and vomiting, and one patient had nausea. Mean heart rate was elevated by 19% (2.5 mg) and 16% (5.0 mg). Blood pressure was significantly reduced after 2.5 mg P (23% systolic and 26% diastolic pressure), and after 5.0 mg P by 25% systolic and 23% diastolic pressure.
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    URL: http://dx.doi.org/10.1007/BF00315148
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  • 75
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    Continuous infusion of high-dose metoclopramide: comparison of pharmacokinetically adjusted and standard doses for the control of cisplatin-induced acute emesis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 283-286 
    Details
    ISSN: 1432-1041
    Keywords: Metoclopramide cancer chemotherapy ; emesis ; continuous infusion ; pharmacokinetics ; cisplatin ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Metoclopramide was administered by continuous infusion to two groups each of 14 patients on chemotherapy, randomized to receive either doses adjusted to individual pharmacokinetic parameters or doses adjusted as usual to body weight. The mean plasma concentration at the end of the infusion in the adjusted group was 1.01 mg · 1−1, close to that aimed for (1.20 mg · 1−1). It was significantly different from that in the other group, v0.54 mg · 1−1. Antiemetic efficacy, defined as ⩽2 emetic events in the 24 h following cisplatin, was similar in both groups (being found in 12/14 (86%) and 10/14 patients (71%), respectively). Analysis of the cumulative percentage of responders according to plasma concentration showed a clear plasma concentration-effect relationship. Routine MCP pharmacokinetic dosage adjustment is not indicated, but this therapeutic approach can be used to optimize antiemetic therapy in poor responder patients.
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    URL: http://dx.doi.org/10.1007/BF00315210
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  • 76
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    Magnesium-L-aspartate-HCl and magnesium-oxide: bioavailability in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 437-438 
    Details
    ISSN: 1432-1041
    Keywords: Magnesium deficiency ; oral replacement therapy ; bioavailability ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265863
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  • 77
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    Effects of diltiazem and metoprolol on blood pressure, adverse symptoms and general well-being (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 453-460 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; metoprolol ; quality of life ; hypertension ; multicentre study ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary General well-being, adverse effects and antihypertensive efficacy have been investigated in a double blind, parallel-group, dose-response multicentre study of diltiazem and metoprolol monotherapy for hypertension. 128 patients with primary hypertension were included from 10 participating centres. The patients were randomized to receive oral diltiazem 120–240–360 mg/day or metoprolol 50–100–200 mg/day. Each dose was given for a 4-week period as a forced titration regime. In all 119 patients, 59 and 60, respectively, on diltiazem and metoprolol completed the study protocol. There were dose-dependent reductions in supine and standing blood pressures (BP) after both diltiazem and metoprolol therapy. In the diltiazem group, supine BP was reduced by 10 (11)/10 (6) mm Hg (SBP/DBP) at the highest dose level, and the corresponding values for the metoprolol group were 7 (16)/8 (9) mm Hg (SBP/DBP). Target pressures (DBP ≤ 90 mm Hg and/or a reduction in DBP of ≥ 10%) were reached in 63% and 48% of the patients, respectively. The incidence and severity of dose-dependent adverse effects, as evaluated by spontaneous reports or open and direct questioning, did not differ between treatments. Subjective well-being, evaluated by a self-administered questionnaire, the MSE-profile, did not differ significantly between diltiazem and metoprolol therapy. However, after an initial slight deterioration, contentment and vitality tended to improve with increasing doses of diltiazem, while a dose-related deterioration in these variables was observed on metoprolol therapy. At the highest dose levels, contentment and vitality tended to be better in the diltiazem than the metoprolol group. Thus, diltiazem and metoprolol in daily doses of 120–360 mg and 50–200 mg, respectively, produce comparable and parallel reductions in supine and standing BP. However, while subjective well-being tended to improve with increasing doses of diltiazem, there was a negative trend for metoprolol. It is concluded that diltiazem, given as monotherapy to hypertensive patients, does not impair subjective well-being.
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    URL: http://dx.doi.org/10.1007/BF00315222
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    Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients — a comparison of two oral formulations (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 585-591 
    Details
    ISSN: 1432-1041
    Keywords: Morphine ; metabolites ; clinical trial ; pharmacokinetics ; controlled release formulation ; cancer patients ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC. There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution. After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively. Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.
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    Comparison of postpartum pain treatments using a sequential trial design. I. Paracetamol versus placebo (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 343-347 
    Details
    ISSN: 1432-1041
    Keywords: Paracetamol ; pain uterine cramping ; episiotomy pain ; placebo ; adverse effects ; sequential trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new sequential test has been used to compare the effect of paracetamol and placebo on uterine cramping. Paracetamol was significantly superior to placebo at the 5% level. 75 patients were included in the trial, whereas in a fixed sample study 90 patients would have been required to obtain the same significance level and power. The magnitude of the difference in treatment effect was estimated following the sequential test. In addition to the effect on uterine pain, which was the primary variable, the effect on episiotomy pain was also estimated. Paracetamol was also superior to placebo against the episiotomy pain.
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    URL: http://dx.doi.org/10.1007/BF00265841
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  • 80
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    Distribution of CGRP-, VIP-, DβH-, SP-, and NPY-immunoreactive nerves in the periosteum of the rat (1991)
    Springer
    Cell & tissue research 264 (1991), S. 469-480 
    Details
    ISSN: 1432-0878
    Keywords: Bone ; Calcitonin gene-related peptide (CGRP) ; Vasoactive intestinal peptide (VIP) ; Neuropeptide Y (NPY) ; Sensory nerves ; Sympathetic nerves ; Rat (Sprague-Dawley)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary In light of the possible role peripheral nerves may play in bone metabolism, the morphology of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal peptide (VIP)-, substance P (SP)-, neuropeptide Y (NPY)-, and dopamine-β-hydroxylase (DβH)-immunoreactive nerve fibers was examined in whole-mount preparations of periosteum of membranous bones (calvaria, mandible) and long bones (tibia) from the rat. Periosteum from animals treated to remove selectively either the sympathetic or fine-caliber primary afferent nerves was also examined to determine the origin of the nerve fibers. We found a consistent and often dense innervation of the periosteum. The innervation patterns of the calvaria and mandible were similar, with networks of nerves spread across the surface of the bone. Nerves in the tibial periosteum were oriented in the longitudinal axis and were more numerous at the epiphyses than in the mid-shaft region. CGRP-immunoreactive fibers were widely and densely distributed. The presence of populations of CGRP-immunoreactive fibers of differing calibers and perivascular arrangements suggests that such nerves in bone tissues may serve different functions. SP-immunoreactivity was present in a fine network of varicose fibers in the superficial layers of the periosteum. CGRP- and SP-immunoreactive nerve fibers were dramatically reduced in periosteum of capsaicin-treated animals as compared to controls, indicating the sensory origin of these nerves. VIP-immunoreactive nerve fibers were distributed in the periosteum of mandible and calvaria as small networks and individual fine varicose fibers. In tibial periosteum, larger networks of these fibers were visible. VIP-immunoreactive nerve fibers in the periosteum were associated with both vascular and nonvascular elements within the layers of cells closest to the bone, suggesting that VIP may serve more than one function in periosteal tissues. NPY-immunoreactive fibers were largely confined to vascular elements; occasional fibers were observed among the bone-lining cells. DβH-immunoreactivity was associated only with blood vessels. VIP-, NPY-, and DβH-immunoreactivities were dramatically reduced in the periosteum of guanethidinetreated animals, indicating the sympathetic origin of these nerves.
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    Expression of vigilin in chicken cartilage and bone (1993)
    Springer
    Cell & tissue research 273 (1993), S. 381-389 
    Details
    ISSN: 1432-0878
    Keywords: Vigilin ; Cartilage ; Bone ; Differentiation ; In-situ hybridization ; Chicken
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The expression of vigilin was followed during chick embryonal development by in situ hybridization. Vigilin mRNA is abundantly expressed in tissues of mesenchymal and ectomesenchymal origin. The mesenchymal primordial cells of cartilage and bone did not show any significant, expression of vigilin. As tissue differentiation proceeded, vigilin mRNA levels increased in hyaline cartilage and in both endochondral as well as intramembranous bone. The results suggest that the expression of vigilin mRNA in cartilage- and bone-forming cells chondrocytes and osteobalsts, is dependent on the stage of development and cellular differentiation, although not a unique process of bone formation. Most striking is the correlation of the maximum vigilin mRNA expression in osteoblasts and hypertrophic chondrocytes to periods when cell-specific genes were highly transcribed and substantially translated, e.g., synthesis of procollagen and formation of extracellular matrix in bone and cartilage.
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    Transformation of fetal secondary cartilage into embryonic bone in organ cultures of human mandibular condyles (1993)
    Springer
    Cell & tissue research 271 (1993), S. 317-322 
    Details
    ISSN: 1432-0878
    Keywords: Cartilage ; Bone ; Organ culture ; Joints ; Man (Primates)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Mandibular condyles of human fetuses, 14–21 weeks in utero, were kept in an organ culture system for up to 60 days. After 6 days in culture, the cartilage of the mandibular condyle appeared to have maintained its inherent structural characteristics, including all its various layers: chondroprogenitor, chondroblastic, and hypertrophic. After 12 days in culture, no chondroblasts could be seen; instead, the entire cartilage was occupied by hypertrophic chondrocytes. At the same time, the mesenchymal cells in the vicinity of the chondroprogenitor zone differentiated into osteoblast-like cells that produced type I collagen. The progenitor cells were still actively incorporating 3H-thymidine. The newly formed osteoid-like tissue lacked both metachromatic reactivity and a response to antibodies against chondroitin sulfate. Instead, the tissue reacted positively for osteocalcin (bone gla-protein). The process of new bone formation further progressed and, by the 20th day in culture, the new bone reacted positively for type I collagen, osteonectin, and to a lesser extent for chondroitin sulfate. The osteoid also underwent mineralization as revealed by both the von Kossa stain and vital staining with tetracycline. The above feature appeared even more intense in 40-day-old cultures. After 60 days, the newly formed bone contained osteoblasts and osteocytes, whereas the extracellular matrix revealed a high degree of matrix polarization. The results of the present study recapitulate findings reported for organ cultures of mice mandibular condyles. However, the in vitro process of de novo bone formation in human specimens requires a 6-fold longer culture time than that needed for mice condyles.
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    Fine structure of the developing frontal bones and scales of the cranial vault in the cichlid fish Hemichromis bimaculatus (Teleostei, Perciformes) (1993)
    Springer
    Cell & tissue research 273 (1993), S. 511-524 
    Details
    ISSN: 1432-0878
    Keywords: Bone ; Scales ; Development ; Hemichromis bimaculatus (Teleostei, Perciformes)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The development of the frontal bone and the formation of the first head scales are described during post-embryonic ontogeny of Hemichromis bimaculatus, using light and transmission electron microscopy. The frontal bone originates close to the cartilaginous taenia marginalis in a loose mesenchymal cell condensation (=primordium) lying 1 μm from the epidermis with which it establishes no cell contacts. The anlage appears at 4.2 mm standard length (SL) in the form of the membranodermal component of the bone, and extends first over the brain and then over the eye; the neurodermal component forms later to surround the supraorbital canal. The first head scales appear at 10.0 mm SL in a dense cell condensation (papilla) adjoining the epidermal-dermal junction and, once formed, remain in this position. In both organs, the initial matrix is similarly composed of “woven-fibred” bone that soon mineralizes in a similar manner to other dermal elements. In some areas of the frontal bone, “parallel-fibred” bone is deposited unequally on both surfaces, whereas isopedine is deposited in scales on the deep surface only. Osteoblastic features confirm this eccentric growth. Differences in the shape, organization and localization of the mesenchymal condensations giving rise to the frontal bone and to the scale reflect the existence of two types of dermal cell condensations. Our data are compared with those available for the post-cranial dermal skeleton of fishes both from a developmental and structural viewpoint. Structural differences in the matrices of the frontal bone and scales are discussed in a phylogenetic perspective.
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    The human tibia: Static testing in bending by anin vivo method (1982)
    Springer
    Annals of biomedical engineering 10 (1982), S. 281-294 
    Details
    ISSN: 1573-9686
    Keywords: Tibia ; Strength ; Bone ; Elastic modulus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract We have developed a method for static testing of the human tibia in bending in the living subject, and fabricated a prototype device for carrying it out. Model testing indicates that the device and model system are inherently accurate and reliable. However, the biological system is more complex, and while more than 200 tests have been conducted with perfect safety, the variability of replicate tests suggests that the method does not yet have general clinical utility. In some subjects, that variance is relatively small, possibly because they are more relaxed and perhaps also for anatomical reasons. In two subjects, postmortem tests corresponded very well with antemortem tests on the tibiometer. We conclude that with further refinements the method may have clinical potential, if only in carefully selected subjects.
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    URL: http://dx.doi.org/10.1007/BF02367309
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    Effect of ultraviolet light on the dielectric behavior of bone at microwave frequencies (1982)
    Springer
    Annals of biomedical engineering 10 (1982), S. 139-144 
    Details
    ISSN: 1573-9686
    Keywords: Dielectric constant ; Bone ; Collagen ; Apatite
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract The dielectric constant of bone and its two components (collagen and apatite) were determined at 9.2 GHz in a room temperature environment by the cavity perturbation technique. After samples were exposed to ultraviolet light, repeat measurements under identical conditions showed decreases in both the real and the imaginary parts of the dielectric constant in all cases. The present work describes the technique and a possible mechanism of ultraviolet interaction with bone.
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    URL: http://dx.doi.org/10.1007/BF02367462
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    Magnetic and electric fields produced during pulsed-magnetic-field therapy for non-union of the tibia (1982)
    Springer
    Medical & biological engineering & computing 20 (1982), S. 501-511 
    Details
    ISSN: 1741-0444
    Keywords: Bone ; Electric fields ; Magnetic fields ; Pulsed-magnetic-field therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Pulsed-magnetic-field therapy for non-union of the tibia is becoming, in some centres, an established orthopaedic technique. The field is generated by passing pulses of current through coils positioned around the leg, but the mechanism of interaction is not understood. This paper gives a qualitative description of the fields produced and then develops a theoretical model to calculate the fields for simple geometries. Good agreement is found between calculation and measurement, validating the model and showing that the form of the fields produced in a limb can now be described.
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    URL: http://dx.doi.org/10.1007/BF02442413
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