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Results for “Diphosphonates”

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PubMed1979

Increase in alkaline phosphatase activity in calvaria cells cultured with diphosphonates.

1. Dichloromethanediphosphonate and to a lesser degree 1-hydroxyethane-1,1-diphosphonate, two compounds characterized by a P-C-P bond, increased the alkaline phosphatase activity of cultured rat calvaria cells up to 30 times in a dose-dependent fashion. 2. Both diphosphonates also slightly inhibited the protein synthesis in these cells. 3. Thymidine, an inhibitor of cell division, did not inhibit the induction of the enzyme, indicating that the increase in enzyme activity was not due to the formation of a specific population of cells with high alkaline phosphatase activity. 4. The effect on alkaline phosphatase was suppressed by the addition of cycloheximide, an inhibitor of protein synthesis. 5. After subculturing the stimulated cells in medium without diphosphonates, the enzyme activity fell almost to the control value. 6. Bovine parathyrin diminished the enzyme activity of the control cells and the cells treated with dichloromethanediphosphonate; however, at high concentration the effect of parathyrin was greater on the diphosphonate-treated cells than on the control cells. 7. The electrophoretic behaviour, heat inactivation, inhibition by bromotetramisole or by phenylalanine, and the Km value of the induced enzyme were identical with that of the control enzyme.

Alkaline Phosphatase↗

PubMed1976

The alteration of osteoclast morphology by diphosphonates in bone organ culture.

Two diphosphonates alter the morphology of the osteoclast, as they inhibit the calcium45 release from bones stimulated to resorb by lipopolysaccharide. Disodium dichloromethylene diphosphonate was more potent than disodium ethane-1-hydroxy-1, 1-diphosphonate in both inhibiting 45calium release and altering osteoclast morphology. Alteration in the morphology of osteoclasts is associated with little or no change in the morphology of the surrounding non-osteoclast cells. These results indicate a specific morphological effect of diphosphonates on osteoclasts.

Animals↗

PubMed1975

Pyrophosphate and diphosphonates in skeletal metabolism. Physiological, clinical and therapeutic aspects.

Pyrophosphate and diphosphonates produce striking results on calcium metabolism in experimental animals and man. Compounds containing P-O-P- bonds (e.g. inorganic pyrophosphate [PP-ii1 or P-C-P bonds (diphosponates) inhibit both the formation and dissolution of calcium phosphate crystals in vitro. PP-i may have a physiological function in regulating calcification and bone turnover, and obnormalities in its metabolism may occur in some human diseases notably hypophosphatasia and pseudogout. Diphosphonates inhibit ectopic calcification, and slow down resorption and bone turnover in several experimental systems in vivo. They have helped in studies of various aspects of the regulation of calcium metabolism. The diphosphonate, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) has been shown in clinical studies to be effective against ectopic calcification particularly in myositis ossificans progressiva and in disorders of increased bone resorption such as Paget's diseases and some types of osteoporosis. -99mTechnetium complexes of EHDP, PP-i and other polyphosphates have also recently been used successfully as bone scanning agents.

Animals↗

PubMed1975

Technetium-99m-methylene diphosphonate--a superior agent for skeletal imaging: comparison with other technetium complexes.

Methylene diphosphonate (MDP) was formulated as a complex of 99mTc for skeletal imaging. This agent was compared with three other bone-seeking technetium agents: ethane-1-hydroxy-1, 1-diphosphonate (EHDP), pyrophosphate, and polyphosphate. In tissue radioassay experiments in rodents, the technetium complexes of MDP and EHDP were similar, but skeletal concentration with both of these agents was higher than that with pyrophosphate or polyphosphate. The total-body retention of MDP and EHDP complexed with 95mTc was studied in beagle dogs for 35 days by excretion measurements and total-body counting and compared with polyphosphate and pertechnetate. The long-term retention was greater for MDP. The 5-day cumulative fecal excretion of 95mTc was low when administered as EHDP or polyphosphate complexes and negligible when administered as MDP complex. In six human volunteers the blood clearance of 99mTc-mdp was similar to that of 18F and significantly faster than that of 99mTc-EHDP. Pyrophosphate cleared from the blood much faster than polyphosphate but slower than the diphosphonates. The urinary excretion of the MDP complex was greater than for EHDP within the first 2-3 hr after injection. The 24-hr urinary excretion of pyrophosphate and polyphosphate complexes was not as complete as for the diphosphonates. All four 99mTc complexes proved satisfactory for clinical imaging studies. The MDP complex produced images of superior quality as early as 2 hr after administration, attributable to its more rapid clearance from the blood and soft tissues. On the contrary, a longer interval of 3-4 hr after injection was usually needed for 99mTc-EHDP; pyrophosphate and polyphosphate complexes regularly required a waiting period of 4 hr. Comparitive radiation dose estimates were made based on the available biologic distribution data for these 99mTc skeletal-localizing agents.

Animals↗

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↗

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↗

PubMed1978

The inhibitory effect of new diphosphonic acids on aortic and kidney calcification in vivo.

Three new diphosphonic acids, i.e. compounds containing a P-C-P bond, have been investigated for their ability to inhibit the vitamin D-induced calcification of aortas and kidneys in rats. The compounds were applied orally in various doses. All of the compounds, which had previously been shown to effectively inhibit the in vitro crystallization of apatite, markedly decreased the amount of calcium deposited in aortas and kidneys. One of the new compounds was substantially more effective than ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), which was used as a reference compound. Diphosphonic acids might be used therapeutically in man against soft tissue calcification.

Animals↗

PubMed1977

[Sources of error in the interpretation of bone scans with 99mTc-diphosphonate (author's transl)].

Errors in the interpretation of bone scans with 99mTc-diphosphonate may be due to summation of radio-activity from superimposition of various bone structures. Lesions with increased bone turn-over as well as reactive hyperaemia result in increased uptake. The possibility of extraosseous uptake of diphosphonate must be borne in mind during the evaluation of bone scans. The kidneys and lower urinary tract must be considered. Absent or slight uptake by the kidneys with good demonstration of bone suggests increased diphosphonate uptake by the bones. Special attention should also be paid to zones of decreased uptake, since these are also due to abnormalities in the bone.

Bone Diseases↗

PubMed1979

Myocardial infarct imaging with 99mTc-pyrophosphate and 99mTc-methylene diphosphonate: lack of correlation.

A prospective study of eight patients with recent transmural myocardial infarction was performed using 99mTc-Sn-pyrophosphate and 99mTc-Sn-methylene diphosphonate in each patient. All pyrophosphate scans were strongly positive whereas the diphosphonate scan was strongly positive in only one case. We conclude that 99mTc-Sn-pyrophosphate is preferable to 99mTc-Sn-methylene diphosphonate for myocardial imaging.

Diphosphates↗

PubMed1977

Localization of technetium-99m diphosphonate in acutely injured muscle. Relationship to muscle calcium deposition.

In rats with experimental ischemic myopathy, there was a significant correlation (r = 0.778, p less than 0.001) between muscle uptake of technetium-99m (99mTc) diphosphonate and tissue calcium concentration. In addition, the accumulation of both calcium and 99mTc-diphosphonate in acutely injured muscles was further increased in rats with vitamin D-induced hypercalcemia. Histologic studies demonstrated staining of damaged muscle fibers with alizarin red, indicating the presence of microcrystalline or ultramicrocrystalline calcium salts. Staining of muscle fibers was most intense in the outer marginal zones of individual microscopic infarcts. Our results suggest that the uptake of 99mTc-diphosphonate in acutely damaged skeletal muscle is directly related to the deposition of calcium salts within the injured muscle fibers.

Acute Disease↗

PubMed1978

Synthesis, radiotechnetium labelling, and comparison of biologic behavior of longer-chain analogs of methylene diphosphonate.

Polymethylene diphosphonic acids of different chain lengths ( n = 2, 3, and 10) were synthesized and labeled with technetium-99m. Their biologic behavior was compared with that of Tc-99m-labeled methylene diphosphonate (MDP) in experimental animals. With n = 2 (ethylene diphosphonic acid), the compound resembled MDP in bone affinity. The longer-chain analogs had lower bone affinity.

Animals↗

PubMedDate not supplied

Vascularity of the femoral head. Tc diphosphonate scintigraphy validated with tetracycline labeling.

99MTc diphosphonate scintigraphy and tetracycline labeling were performed on 22 hips in 20 patients in whom the femoral heads were subsequently removed. Twelve of the hips had acute neck fractures, and 10 hips had roentgenographic evidence of avascular necrosis. This technique is of greater value for recent fractures, for once revascularization begins to occur, increased radioactivity is usually found by scintiscan. There was good correlation between roentgenogram, scintiscan and tetracycline fluorescence. 99mTe diphosphonate scintigraphy, which can be performed outside the operating theater with little discomfort to the patient, proved to be a reliable, noninvasive method of assessing the blood flow to the femoral head. 99mTc diphosphonate scintigraphy is not a quantitative technique; it detects the presence or absence of femoral head blood flow, not the adequacy of that blood supply.

Adult↗

PubMed1979

Effect of ethane-1-hydroxy-1,1-diphosphonate and vitamin D on bone mineralization.

Administration of large quantities of ethane-1-hydroxy-1,1-diphosphonate to growing chicks resulted in a decrease in percent bone ash and an increase in percent osteoid. The degree of inhibition of bone mineral accumulation was a function of both duration and quantity of ethane-1-hydroxy-1,1-diphosphonic acid administration. The inhibition of bone mineral accumulation could be partially corrected with administration of 1,25-dihydroxyvitamin D3. Administration of high levels of ethane-1-hydroxy-1,1-diphosphonate also resulted in inhibition of intestinal calcium absorption. This could be reversed or prevented by the administration of 1,25-dihydroxyvitamin D3.

Animals↗

PubMed1975

Quantitative determination of ethane-1-hydroxy-1,1-diphosphonate in urine and plasma.

A technique has been developed to measure the diphosphonate ethane-1-hydroxy-1, 1-diphosphonate (EHDP) quantitatively in 5 ml of urine or 2 ml of plasma. The procedure is based on a coprecipitation of EHDP with calcium phosphate, elimination of inorganic phosphate as an insoluble triethylamine-phosphomolybdate complex, decomposition of the P-C-P bond with ultraviolet light and spectrophotometric determination of the inorganic phosphate released. A trace amount of [14C] EHDP is used to correct for losses. The method appears specific for the diphosphonate, exhibits quantitative recoveries, and has a mean coefficient of variation of 3.7% for urine and 7.3% for plasma. The limit of detection is in the order of 2.5 mumol/1 in 5 ml urine and 0.5 mumol/1 in 2 ml of plasma.

Chemical Precipitation↗

PubMed1979

Treatment of calcium urolithiasis with diphosphonate: efficacy and hazards.

The effect of treatment of renal stone formation with 5 to 20 mg./kg. per day oral disodium ethane-1-hydroxy-1,1-diphosphonate for up to 30 months was examined in 12 patients with active renal (calcium) stone disease. The over-all incidence of stone passage decreased from 17.8 stones per year per patient before treatment to 7.7 stones per year per patient during therapy. Of the 12 patients 7 passed fewer stones or no stones during treatment. However, the incidence of stone passage was not changed substantially by disodium ethane-1-hydroxy-1,1-diphosphonate in 5 patients. Symptoms of muscle weakness and pain in the back, hips and shoulders occurred in 3 patients during treatment, 2 patients had an increase in serum alkaline phosphatase and 1 patient had a decrease in bone density. Although disodium ethane-1-hydroxy-1,1-diphosphonate may be clinically useful to manage calcium urolithasis in certain patients its over-all use is limited because of its ineffectiveness in some patients and owing to its potential to induce osteomalacia.

Administration, Oral↗

PubMed1975

The effects of a diphosphonate and dietary calcium on the metabolism of vitamin D3 (cholecalciferol) in the chick.

1. Vitamin D-deficient chicks, maintained on a diet adequate in calcium and treated with ethane-1-hydroxy-1,1-diphosphonate for 2 days before a single oral dose of cholecalciferol (vitamin D3), converted the vitamin into 24,25-dihydroxycholecalciferol instead of into the normal metabolite 1,25-dihydroxycholecalciferol. 2. This inhibition of the renal 1-hydroxylase disappeared on withdrawal of the diphosphonate. 3. Kidneys from chicks given diphosphonate for 12 days converted 25-hydroxycholecalciferol into 24,25-dihydroxycholecalciferol on incubation in vitro. 4. The inhibition of the 1-hydroxylase was markedly accelerated by treating the birds with cholecalciferol. 5. No inhibition of renal 1-hydroxylation was observed in birds maintained on a diet low in calcium. 6. A possible mechanism producing this effect is discussed.

Animals↗

PubMed1979

Regional 99m technetium diphosphonate uptake in experimental dog heart infarct: relation to duration and severity of ischaemia.

Regional uptake of 99mTechnetium diphosphonate was compared with regional myocardial blood flow 6, 12 and 24 h after the onset of myocardial infarction in dogs, and with regional creatine kinase depletion 24 h after the onset. Uptake of the imaging agent increased from 6 to 24 h, but no consistent relationship could be demonstrated between regional myocardial blood flow and regional uptake of the diphosphonate nor between uptake and regional creatine kinase depletion at the centre or border of the infarct. In addition, inappropriately high levels of 99m Technetium uptake could be demonstrated in the epicardial layer of the normal tissue surrounding the infarct. We conclude that diphosphonate uptake is not quantitatively related to the severity of ischaemia, and that use of this substance for imaging may over-estimate myocardial infarct size.

Animals↗

PubMed1977

Detection of sacro-ilitis. A comparison between profile scanning with the use of 99m Tc pertechnetate and scintigraphy with 99m Tc diphosphonate.

Comparative evaluation of the sensitivity of 99mTc pertechnetate scanning and of 99mTc diphosphonate scintigraphy in detecting sacro-iliac arthritis (S.I.) was performed in 32 patients with definite S.I., 14 with probable S.I., and 6 with inactive S.I., 14 patients without any evidence of S.I. served as controls. Greater diagnostic accuracy was obtained by 99mTc pertechnetate scanning than with 99mTc diphosphonate scintigraphy in patients with active S.I. in the early stages before radiological changes had become evident and in patients 22 years old and younger. In patients with inactive S.I. a close correlation was found between clinical, radiological, and scintigraphical results with 99mTc diphosphonate scintigraphy. An index obtained by adding the uptake values measured by both methods in each subject yielded valuable information in patients with S.I. that is clinically difficult to differentiate.

Adolescent↗