Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal functions were damaged at the reabsorptive site by the injection of cadmium-metallothionein (Cd-MT) and its effect on discrimination of chemically similar elements was examined for the two alkaline-earth elements, calcium (Ca) and strontium (Sr). Tubular damage was induced in female Wistar rats, 7 wk old, body wt 145.1 +/- 3.5 g (mean +/- S.D.), by an intraperitoneal injection of Cd-MT (400 micrograms Cd/kg body wt). The Cd-MT injection caused increases in urinary enzymes (lactate dehydrogenase; alkaline phosphatase), glucose, and total protein. Urinary Ca and Sr increased and urinary Sr/Ca ratio decreased rapidly after the Cd-MT injection. Both changes remained at significant levels throughout the experiment. On the other hand, renal Ca and Sr levels increased with time after 18 or 24 h and changed similarly. Although plasma levels of Ca and Sr slightly increased after 30 or 36 h post-injections, the plasma Sr/Ca level remained constant. A close exponential relationship formed between the relative clearances of Ca and Sr. There was no significant difference between the exponent of the following equation (K) for the Cd-MT-injected group and that for the control group. Sr clearance/creatinine clearance = (Ca clearance/creatinine clearance)K where K = 0.408 from experimental data for the two groups. This suggests that the discrimination mechanism between Sr and Ca during the reabsorptive step in the kidney is strictly regulated.
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PMID:Renal discrimination between strontium and calcium in rats. Effects of renal damage caused by cadmium-metallothionein. 248 30

To clarify the cause of the stimulation of p-aminohippurate (PAH) accumulation in rat kidney cortical slices by barium, an experiment was carried out with basolateral membrane vesicles isolated from rat kidney cortex. The effect of barium on PAH uptake by the membrane vesicles was compared with that of verapamil which also stimulated PAH accumulation in the slices. The enzyme marker for basolateral membrane, (Na+ + K+)- ATPase, was enriched 15-fold and the brushborder enzyme marker, alkaline phosphatase, was 1.3-fold in our membrane preparation. Contamination in this preparation by lysosomes, mitochondria and cytosol was also low but that by endoplasmic reticulum was slightly high as judged by the enzyme markers. PAH uptake by the membrane vesicles possessed the usual characteristics, i.e., sodium-dependence and probenecid-sensitivity. PAH uptake by the membrane vesicles was enhanced by barium, but not by verapamil. On the other hand, barium did not affect tetraethylammonium (TEA) uptake by the vesicles, and verapamil strongly inhibited it. Manganese also stimulated PAH uptake to the same extent as did barium, but calcium and strontium did not affect the uptake. Barium did not act on sodium transport in the membrane vesicles. An 'anion-sensitively transported lipophilic cation', triphenylmethylphosphonium iodide (TPMP), uptake was depressed by barium. These results suggest that barium stimulates selectively PAH uptake in basolateral membrane vesicles. Its stimulatory action may contribute at least partly to an increase in PAH accumulation in rat kidney cortical slices by this ion and may prove useful in an analysis of the mechanism of PAH transport system in renal basolateral membranes.
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PMID:Effect of barium ion on p-aminohippurate transport in basolateral membrane vesicles isolated from rat kidney cortex. 299 5

The localization of ATPases in 7 osteogenic sarcomas of osteoblastic, chondroblastic and fibroblastic type was investigated at the fine structural level using two types of substrates: one with lead as capturing ion and one with strontium (the latter presumed to reveal sites of Na+-K+-dependent transport ATPase). Reaction product with the lead-ATP medium was located on the plasma membrane and the membranes bordering subjacent vesicles and vacuoles in all the various types of osteoblastlike and fibroblastlike cells and also in types 1 and 3 chondroblastlike cells, and multinucleated giant cells believed to be neoplastic. Furthermore, deposits of reaction product were demonstrated in lysosomelike organelles in all the aforementioned cells. Except in the case of chondroblastlike cells, precipitates marking the localization of enzyme were confined to areas of the plasma membrane where adjacent cells were closely applied (the free surface lacked precipitates). In chondroblastlike cells the reaction product was usually deposited along the whole plasma membrane. Presence of L-Homoarginine or L-Tetramisole in the incubation medium in concentrations that have been shown to completely abolish alkaline phosphatase activity did not affect the occurrence of the reaction product with ATP as substrate indicating that the enzyme hydrolysing ATP was substrate-specific. Reaction product marking sites of Na+-K+-dependent ATPase was confined to plasma membranes and lysosomes of cells in vessel walls. The observations strengthen the notion obtained in studies on the localization of alkaline phosphatase, namely that osteoblastlike, chondroblastlike, and fibroblastlike cells in osteogenic sarcomas are histogenetically related to one another and to those multinucleated giant cells that presumably are of a neoplastic nature.
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PMID:Human osteogenic sarcoma: fine structural localization of adenosine triphosphatase. 300 94

The use of cerium ions as a primary capture reagent in phosphatase histochemistry on the light and the electron microscopic level is a progress in the field of enzyme localization. Many influences of other captures (as of lead ions), e.g. enzyme inhibition, diffusion and other artefacts, are restricted when cerium-based methods are used. But the broader use of cerium is difficult, because cerium ions are at alkaline pH converted to the insoluble cerium hydroxide, which intensively precipitates in the incubation medium. This is an important disadvantage for a successful histochemical detection of alkaline phosphatase. The aim of this paper is to describe a new cerium-based method for the light microscopical detection of alkaline phosphatase, which is free from all these above mentioned problems. It is proposed a collidine buffer-sucrose containing medium, which holds cerium ions at pH = 9.0 in solution. The histochemical results of this method are excellent. The method is compared with a strontium based technique, the coupling azo dye technique for alkaline phosphatase as well as with in vitro and histochemical experiments with several chelator agents. The cerium-based collidine-sucrose technique is superior to all other procedures tested here and is recommended for a broader use.
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PMID:Light microscopical localization of enzymes by means of cerium-based methods. II. A new cerium-lead-technique for alkaline phosphatase. 393 56

The effects of regular sunlight exposure on levels of vitamin D metabolites and on other indices of calcium metabolism have been studied in elderly rest-home residents. Fifteen subjects who formerly went outdoors very infrequently were studied over a 4-week period while spending 0, 15 or 30 minutes daily sitting on the rest-home verandah. During this time, levels of 25-hydroxyvitamin D [25(OH)D] rose by 7.4 +/- 1.2 (s.e.m.) microgram/1 in the group spending 30 minutes per day outdoors (P less than 0.005) and there was a smaller but nonsignificant increase in the 15 minutes per day group also. Serum 1,25 (OH)2D levels did not change during the study but serum ionized calcium and alkaline phosphatase showed small, but significant, decreases. Intestinal strontium absorption increased in both treatment groups (P less than 0.05), indicating a similar change in calcium absorption. It is concluded that 30 minutes spent outdoors each day leads to a substantial increase in 25(OH)D levels in elderly subjects and that this has significant effects upon other indices of calcium metabolism. This regimen provides a safe and inexpensive method for the prevention of osteomalacia in frail elderly subjects.
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PMID:Prophylaxis against vitamin D deficiency in the elderly by regular sunlight exposure. 395 29

Twenty-one patients with histologically proved osteomalacia from various causes were investigated for biochemical and radiological evidence of osteomalacia and secondary hyperparathyroidism. Among the 15 who maintained a normal serum calcium, seven had a raised phosphate excretion index, seven had a raised serum alkaline phosphatase, and six had phalangeal erosions. On the other hand, six patients had a subnormal serum calcium; of these, none showed a raised phosphate excretion index, one had a raised serum alkaline phosphatase, and one had erosions. The phosphate excretion index and the alkaline phosphatase were strongly correlated (r = +0.84). It is concluded that this absence of manifest secondary hyperparathyroidism in some patients with osteomalacia is due to failure of an increase in the release of parathyroid hormone. Measurement of phosphaturia does not appear to be a useful means of detecting osteomalacia. Subsequently, the 24-hour (stable) strontium space measurement was found to be the most sensitive single biochemical screening test for osteomalacia.
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PMID:Secondary hyperparathyroidism in osteomalacia. 541 49

The aim of the strontium ranelate (SR) for treatment of osteoporosis (STRATOS) trial was to investigate the efficacy and safety of different doses of SR, a novel agent in the treatment of postmenopausal osteoporosis. A randomized, multicenter, double-blind, placebo-controlled trial was undertaken in 353 osteoporotic women with at least one previous vertebral fracture and a lumbar T-score <-2.4. Patients were randomized to receive placebo, 0.5 g, 1 g, or 2 g SR/d for 2 yr. The primary efficacy endpoint was lumbar bone mineral density (BMD), assessed by dual-energy x-ray absorptiometry. Secondary outcome measures included femoral BMD, incidence of new vertebral deformities, and biochemical markers of bone metabolism. Lumbar BMD, adjusted for bone strontium content, increased in a dose-dependent manner in the intention-to-treat population: mean annual slope increased from 1.4% with 0.5 g/d SR to 3.0% with 2 g/d SR, which was significantly higher than placebo (P < 0.01). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment with 2 g/d SR [relative risk 0.56; 95% confidence interval (0.35; 0.89)]. In the 2 g/d group, there was a significant increase in serum levels of bone alkaline phosphatase, whereas urinary excretion of cross-linked N-telopeptide, a marker of bone resorption, was lower with SR than with placebo. All tested doses were well tolerated; the 2 g/d dose was considered to offer the best combination of efficacy and safety. In conclusion, SR therapy increased vertebral BMD and reduced the incidence of vertebral fractures.
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PMID:Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis--a 2-year randomized placebo controlled trial. 1199 41

Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable non-radioactive strontium. In vitro, strontium ranelate increases collagen and non-collagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cells replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cells and collagen as well as non-collagenic protein synthesis in osteoblasts provides substantial evidence to categorise SR ranelate as a bone forming agent. In the mouse calvaria culture system, SR ranelate induces a dose-dependent inhibition of labelled calcium release. The inhibitory effects of SR ranelate on bone resorption were close to those of salmon calcitonin. In the isolated rat osteoclast assay, a pre-incubation of bone slices with SR ranelate induced a dose-dependent inhibition of the bone resorbing activity of a treated rat osteoclast. SR ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both CA II and the alpha-subunit of the vitronectin receptor. These effects showing that SR ranelate significantly affects bone resorption due to direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation are compatible with the profile of an anti-resorptive drug. In normal rats, administration of SR ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. This was not related to any change in the stiffness, suggesting the absence of a mineralisation defect. After oral administration of SR ranelate in humans, the absolute bio-availability of SR ranelate is 27 % after a dose of 2g is given as sachets. The simultaneous intake of SR ranelate and calcium remarkably reduces the bio-availability of SR. SR ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg, 1 g of SR ranelate were compared to a placebo. At the conclusion of the study, the percent variation of lumbar adjusted BMD from baseline was significantly different in the group receiving 1 g/day of SR as compared to placebo (+ 1.41 % versus 0.98 % respectively). Increase in total hip and neck BMD averages respectively 3.2 % and 2.5 %. SR ranelate does not induce any significant adverse reaction compared to those observed in women receiving a placebo for the same duration. In a phase II study, the effect of SR ranelate in postmenopausal women with vertebral osteoporotic fractures were assessed during a double-blind, placebo-controlled trial. SR ranelate (500 mg, 1 g, 2 g per day) or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this two-year study, the annual increase in lumbar adjusted BMD of the group receiving 2 g of SR ranelate was + 2.97 %. This result was significantly different as compared to placebo. A significant decrease in pyridinium crosslinks (NTX) and an increase in bone specific alkaline phosphatase were evident after 3 and 6 months of treatment. During the second year of treatment, the dose of 2 g was associated with a 4 % reduction in the number of patient experiencing a new vertebral deformity. Bone histomorphometry showed no mineralisation defects. The same percentage of withdrawal following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. Currently, strontium ranelate is further investigated in a large Phase III program that includes two extensive trials for the treatment of severe osteoporosis, one assessing SR ranelate effects on the risk of vertebral fractures (SOTI) and one evaluating the effects of SR ranelate on peripheral (non spinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates are expected to be released during the summer 2002.
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PMID:Strontium ranelate in osteoporosis. 1217 30

Early postmenopausal women ( n = 160) were randomised to receive placebo or strontium ranelate (SR) 125 mg/day, 500 mg/day or 1 g/day for 2 years (40 participants per group). All participants received calcium 500 mg/day. The primary efficacy parameter was the percent variation in lumbar bone mineral density (BMD), measured using dual-energy X-ray absorptiometry. Secondary efficacy criteria included hip BMD and biochemical markers of bone turnover. At month 24, SR 1 g/day significantly increased lumbar BMD compared with placebo [mean (SD) +5.53% (5.12); p<0.001] for measured values and [mean (SD) +1.41% (5.33%); p<0.05] for values adjusted for bone strontium content. The annual increase for adjusted values was +0.66% compared with -0.5% with placebo, with an overall beneficial effect after 2 years of about 2.4% with SR 1 g/day relative to placebo. There were no other significant between-group differences in adjusted lumbar BMD. Femoral neck and total hip BMD were also significantly increased at month 24 with SR 1 g/day compared with placebo [mean (SD): +2.46% (4.78) and +3.21% (4.68), respectively; both p<0.001)]. SR 1 g/day significantly increased bone alkaline phosphatase at all time points ( p<0.05) compared with baseline and between-group analysis showed a significant increase, compared with placebo, at month 18 ( p = 0.048). No effect on markers of bone resorption was observed. SR was as well tolerated as placebo. The minimum does at which SR is effective in preventing bone loss in early postmenopausal non-osteoporotic women is therefore 1 g/day.
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PMID:Prevention of early postmenopausal bone loss by strontium ranelate: the randomized, two-year, double-masked, dose-ranging, placebo-controlled PREVOS trial. 1245 34

Not one of the currently available medications has, so far, unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once osteoporosis is established. Therefore, several new therapies are currently under development to optimize the risk/benefit ratio of osteoporosis treatment. Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable nonradioactive strontium. In vitro, strontium ranelate increases collagen and noncollagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cell replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cell and collagen, as well as noncollagenic protein synthesis in osteoblasts, provides substantial evidence to categorize strontium ranelate as a bone-forming agent. In the isolated rat osteoclast assay, a pre-incubation of bone slices with strontium ranelate induced a dose- dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both carbonic anhydrase II and the alpha-subunit of the vitronectin receptor. These effects showing that strontium ranelate significantly affects bone resorption due to a direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation, are compatible with the profile of an anti-resorptive drug. In normal rats, administration of strontium ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. Strontium ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg and 1 g of strontium ranelate were compared with a placebo. At the conclusion of the study, the percent variation of lumbar-adjusted bone mineral density from baseline was significantly different in the group receiving 1 g/day of strontium ranelate compared with placebo (+1.41% vs. -0.98%, respectively). Increase in total hip and neck bone mineral density averages, respectively, 3.2% and 2.5%. Strontium ranelate does not induce any significant adverse reaction compared with those observed in women receiving a placebo for the same duration. In a phase II study, the effect of strontium ranelate in postmenopausal women with vertebral osteoporotic fractures was assessed during a double-blind, placebo-controlled trial. Doses of 500 mg, 1 g and 2 g daily of strontium ranelate or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar-adjusted bone mineral density of the group receiving 2 g of strontium ranelate was + 2.97%. This result was significantly different compared with placebo. A significant increase in bone alkaline phosphatase and, over a 6-month period, a significant decrease in urinary-pyridium crosslinks (NTX) were evidenced. During the second year of treatment, the dose of 2 g was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralization defects. The same percentage of withdrawals following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. The compound was further investigated in a large phase III program that included two extensive trials for the treatment of severe osteoporosis, one assessing the effects of strontium ranelate on the risk of vertebral fractures (SOTI) and one evaluating its effects on peripheral (nonspinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates, revealed a 41% reduction in the relative risk of expein the relative risk of experiencing a first new vertebral fracture with strontium ranelate, throughout the 3-year study, compared with placebo. The TROPOS study, showed a significant (p = 0.05) reduction in the relative risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study compared with placebo in the intention-to-treat population. A 41% reduction in the relative risk of experiencing a hip fracture was demonstrated in the per protocol population. All these results imply that strontium ranelate is a new, effective and safe treatment for vertebral and nonvertebral osteoporosis, with a unique mode of action.
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PMID:Strontium ranelate: a new paradigm in the treatment of osteoporosis. 1269 4


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