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At least 19 recordsLinked to original sources
PubMed1987

Effects of a new aminodiphosphonate (aminohydroxybutylidene diphosphonate) in patients with osteolytic lesions from metastases and myelomatosis. Comparison with dichloromethylene diphosphonate.

We have compared in an open trial the clinical and biochemical effects of a new aminodiphosphonate, aminohydroxybutylidene diphosphonate, with those of dichloromethylene diphosphonate, which has been proved effective. The patients presented extensive and symptomatic bone involvement from multiple myeloma, breast cancer, and other metastatic tumors. The treatment consisted of aminohydroxybutylidene diphosphonate, 2.5 mg/d intravenously for five days, or dichloromethylene diphosphonate, 300 mg/d intravenously for seven days, followed by 100 mg/d intramuscularly for ten days. Twelve patients treated with aminohydroxybutylidene diphosphonate and 16 patients treated with dichloromethylene diphosphonate were assessable and were followed up for one to six months. Therapy with aminohydroxybutylidene diphosphonate showed a quicker action in reducing bone pain and reduced significantly more the serum calcium level than did therapy with dichloromethylene diphosphonate. Aminohydroxybutylidene diphosphonate therapy also affected urinary calcium levels and hydroxyproline excretion more markedly than did dichloromethylene diphosphonate, although the differences are not statistically significant. However, the biochemical indexes rebounded more quickly in patients treated with aminohydroxybutylidene diphosphonate, indicating that the loading amount (only 12.5 mg) used in this preliminary study is insufficient to sustain a prolonged effect. The effectiveness and lack of side effects render aminohydroxybutylidene diphosphonate an attractive treatment for malignant bone resorption.

Adult↗
PubMed1984

Correlation of skeletal uptake of 99mTc-diphosphonate and alkaline phosphatase before and after oral diphosphonate therapy in Paget's disease.

In Paget's disease of bone, quantitation of skeletal uptake of radiolabeled diphosphonate has been proposed as a means of monitoring response to therapy. However, the validity of such techniques has been questioned during oral diphosphonate therapy because of possible interaction between oral and radiolabeled diphosphonate. In the present study 18 patients with Paget's disease received a 6 month course of oral diphosphonate therapy. Measurements of 24 h whole body retention (WBR) of 99mTc-labeled hydroxyethylidene diphosphonate (HEDP), serum alkaline phosphatase (SAP), and urinary hydroxyproline excretion were obtained before, during, and after treatment. WBR correlated well with SAP and urinary hydroxyproline throughout the course of therapy. In addition, the relationship between WBR and SAP was maintained after cessation of oral diphosphonate. It would thus appear that in Paget's disease 24 h WBR of HEDP, a quantitative measure of skeletal uptake of diphosphonate, will reflect disease activity even in the presence of an oral diphosphonate load.

Administration, Oral↗
PubMed1980

Bone-seeking properties of Tc-99m carbonyl diphosphonic acid, dihydroxy-methylene diphosphonic acid and monohydroxy-methylene phosphoinic acid: concise communication.

Carbonyl diphosphonic acid, dihydroxy-methylene diphosphonic acid and monohydroxy-methylene diphosphonic acid were synthesized and labeled with Tc-99m. Their chemical structures were confirmed and their bone-seeking relationships were compared with those of Tc-99m MDP in experimental animals. MKonohydroxy-methylene diphosphonic acid was found to have higher bone affinity and faster blood clearance than MDP, whereas carabonyl diphosphonic acid and dihydroxy-methylene diphosphonic acid demonstrated lower bone affinity and slower blood clearance than MDP.

Animals↗
PubMed2005

Solid-state molecular organization and solution behavior of methane-1,1-diphosphonic acid derivatives of heterocyclic amines: the role of the topochemical ring modification and the intramolecular hydrogen bonds in monosubstituted piperid-1-ylmethane-1,1-diphosphonic acids.

The crystal structures of 3-methylpiperid-1-ylmethane-1,1-diphosphonic (2), 4-methylpiperid-1-ylmethane-1,1-diphosphonic (3), 2-ethylpiperid-1-ylmethane-1,1-diphosphonic (4), and 2-methylpiperid-1-ylmethane-1,1-diphosphonic (5) acids have been determined and are discussed with respect to their molecular organization and crystal-packing preferences. The chair conformation, predominant also in solution, favors equatorial positioning of the bulky substituents of the heterocyclic N and C atoms. The molecular geometry also provides access to intramolecular hydrogen-bond formation between the axial protons located on the nitrogen atoms, as well as the carbon atoms closest to it, and phosphonic/phosphonate oxygen atoms. The molecules preferably arrange in monolayers, observed in all crystals with an exception of 3. The layers are held in place in the third direction through van der Waals interactions. The analysis of two-dimensional hydrogen-bonded networks is concentrated on revealing how the substituent's topology of the molecule affects the solid-state organization in well-defined structures and is aimed at unraveling the consequences and the possible conformational changes by stepwise network disruption upon crystal dissolution in water. The solution NMR studies are focused on revealing the role that the topochemistry of the substituent plays for the stereodynamics in 2-5. It is demonstrated that in contrast to piperid-1-ylmethane-1,1-diphosphonic acid (1), in which the ring inversion/rotation around the C-N bond concerted with the N-H...O hydrogen-bond breaking/formation process leads to a mixture of two interconverting conformers, the concerted N-H...O breaking/rotation/N-H...O formation process in 2 and 3 allows for a predominance of one conformer in solution. However, placement of a substituent at 2-position in the ring hampers the rotation around the C-N bond; this makes 4 and 5 significantly less flexible relative to compounds 1-3. In addition, both compounds 4 and 5 are proved to exist as a mixture of two conformers, the equilibrium of which in acidic solution is shifted towards the conformer found in solid state. In alkaline solutions of 4 and 5, the equilibrium is shifted towards the conformer that is forced by the flipping of the heterocyclic ring. These results correlate well with recently documented differences in the biological potency of this group of compounds.

Amines↗
PubMed1983

New diphosphonate compounds for skeletal imaging: comparison with methylene diphosphonate.

Three-hour biodistribution of Tc-99m complexes of six diphosphonates was compared in rabbits with tibial lesions to determine which was best for detection of focal bone lesions. Sr-85 was used as a standard. N,N-dimethylaminomethylene diphosphonate (DMAD) was the only agent with a higher lesion/normal bone ratio than methylene diphosphonate (MDP), attributable to lower concentration in normal bone. Hydroxymethane diphosphonate (HDP) and 2,3-dicarboxypropane-1, 1-diphosphonate (DPD) demonstrated higher concentration than MDP in normal bone without improving lesion contrast. They also exhibited much higher uptake in the liver and kidney, as well as muscle and red marrow in the case of DPD. None was superior to MDP as an all-purpose skeletal agent, though others may be better for specific applications.

Animals↗
PubMed1989

Effects of intracellular diphosphonates on cells of the mononuclear phagocyte system: in vivo effects of liposome-encapsulated diphosphonates on different macrophage subpopulations in the spleen.

The intracellular effects of different diphosphonates on splenic macrophages were compared after intravenous injection of liposomes with encapsulated dichloromethylene diphosphonate (C12MDP), 3-amino-1-hydroxypropane-1,1-diphosphonate (APD), or 1 hydroxyethane-1,1-diphosphonate (EHDP) in similar concentrations. Intracellular C12MDP was by far the most toxic compound for macrophages in the spleen. APD encapsulated in liposomes in the highest possible concentration eliminated marginal zone macrophages only and EHDP did not affect any of the macrophage subpopulations in the spleen.

Animals↗
PubMed1991

The diphosphonate space: a useful quantitative index of disease activity in patients undergoing hydroxy methylene diphosphonate (HMDP) bone imaging for Paget's disease [corrected].

Comparison between the plasma levels of intravenously injected technetium 99m hydroxy methylene [corrected] diphosphonate (99mTc-HMDP) and chromium 51 ethylene diamine tetra-acetic acid (51Cr-EDTA) reflects the uptake of diphosphonate into bone (the diphosphonate space). This can be used as an index of skeletal function in metabolic bone disease. In a series of 49 patients with Paget's disease the diphosphonate space (DPS) correlated well with other indicators of disease activity such as alkaline phosphatase and urinary hydroxyproline levels. The DPS is a good predictor of the volume of skeletal involvement as estimated from bone images. The DPS also provides a sensitive indicator of response to treatment with intravenously administered bisphosphonate. The DPS is simple to perform and is a useful adjunct to routine bone imaging.

Alkaline Phosphatase↗
PubMed1982

The effects of disodium ethane-hydroxy-1,1-diphosphonate and disodium dichloromethylene diphosphonate on lanthanide-induced calcergy.

Systemic treatment with disodium ethane-hydroxy-1,1-diphosphonate is ineffective in inhibiting the calcergenic reactions induced in mouse skin by the lanthanides. In contrast, disodium dichloromethylene diphosphonate prevents lanthanide calcergy induced by 12 of the 15 compounds tested but only when treatment with Cl2MDP is given prior to the subcutaneous (sc) injection of the lanthanide. This is the first experimental calcification system in which EHDP was ineffective in inhibiting the calcification and the first in which Cl2MDP was found to be effective in this regard. It is increasingly apparent that individual members of the diphosphonates show variable anti-calcific effects, that the activity of one particular compound may vary from one test system to another and that the time of application of treatment of the compounds in respect to the application of the initiating stimulus to calcification may be an important factor in determining the efficacy of a particular compound.

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↗
PubMed1990

Effects of propane-2, 2-diphosphonate (PDP) on matrix-induced ectopic bone formation in comparison to ethane-1-hydroxy-1, 1-diphosphonate (EHDP).

The most prominent effect of propane-2, 2-diphosphonate (PDP) and ethane-1-hydroxy-1, 1-diphosphonate (EHDP) on matrix-induced ectopic bone in the rat was a dose-dependent inhibition of osteogenesis in the early phases of development. The delay was seen as a consequence of osteoprogenitor cell inhibition. Additionally, later phases of bone maturation were disturbed by interference with the mineralization and remodeling processes. However, direct effects on the calcium phosphates of bone are only of minor additional value, which remains of lesser importance in comparison to the cellular impairment. After withdrawal of diphosphonates, the effects were nearly completely remitted. Neither PDP nor EHDP, even given in high doses, resulted in a lasting reduction in ectopic mass. The remission may be referred to the recovery of cell activities, whereas the mineral impregnation of osteoidosis was, if at all, of little importance. For treatment of ectopic osteogenesis PDP proved inefficient.

Animals↗
PubMed1992

Cytotoxicity of dichloromethane diphosphonate and of 1-hydroxyethane-1,1-diphosphonate in the amoebae of the slime mould Dictyostelium discoideum. A 31P NMR study.

Two pyrophosphate analogues, dichloromethane diphosphonate (Cl2MDP), and 1-hydroxyethane-1,1-diphosphonate (EHDP), at concentrations of 0.5-1 mM, efficiently inhibited the growth of amoebae of the slime mould Dictyostelium discoideum. Cell viability decreased markedly upon incubation with the diphosphonates. The mechanism of toxicity was investigated by in vivo 31P NMR spectroscopy and the formation of analogues of ATP [adenosine 5'-(beta, gamma-dichloromethane triphosphate) and adenosine 5'-(beta, gamma-1-hydroxyethane triphosphate)] was demonstrated. These two compounds were identified from their 31P NMR spectra in perchloric acid extracts prepared from amoebae poisoned with Cl2MDP or EHDP and may have been synthesized by reversible pyrophosphate exchange catalysed by cytosolic aminoacyl-tRNA synthetases.

Animals↗
PubMed1975

Effects of dichloromethylene diphosphonate, ethane-1-hydroxy-1,1-diphosphonate, and rickets in rats.

This study compared bone remodeling, bone mineralization, and parathyroid hormone secretion in rats treated with ethane-1-hydroxy-1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (Cl2MDP). The results were compared with findings in rachitic and control rats. In addition, calcification was induced in the skin by administration of lead acetate intravenously and polymyxin B subcutaneously; the efficacies of EHDP and Cl2MDP in preventing the calcific plaque were compared. Both the serum biochemical values and the morphologic findings indicate that Cl2MDP and EHDP influence bone and mineral metabolism differently. Even with the relatively large doses used in this study, Cl2MDP had a minor or no effect while EHDP had a marked effect that, in general, is undersirable. EHDP caused increase in circulating immunoreactive parathyroid hormone to levels greater than those in rachitic rats. Both diphosphonates appear to have a similar effect on the ectopic mineralization produced by calciphylaxis, suggesting that Cl2MDP may be the agent of choice in this problem because the undersirable side-effects would be avoided.

Acetates↗
PubMed1984

Comparison of the kinetics of methylene-diphosphonate (MDP) and dicarboxypropan-diphosphonic acid (DPD), two radio-diagnostics for bone scintigraphy.

Two 99mTc-labelled radio-diagnostics for bone scintigraphy, dicarboxypropan-diphosphonic acid (DPD) and methylene-diphosphonate (MDP) were compared. The test parameters were the time-activity curves of serum and of deproteinised serum, time-activity curves in regions of interest above the femur, the sacrum and the soft tissue medial of the femur, and the urinary excretion. The ratio of bone lesion to normal bone was compared for 6 h after the injection of each compound. The time-activity curves in the serum and the deproteinised serum were not very different, therefore the percentage of the radio-diagnostics bound to protein in blood were nearly the same. At 14 h post-injection nearly 80% of the activity remaining in the blood pool was bound to protein. The urinary excretion of MDP was 25% higher than that of DPD, because the renal clearance of DPD was 41% lower than that of MDP. The non-excreted activity was bound to bone; therefore in the regions of interest set above the sacrum, the femur and the soft tissue the activity ratio was 27% higher for DPD for the ratio os sacrum to soft tissue and 21% higher for the ratio femur to soft tissue, but there were similar results for both substances for the ratio bone lesion to normal bone; therefore MDP was not better than DPD in detecting bone lesions.

Adult↗
PubMed1980

A radiopharmaceutical and clinical comparison of 99mTc-Sn-hydroxymethylene diphosphonate with 99mTc-Sn-hydroxyethylidene diphosphonate.

A comparison of 99mTc labeled hydroxyethylidene diphosphonate (99mTc-HEDP) and hydroxymethylene diphosphonate (99mTc-HMDP), two bone scanning agents differing by a single methyl group, was performed in 20 patients. In nine patients, no difference in scan quality was found. Of the other 11, HMDP had significantly better bone delineation (p = 0.012), lower soft tissue background (p = 0.001), and improved overall scan quality (p = 0.012) in 10, while HEDP was preferred for bone delineation and overall quality in only a single patient. No significant difference in lesion detection was noted.

Adult↗
PubMed1980

Tc-99m HMDP (hydroxymethylene diphosphonate): a radiopharmaceutical for skeletal and acute myocardial infarct imaging. II. Comparison of Tc-99m hydroxymethylene diphosphonate (HMDP) with other technetium-labeled bone-imaging agents in a canine model.

Technetium-99m hydroxymethylene diphosphate (Tc-HMDP) was compared with the two other diphosphonates (Tc-MDP and Tc-HEDP) and Tc-99m pyrophosphate (Tc-PPi) in a canine model of acute myocardial infarction. The TC-HMDP showed higher uptake in infarcted myocardium than the other two diphosphonates, and uptake equivalent to that of Tc-PPi.

Animals↗
PubMed2004

Evaluation of mandibular invasion by head and neck cancers using 99mTc-methylene diphosphonate or 99mTc-hydroxymethylene diphosphonate and 201Tl chloride dual isotope single photon emission computed tomography.

Whether a patient with head and neck cancer has mandibular invasion or not is important in determining the method of resection surgery. But, no modality is adequately reliable when used alone in the evaluation of mandibular invasion. Therefore, to more accurately diagnose mandibular invasion in head and neck cancer, we used a new modality, namely, 99mTc methylene diphosphonate (MDP) or 99mTc hydroxymethylene diphosphonate (HMDP) and 201Tl chloride dual isotope single photon emission computed tomography (Tc/Tl SPECT). The aim of this study is to disclose the usefulness of Tc/Tl SPECT in the assessment of mandibular invasion by head and neck cancers. 99mTc-MDP or -HMDP SPECT (Tc SPECT)s and 201Tl chloride SPECT (Tl SPECT)s were performed in 34 patients with suspected mandibular involvement of head and neck cancer. Thirty of 34 cases underwent both TcMTl SPECT and CT examination. Tc/Tl SPECT fusion images were obtained using the Automatic Registration Tool (ART, TOSHIBA, Japan) system. In the diagnosis of mandibular invasion on Tc/Tl SPECT fusion images, a problem was that the range of Tc and Tl uptake was changed by the condition of display used in the reconstruction and expression of the images. Then, prior to clinical evaluation, to reveal the most appropriate upper window level for display, a phantom study was performed. In a clinical study, the upper window level was set at 40 or 50%, which were verified to be the proper values in the preliminary study. The diagnostic accuracy obtained using Tc SPECT, TcMTl SPECT and CT was compared with the histopathological findings. Tc/Tl SPECT at 40 and 50% upper window level had higher specificity, accuracy, and positive predictive value (73.3%, 85.3%, 81.8%) than Tc SPECT alone (21.4%, 67.6%, 64.5%) and higher sensitivity and negative predictive value (94.7%, 91.7%) than CT (70.6%, 72.2%) for detecting mandibular invasion. Tc/Tl SPECT was a useful diagnostic procedure for the assessment of mandibular invasion by head and neck cancers.

Head and Neck Neoplasms↗
PubMed1987

Pharmacokinetics of the osteotropic diphosphonate 3-amino-1-hydroxypropane-1,1-diphosphonic acid in mammals.

3-Amino-1-hydroxypropane-1,1-diphosphonic acid (APD) is a potent drug in treatment of tumor induced osteolytic bone destruction and other bone diseases. The fate of 14C-labelled APD was studied in rats following oral and intravenous application. Intestinal absorption of APD was about 0.5% of the dose administered and radioactivity was mainly deposited in bone tissue. Liver, kidneys and blood contained very small amounts of radioactivity. After intravenous application, autoradiographic studies revealed high APD accumulation in sites of high bone turnover, in tracheal cartilage, and--only at high doses--in the liver. Biliary excretion of 14C-APD was very low. Body distribution of 14C-APD in mice was similar to that in rats. After intravenous application, APD was mainly excreted in the urine, in which no metabolites could be detected. Biological half-life of APD in rat bone was approximately 300 days. This seemed to be an important fact with regard to a possible use of APD in prophylactic treatment of cancer patients to prevent bone metastases.

Absorption↗
PubMedDate not supplied

Analysis of selected diphosphonic acid derivatives used in treatment of osteoporosis. Part I. Complexometric determination of diphosphonic acid derivatives.

The purpose of the study was to develop a simple method for determination of diphosphonic acid derivatives in pharmaceutical preparations used in treatment of osteoporosis: disodium etidronate, disodium clodronate, disodium tiludronate, disodium pamidronate, sodium alendronate. The analysis performed by the visual end point titration method with complexing reagent Th(DCTA) in presence of xylenol orange used the ability of these compounds to form complexes.

Alendronate↗