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At least 19 recordsLinked to original sources
PubMed1975

[A comparison of osteotropic radiopharmaceuticals. II. Plasma clearance of 18F and 99mTc-EHDP (author's transl)].

Renal and extra-renal clearance of 18F and 99mTc-EHDP were compared in the same individuals. The 18F space is twice that of 99mTc-EHDP, as is its renal clearance. 99mTc undergoes glomerular filtration, 18F is excreted by glomerular filtration and tubular secretion. Extraction rate was determined indirectly by a comparison with extra-renal clearance, and for patients without bone disease it was four times as high for 18F as it was for 99mTc-EHDP. In patients with secondary hyperparathyroidism extra-renal clearance is greatly increased. This is explained by an increased extraction rate, which may be different for the two substances.

Bone Diseases↗
PubMed1978

[On the effect of methane-bis--phosphonate in vivo (author's transl)].

After s.c. injections of methane-bis-phosphonate into rabbits, calcified incrustations developed around the injection sites. These incrustations were less radiolucent than the surrounding tissues. They appeared to have a good crystalline apatite structure in X-ray diffraction. The findings agree with our previous in vitro studies but disagree with the findings in the literature that ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethyle-nediphosphonate (Cl2MDP) inhibit crystal growth of apatite already formed.

Animals↗
PubMed1979

[Effect of 2 phosphonates on the osteolysis induced by tumor extracts].

An in-vitro model is proposed to test the potential effect of diphosphonates in treatment or preventing bone metastases. This model involves culturing of neonatal mice calvaria in sterile conditions in an appropriate medium and measuring 45Ca release from bone to medium, the mice being injected with 45Ca on the day of birth. Tumour extracts added to the medium usually increase the bone lysis; this effect is significantly decreased when the mice have been treated with either ethane-hydroxy-diphosphonate (EHDP) or dichloromethylene-diphosphonate (Cl2MDP). These experiments represent a first step in a group of experiments with a view to clinical trials in cases of bone metastases.

Animals↗
PubMed1977

The comparative effects of dichloromethylene diphosphonate (C12MDP) and ethane-1-hydroxy-1,1-diphosphonate (EHDP) on growth and modeling of the rat tibia.

Male rats weighing 100 g were assigned to groups and injected daily for 10 days with vehicle (control), 0.4, 2.0, 4.0, 10.0, or 20.0 mg/kg/day of ethane-1-hydroxy-1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (C12MDP). The proximal tibial metaphysis and epiphysis were assayed for changes in percentage of hard tissue and bone formation parameters. From the data, information about hard tissue resorption was deduced. All doses of C12MDP and doses of 2.0 mg EHDP/kg/day and greater caused significant increases in percentage of hard tissues with C12MDP being more effective than similar doses of EHDP in decreasing bone resorption. Osteoclast population parameters were increased with all doses of both C12MDP and EHDP with C12MDP having a greater effect than similar doses of EHDP. Decreases in the proliferation of the osteoprogenitor pool parallel the decreases in osteoblasts and bone formation parameters. These decreases in osteoprogenitor pool proliferation do not account for the increases with diphosphonates in osteoclast population parameters.

Animals↗
PubMed1979

Effects of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on rabbit articular chondrocytes in culture.

Investigations were carried out to assess the effects of disodium 1-hydroxyethane-1,1-diphosphonate and disodium dichloromethanediphosphonate (compounds containing a P-C-P bond) on isolated rabbit articular chondrocytes in culture. Studies on growth behaviour showed that both diphosphonates displayed inhibitory actions, dichloromethanediphosphonate producing the larger effect. Both compounds inhibited the uptake of 2-deoxy-d-glucose, dichloromethanediphosphonate once more being the more potent of the two. The uptake of alpha-aminoisobutyrate was considerably increased by chondrocytes treated with dichloromethanediphosphonate, whereas 1-hydroxyethane-1,1-diphosphonate showed no effects. The biosynthesis of sulphated extracellular macromolecules secreted by the cells into the pericellular space as well as into the growth medium was greatly increased by dichloromethanediphosphonate but not by 1-hydroxyethane-1,1-diphosphonate. The stimulatory effect was dose-dependent. Short-term exposure of already confluent cells to dichloromethanediphosphonate as opposed to growing the cells to confluence in the presence of the diphosphonate revealed that the stimulatory effects were already evident after 24h, indicating that cell division is not necessarily required to produce the observed effects. The increment in proteoglycan synthesis was still evident with cells that were exposed continuously to the diphosphonate in primary as well as secondary culture. Pulse-chase experiments together with studies on the enzyme arylsulphatase revealed that the appearance of increased amounts of proteoglycans was the result of a stimulation in synthesis and not due to an inhibition in turnover.

Aminoisobutyric Acids↗
PubMed1979

Effects of diphosphonate and colchicine administration upon acid-base changes induced in rats by bilateral nephrectomy.

1. The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and colchicine on acid--base balance were examined in intact and nephrectomized rats. 2. Both drugs increased extracellular hydrogen ion concentrations and depressed extracellular bicarbonate concentrations in nephrectomized rats compared with controls but did not alter these parameters in intact animals. 3. Intracellular hydrogen ion concentrations in the skeletal muscle of nephrectomized rats given EHDP were higher than those of control animals. 4. It is postulated that colchicine and EHDP inhibit skeletal buffering of non-volatile acids produced endogenously in nephrectomized rats.

Acid-Base Equilibrium↗
PubMed1979

Potassium permanganate induced calcergy: a model to study the effects of drugs on hydroxyapatite crystal deposition.

Hydroxyapatite crystal deposition is thought to play a role in the inflammatory episodes of osteoarthritis. A plaque of hydroxyapatite crystals was produced by local subcutaneous injection of a potassium permanganate solution. Transmission electron microscopy with X-ray energy spectroscopy was used to identify the crystal deposits as hydroxyapatite. The effects of dexamethasone, indomethacin, ethane 1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diposphonate (Cl2MDP) on the development of the apatite plaque was studied. EHDP strongly inhibited the apatite deposition. Cl2MDP slowed the natural resorption of the apatite plaque. Dexamethasone and indomethacin failed to affect the crystal deposition process. The results suggest that EHDP could inhibit crystal deposition in the osteoarthritic joint and that Cl2MDP might have a role in slowing apatite crystal shedding from osteoarthritic cartilage and so reduce the synovitis seen in Osteoarthritis.

Animals↗
PubMed1977

Effect of the diphosphonate EHDP on plasma inorganic phosphate and hemoglobin oxygen affinity of diabetic and healthy subjects.

The effect of oral disodium ethane-1-hydroxy-1,1-diphosphonate, EHDP (20 mg kg-1 day-1) and placebo given for 28 days on plasma inorganic phosphate (Pi) red cell 2,3-diphosphoglycerate and oxygen affinity of hemoglobin was evaluated in 14 insulin-treated diabetics and 5 healthy volunteers. EHDP significantly increased mean Pi (diabetics: 1.18 to 1.67 mmol/l, p less than 0.01, controls: 1.03 to 1.71 mmol/l, p less than 0.02) and P50 at in vivo pH of the oxyhemoglobin dissociation curve (diabetics: 25.4 to 26.6 mmHg, p less than 0.02; controls: 26.3 to 28.9 mmHg, p less than 0.02). Pi and P50 were correlated in both diabetics and in controls (p less than 0.05). 2,3-DPG increased when the diabetics were on EHDP (p less than 0.005). The study emphasizes the importance of Pi on red cell function and indicates that an elevation of Pi tends to counteract the defect in oxygen release capacity of the red cells in diabetic subjects.

Carbon Dioxide↗
PubMed1977

The effect of pyrophosphate and diphosphonates on calcium transport in red cells.

The effect of 0.5 mM pyrophosphate (PPi), disodium ethane-4-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethane diphosphonate (Cl2MDP) on the ATP-dependent Ca2+ extrusion from the human red cell ghosts was studied. PPi and Cl2MDP had no effect, when introduced into the cells or added outside to the medium. EHDP slightly increased the calcium concentration in the released cells and slightly decreased the rate constant of the calcium transport, having opposite effects when it was inside or outside the cells. PPi and the 2 diphosphonates were not found to move easily across the red cell membrane.

Biological Transport, Active↗
PubMed1976

The effect of several diphosphonates on acid phosphohydrolases and other lysosomal enzymes.

Diphosphonates are known to inhibit bone resorption in tissue culture and in experimental animals. This effect may be due to their ability to inhibit the dissolution of hydroxyapatite crystals, but other mechanisms may be important. Since lysosomal enzymes have implicated in the process of bone resorption, we have examined the effect of several phosphonates and of a polyphosphate (P20,2) on lysosomal hydrolases derived from rat liver and rat bone. Dichloromethylene diphosphonate strongly inhibited acid beta-glycerophosphatase (EC 3.1.3.2) and acid p-nitrophenyl phosphatase (EC 3.1.3.2) and to a lesser degree (in descending order) acid pyrophosphatase (EC 3.1.3.-), arylsulfatase A (EC 3.1.6.1), deoxyribonuclease II(EC 3.1.4.6) and phosphoprotein phosphatase (EC 3.1.3.16) of rat liver. Inhibition of acid p-nitrophenyl phosphatase and arylsulfatase A was competitive. Ethane-1-hydroxy-1, 1-diphosphonate did not inhibit any of these enzymes, except at high concentrations. Neither dichloromethylene diphosphonate nor ethane-1-hydroxy-1, 1-diphosphonate had any effect on beta-glucuronidase (EC 3.2.1.31), arylesterase (EC 3.1.1.2) and cathepsin D (EC 3.4.23.5). Of several other phosphonates tested only undec-10-ene-1-hydroxy-1, 1-diphosphonic acid inhibited acid p-nitrophenyl phosphatase strongly, the polyphosphate (P20, I) had little effect. Acid p-nitrophenyl phosphatase in rat calvaria extract behaved in the same way as the liver enzyme and was also strongly inhibited by dichloromethylene diphosphonate, but not by ethane-1-hydroxy-1, 1-diphosphonate. It is suggested that the inhibition of bone resorption by dichloromethylene diphosphonate might be due in part to a direct effect of this diphosphonate on lysosomal hydrolases.

Acid Phosphatase↗
PubMed1975

Enzymatic inhibition of diphosphonate: a proposed mechanism of tissue uptake.

Enzymes have been proposed as tissue receptors that bine 99mTc-stannous diphosphonate and its analogs. Incubation of diphosphonate with several enzymes demonstrated inhibition of acid and alkaline phosphatase activity but showed no effect on glutamic oxalacetic transaminase and lactate dehydrogenase activity. Complete reversal of the diphosphonate-induced inhibition of alkaline phosphatase activity occurred when calcium ion was added to the reaction. The specificity of calcium to induce reversal was dispelled when magnesium ion gave identical results. Diphosphonate-induced inhibition of acid phosphatase, however, was not reversed by calcium or magnesium.

Acid Phosphatase↗
PubMed1979

Comparative antiinflammatory and bone protective effects of two diphosphonates in adjuvant arthritis.

The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethane diphosphonate (Cl2MDP) were evaluated in the rat adjuvant model of arthritis to directly compare their ability to inhibit arthritic processes. The results of the experiment indicated that both diphosphonates inhibited osseous changes, pedal inflammation, and the change in body weight gain patterns which are characteristic of this model. The latter effects suggest that diphosphonates may have antinflammatory activity that is not related to their previously known actions on bone. Cl2MDP appeared to be more effective than EHDP in this particular model when all aspects were considered. The relationship of these results to the potential safety of these compounds in clinical situations is discussed.

Animals↗
PubMedDate not supplied

Renal handling of alendronate in rats. An uncharacterized renal transport system.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of a variety of bone diseases. Earlier studies from this laboratory have demonstrated that systemically administered alendronate is rapidly either taken up by bone tissues or excreted by the kidney, and that renal excretion is the only route of elimination. The purpose of this study is to characterize the renal handling of alendronate in rats by standard clearance procedures with inulin as a marker of glomerular filtration rate. Alendronate is highly bound to rat serum protein. The excretion of alendronate by the kidney is concentration-and dose-dependent, and saturable, indicating that it is secreted by an active transport mechanism. The secretory mechanism exhibits limitation of transport, with an apparent Tm of approximately 25 micrograms/min/kg. However, high doses of cimetidine, quinine, probenecid, and p-aminohippuric acid had no effect on the renal excretion of alendronate, suggesting that alendronate is not secreted by anionic or cationic transport systems. In contrast, alendronate clearance is inhibited by etidronate, another bisphosphonate, in a dose-dependent manner, implying that these two bisphosphonates compete for an as yet uncharacterized renal transport system. As expected, the renal excretion of alendronate is drastically reduced in rats with acute renal failure. As a consequence of renal impairment, alendronate accumulates in plasma, and the concentration of the drug in bone tissues increases significantly.

Alendronate↗