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PubMed1987

Molecular weights of technetium hydroxyethylidene diphosphonate complexes.

The results of recycle size-exclusion and anion-exchange chromatography are combined to determine molecular weights and radii of gyration for selected components of a carrier-added technetium hydroxyethylidene diphosphonate radiopharmaceutical bone-imaging preparation. Samples evaluated by size-exclusion are selected from fractions collected as the preparation elutes from the anion-exchange column. Polyethylene glycol and polyphosphate molecular weight standards are used, in conjunction with the universal calibration method, to determine Mark-Houwink constants and to estimate molecular weights for the complexes. The results of this study support a spherical shape model for the collection of technetium complexes. Given the combined knowledge of molecular weights, charges, technetium concentration dependencies, and mass spectral data, several formula assignments are proposed, including TcO(OH)L-1, Tc2O(OH)6L-3, Tc2O(OH)2L3(-6), Tc3O2(OH)3L2(-5), Tc3O2(OH)3L3(-7), Tc2O2(OH)4(HL)3(-7) and Tc2O2(OH)4(H2L)4(-8).

Chemical Phenomena↗

PubMed1990

The adsorption of 99mTc(Sn)-diphosphonate complexes on tri-calciumphosphate: the influence of preparation conditions, ligand-type, incubation media and adsorption conditions. The reversibility of the adsorption.

The influence of several variables on the adsorption of 99mTc(Sn)-diphosphonate complexes on tri-calciumphosphate was determined. The composition of the incubation medium influenced the percentage adsorption: with Hank's balanced salt solution (a medium frequently used for bone cell cultures) and Tris buffer lower percentage adsorption was obtained than with physiological saline as the incubation medium. The influence of addition to the incubation medium of some ions and neutral species, some of which occur in bone fluid, is very specific. Addition of Sn(II) or Mg(II) (a component of HBSS) reduces the amount of adsorption. Addition of Ca(II) and Al(III) had no effect. Addition of sodium-citrate and MDP to the medium and an increase of the pH of the medium decreased the percentage adsorption. The ligand that was used in the preparation of the complex mixture influences the percentage adsorption considerably. The Sn(II) concentration used during the preparation of the 99mTc(Sn)-MDP and 99mTc(Sn)-MHDP complexes showed no definite influence on the percentage adsorption. The pH and ligand concentration, used in the preparation, however, did effect the percentage adsorption. It was concluded that the 99mTc(Sn)-disphosphonate mixtures are part reversibly and part irreversibly bound to tri-calcium-phosphate.

Adsorption↗

PubMed1991

The in situ immune response of the rat after intraperitoneal depletion of macrophages by liposome-encapsulated dichloromethylene diphosphonate.

This study concerns the contribution of peritoneal macrophages in vivo to local and systemic immune responses in the rat. Peritoneal macrophages as well as macrophages in the draining parathymic lymph nodes were selectively eliminated by intraperitoneal inoculation of dichloromethylene-diphosphonate-containing liposomes. This depletion resulted in an enhanced immune reaction to intraperitoneally administered trinitrophenyl keyhole limpet haemocyanin in the parathymic lymph nodes, as demonstrated by the higher numbers of specific anti-TNP antibody-forming cells in macrophage-depleted animals than in control animals from day 5 after immunization. The immune reaction peaked at day 7 and remained high until day 10. Specific antibody-forming cells were found occasionally in the mesenteric lymph nodes and spleen, but not in the mucosa of the gut or in the bronchus-associated lymphoid tissue. An elevated immune reaction found in parathymic lymph nodes associated with the depletion of local macrophages by liposome treatment indicates a regulatory role of peritoneal macrophages in local humoral immune response.

Animals↗

PubMed1986

Effect of ethane-1-hydroxy-1,1-diphosphonate on ectopic bone formation induced by murine osteosarcoma-derived bone-inducing substance.

The effects of ethane-1-hydroxy-1,1-diphosphonate (EHDP) on ectopic bone formation were studied qualitatively and quantitatively in an experimental system for ectopic bone formation induced by murine osteosarcoma-derived bone-inducing substance. At a low dose of EHDP (3 mg/kg per day i.p.), histologic sequelae of ectopic bone formation were normal, and the size of the induced bone mass was unaffected. At a high dose of EHDP (30 mg/kg per day i.p.), an unmineralized bone matrix with hematopoietic bone marrow was formed without evidence of retardation. This osteoid tissue showed no radiologic and histologic evidence of mineralization during the period of EHDP administration. When EHDP was withdrawn, its inhibitory effect on mineralization was reversed. The induced bone mass was almost the same size as that in controls. These results suggest that EHDP might not prevent ectopic bone matrix formation, but its mineralization and withdrawal of EHDP might lead to the formation of a normal bone similar in size to that formed without EHDP treatment.

Animals↗

PubMed1991

Effects of ethane-1-hydroxy-1, 1-diphosphonate on cell differentiation, and proteoglycan and calcium metabolism, in the proximal tibia of young rats.

The effects of ethane-1-hydroxy-1, 1-diphosphonate(EHDP) on cell differentiation, and on the metabolism of proteoglycan and calcium in the epiphyseal plate and metaphysis of rats were investigated through histology and autoradiograms of [35S]-sulfate, 45Ca, and [3H]-thymidine. Suppression of bone resorption in the metaphysis due to low dose EHDP administration was associated with a proliferation of osteoclasts with an increased number of nuclei. High dose EHDP induced enlargement of the hypertrophic zone of the epiphyseal plate and suppression of calcification of the cartilage matrix. This change had a significant association not only with the suppression of chondroitin sulfate synthesis and the degradation in the cartilage matrix, but also with the suppression of growth and differentiation of chondrocytes. Calcification was also inhibited in the metaphysis, and growth and differentiation from undifferentiated mesenchymal cells to osteoblasts, osteocytes, and osteoclasts were also suppressed by high dose EHDP.

Animals↗

PubMed2006

Synthesis, characterization, and in vivo skeletal localization of a new (99m)Tc-based multidentate phosphonate chelate: 5-Amino-1,3-bis(ethylamine-(N,N dimethyl diphosphonic acid) acetamido) benzene.

The tetraphosphonate ligand, 5-amino-1,3-bis(ethylamine-(N,N-dimethyl diphosphonic acid) acetamido) benzene (IPTMP) used in the present study was prepared from 5-nitroisophthalate dimethylester to label with radionuclide for targeted diagnosis and therapy. The synthesized multidentate phosphonate ligand was characterized on the basis of spectroscopic techniques, which exhibited good metal ion control properties when complexed to (99m)Tc with high in vitro and in vivo stability. Excellent quality bone images of rabbit were imaged showing rapid clearance of background activity and visualization of skeleton at 1h.

Animals↗

PubMed2005

The effects of 1-hydroxyethane-(1,1-diphosphonic acid) on the adsorptive partitioning of metal ions onto gamma-AlOOH.

1-Hydroxyethane-(1,1-diphosphonic acid) (HEDP) is extensively used in many technical applications. This work, as a first stage, examines the adsorption of aqueous HEDP, Cu(II), and Zn(II) onto boehmite (gamma-AlOOH) as single solutes. These processes can be described by the formation of inner-sphere complexes by the surface complexation model with constant capacitance. Uncomplexed HEDP is adsorbed as a mononuclear complex over the entre pH range. Four mononuclear surface complexes with different protonation levels are required to obtain a good fit of the experimental data for the pH range studied. Cu(II)- and Zn(II)-HEDP complexes at equimolar concentrations are studied at high and low surface density. The results indicate that the presence of HEDP significantly promotes metal adsorption at low pH in defects of surface sites. However, metal adsorption exhibits the same trend in the absence and presence of HEDP when the surface sites are in excess. The constant capacitance model successfully describes the experimental data through a ligand-like adsorption complex at low pH. At high pH, the model predicts separate adsorption of divalent metal and HEDP onto different surface sites as the preferred adsorption form.

Journal Article↗

PubMed2006

Coordination abilities of piperyd-1-yl-methane-1,1-diphosphonic acids towards zinc(II), magnesium(II) and calcium(II): potentiometric and NMR studies.

The combination of the pH-metric and NMR studies is used to examine the stabilities and coordination modes as well as related structural aspects of zinc(II), magnesium(II) and calcium(II) complexation to piperyd-1-yl-methane-1,1-diphosphonic acid (1) and its derivatives containing a topologically modified piperidine ring (2-7). The studied compounds coordinate metal ions exclusively via the phosphonate functions with a nitrogen atom remaining protonated over the whole range of studied pH. Compounds 1-6 readily form soluble multinuclear complexes of type [M(3)(HL)(2)] and [M(3)(HL)(3)](3-) with Zn(2+) or [M(2)(H(2)L)(2)] with Ca(2+) and Mg(2+). These species are formed based on dimers consisting of two head-to-head arranged molecules linked by strong symmetrical hydrogen bonds. The placement of the two methyl groups at 2- and 6-positions on the piperidine ring precludes the molecular recognition via similar hydrogen bonds and accounts for different complexation properties of 7 compared to 1-6. The role that the metal coordination plays on conformation dynamics in 1-7 is also discussed.

Calcium↗

PubMed1992

Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases.

Rhenium-186 (tin)hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in skeletal metastases in patients with advanced cancer. A single intravenous administration of approximately 34 mCi (1,258 MBq) resulted in significant improvement in pain in 33 of 43 evaluable patients (77%) following the initial injection, and in 7 of 14 evaluable patients (50%) following a second treatment. Patients responding to treatment experienced an average decrease in pain of about 60%, with one in five treatments resulting in a complete resolution of pain. The only adverse clinical reaction was the occurrence after about 10% of the administered doses of a mild, transient increase in pain within a few days following injection. Statistically significant but clinically unimportant decreases in total white blood cell counts and total platelet counts were observed within the first 8 weeks following the injection; no other toxicity was apparent. Rhenium-186(Sn)HEDP is a useful new compound for the palliation of painful skeletal metastases.

Bone Neoplasms↗

PubMed1991

Osteodystrophy in liver cirrhosis: detection and treatment evaluation using 99Tcm methylene diphosphonate bone scintigraphy.

To investigate osteodystrophy in liver cirrhosis, 99Tcm MDP (methylene diphosphonate) bone scintigraphy was performed on 36 patients with liver cirrhosis. Abnormal lesions were detected in 17 out of 36 scans (47.2%). On the other hand, areas of increased uptake were uncommon in patients with chronic active hepatitis (1/11 cases). Plasma vitamin D3 fractions [25(OH)D3, 24.25(OH)2D3 and 1.25(OH)2D3] were decreased. Statistically significant depletion of 1.25(OH)2D3 was observed in cases with positive bone scintigraphy. 1 alpha(OH)D3 (1-2 micrograms/day) was administered for 6 months to nine patients having abnormal bone scans. Six of them showed improvement without any apparent side-effects. We conclude that hepatic cirrhotic osteodystrophy can be diagnosed positively by 99Tcm MDP bone scintigraphy and can be treated accordingly.

Adult↗

PubMed1993

Case report: accumulation of 99mTc-hydroxymethylene diphosphonate by liver metastases of prostatic adenocarcinoma.

We describe the case of a man with known prostatic carcinoma and bone metastases who was admitted with jaundice and hepatomegaly. A bone scan showed uptake of diphosphonate by the liver and ultrasound suggested the presence of diffuse metastatic disease. Liver biopsy revealed foci of carcinoma cells in the portal tracts which exhibited positive cytoplasmic staining for prostate-specific antigen, thus confirming the presence of metastatic prostatic adenocarcinoma.

Adenocarcinoma↗

PubMed1994

Effect of 1-hydroxyethane-1,1-diphosphonic acid (HEDP) on new bone formation induced by bone matrix gelatin (BMG).

The effect of the biphosphonate 1-hdroxyethane-1,1 diphosphonic acid (HEDP) on induced ectopic osteoneogenesis was studied by light and electron microscopy. Demineralized bone matrix gelatin (BMG) was implanted into the rectus abdominis muscle of 8-week-old Sprague-Dawley rats, HEDP was administered subcutaneously with a mini-osmotic pump, and histological changes were examined 4 days, 1, 2 and 3 weeks later. Four days after implantation, "acellular mineral deposition" in the control group was suppressed in the HEDP group. Two weeks after BMG implantation, cartilage formation was more intensive in the HEDP-treated group than in the control group. Three weeks after implantation, new lamellar bone with bone marrow was observed in the control group, while immature osteoid tissue detected by type II collagen in the central area was prominent in the HEDP-treated group. HEDP-treatment also suppressed the appearance and activity of osteoclast-like cell.

Animals↗

PubMed1976

Paget's bone disease treated with diphosphonate and calcitonin.

Patients with biochemically active Paget's disease were treated with a combination of disodium ethane-1-hydroxy-1, 1-diphosphonate (E.H.D.P.) and synthetic human calcitonin in low doses. The effect on biochemistry was greater and more consistent than that of even higher doses of human calcitonin. Bone biopsy showed decrease or even disappearance of abnormal osteoblasts and osteoclasts from pagetic lesions, and the addition of calcitonin to E.H.D.P. prevented the development of mineralisation defects.

Aged↗

PubMed1983

Long-term controlled trial with diphosphonate in patients with osteolytic bone metastases.

Thirty-four normocalcaemic women with multiple osteolytic bone metastases from breast cancer were randomly allocated to treatment with disodium dichloromethylene diphosphonate (Cl2MDP) 1600 mg/day orally (17) or placebo (17) for 3-9 months. Fasting urinary hydroxyproline/creatinine and calcium/creatinine ratios declined in the Cl2MDP group but not in the placebo group. Four patients in the placebo group died from hypercalcaemia. New bone metastases were more common in patients on placebo and these patients also required more analgesic drugs than those on Cl2MDP. Cl2MDP seemed to reduce bone pain and bone resorption and prevent the development of hypercalcaemia caused by osteolytic metastases. The formation of new bone metastases and the growth of old ones seemed to be retarded by Cl2MDP.

Adult↗

PubMed1984

Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease.

Transiliac bone biopsies carried out on 13 patients with Paget's disease to evaluate the effects of low-dose diphosphonate (disodium etidronate) therapy showed focal osteomalacia in the 9 patients in whom post-therapy specimens were taken through pagetic bone. Active bone resorption persisted in 5 of these. A mineralisation defect not amounting to osteomalacia--ie, osteoid of increased thickness but of normal extent--was present in the 4 specimens taken through non-pagetic bone. Although 9 patients experienced symptomatic improvement, 2 suffered fissure fractures in affected lower limbs. In Paget's disease, the combination of osteomalacia and continuing active resorption within a lytic lesion may increase the risk of fracture in a weight-bearing bone. It is suggested that although disodium etidronate often provides effective pain relief it should be administered with caution until the optimum dose and duration of therapy are further evaluated.

Aged↗

PubMed1998

Effect of macrophage depletion by liposomes containing dichloromethylene-diphosphonate on endotoxin-induced uveitis.

Footpad injection of lipopolysaccharide (LPS) from Salmonella typhimurium in Lewis rats induces an acute anterior and posterior endotoxin-induced uveitis (EIU). To investigate the role of macrophages in the pathogenesis of EIU, we eliminated macrophages by means of liposomes containing dichloromethylene-diphosphonate (Cl2MDP), a drug which depletes macrophages but not other immunocompetent cells. Intravenous injection of CL2MDP-liposomes clearly inhibited clinical and histological manifestations of uveitis in the anterior segment of the eye (iris/ciliary body) and reduced TNF level in aqueous humor. Specific immunostaining showed that CL2MDP-liposome injections decreased the number of ED2 + resident macrophages in the iris/ciliary body and the choroid. After LPS injection, CL2MDP-liposome treatment reduced the density of infiltrating ED1 + cells (mainly monocytes/macrophages) in the iris/ciliary body but not in the choroid; little or no effect was detected on the OX42 + cellular infiltration (mainly polymorphonuclear leukocytes). The inflammatory cellular infiltration of the retina was not modified by the treatment. These findings suggest that macrophages play a key role in the pathogenesis of ocular inflammation.

Analgesics, Non-Narcotic↗

PubMedDate not supplied

Effect of combined Cyclosporine A and liposome encapsulated dichloromethylene diphosphonate on the organisation of the rat thymus: evidence for a role of macrophages in guiding the post Cyclosporine A thymic reorganisation.

Cyclosporine A (CsA) is a powerful immunosuppressant inducing marked involution of the thymic medulla, and disappearance of interdigitating cells (IDCs) and reducing the number of macrophages (Mphi). Usually, while the thymus of rats receiving a short course of CsA promptly recovers after stopping CsA treatment, long term CsA treatment, like mediastinal irradiation, impairs the normal thymic recovery and is thought to be responsible for the development of autoimmune diseases. In the present study we evaluated the role played by the IDCs and Mphi in the normal recovery of the thymic histology at light and ultrastructural level. Besides CsA administration, we also used liposome-encapsulated dichloro-methylene-diphosphonate (lip-CL2MDP), that induces a total depletion of the Mphi resistant to CsA. After a short (21 days) course of CsA and lip-CL2MDP administration, we did not observe the normal recovery of the thymic parenchyma but only cortical zones consisting of lymphoblasts, epithelial cells and Mphi. The CsA/lip-CL2MDP treatment determining the loss of IDCs and Mphi and consequently the loss of the normal thymic histology seems to simulate in the rats, the long term CsA treatment or the mediastinal irradiation. The results obtained suggest that the loss of IDCs and the depletion of Mphi interfere with the normal thymic recovery. The delay in the recovery of I DCs could be a consequence of the absence of macrophages. These findings would indicate that the IDCs, determining the negative selection of T-lymphocytes, are the main cells responsible for the thymic microenvironment.

Animals↗

PubMed1999

Autoradiographic evaluation of 99mTc-methylene diphosphonate accumulation in oral cancer invading the mandible.

PURPOSE: Skeletal scintigraphy, a sensitive diagnostic tool used to detect changes in bone, is helpful for evaluating bone invasion by oral cancer. However, the exact sites of accumulation of 99mTc-phosphate compounds in the mandible have not yet been fully elucidated. The aim of this study was to determine the localization of 99mTc-methylene diphosphonate (MDP) in the areas of mandible that have been invaded by cancer. PATIENTS AND METHODS: Seven patients with oral cancer (lower gingiva, 4; tongue, 2; floor of the mouth, 1) who underwent surgical treatment with mandibular bone resection were included in the study. Autoradiography and contact macroradiography were used for evaluation of 99mTc-MDP accumulation. RESULTS: Radioactivity reflecting accumulation of 99mTc-MDP was documented encircling the portion of the mandible with cancerous invasion, suggesting that 99mTc-MDP accumulated in immature bone. High uptake also was found in the periosteal reactive bone around the cortical bone. CONCLUSIONS: The amount of increased 99mTc-MDP circumscribing carcinoma invasion varies among cases. Additionally, uptake may not correspond directly with the amount of the carcinoma invasion; that seen in periosteal bone could be attributed mistakenly to bone invasion in planar scintigraphy.

Aged↗