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PubMed1988

In vitro and in vivo elimination of macrophage tumor cells using liposome-encapsulated dichloromethylene diphosphonate.

It is shown in the present study that RAW 264 tumor cells can be killed by liposome-entrapped dichloromethylene diphosphonate (DMDP), both in vitro and in vivo. DMDP is ingested by phagocytic cells when entrapped in liposomes. Once phagocytized the liposomal membranes are digested and the drug is released into the cell and is ready for action. In vitro, even low doses of liposome-entrapped DMDP caused an significant reduction in cell numbers. In vivo, liposome-encapsulated DMDP markedly reduced tumor formation in the liver, when given 1 day after injection of 1 x 10(6) RAW 264 tumor cells. Liposome-encapsulated DMDP, given 4 or more days after injection of the tumor cells had no significant effect. We concluded that tumor formation by RAW 264 cells is only susceptible to in vivo treatment with liposome-entrapped DMDP during a short period of time after injection of the cells. Obviously, phagocytosis of the tumor cells is reduced after this period making the cells less susceptible to treatment with the liposome-entrapped drug.

Animals↗
PubMed1985

Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. Ultrastructural aspects of elimination of marginal zone macrophages.

It is shown ultrastructurally that intravenously injected and liposome-entrapped dichloromethylene diphosphonate (DMDP) causes marked damage to marginal zone macrophages in the mouse spleen which finally results in the elimination of these cells. Marginal zone lymphocytes are also affected by this treatment, probably as a result of action of the enzymes released by dying macrophages. Marginal zone macrophages largely disappear, 24 h after i.v. injection, leaving an open-meshed reticulum in which a few viable and necrotic lymphocytes are present. The proposed method to eliminate macrophages for some time may be used to study functional aspects of these cells in vivo.

Animals↗
PubMed2005

Reversible metastatic visceral calcification detected by 99mTc-methylene diphosphonate bone scanning in breast cancer.

Diffuse metastatic visceral calcification is rare in breast cancer. We report on a 57-year-old woman with breast cancer and hypercalcemia who had diffuse metastatic visceral calcifications on lungs, myocardium, stomach, and thyroid on a (99m)Tc-methylene diphosphonate bone scan. Visceral calcifications were completely resolved 6 months after successful anticancer and zoledronic acid treatments. Bone scanning offers a useful diagnostic tool for both identifying visceral calcification and assessing the response to therapy in chemosensitive malignities with hypercalcemia such as breast cancer.

Antineoplastic Agents↗
PubMed1982

Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate.

Dichloromethylene diphosphonate (Cl2MDP) a potent inhibitor of osteoclast-mediated bone resorption, lowers serum calcium in hypercalcemia associated wit malignancies and with primary hyperparathyroidism, and reduces excess calcium mobilization from bone in multiple myeloma and in Paget's disease. We have evaluated the effectiveness of intravenously administered Cl2MDP in five patients with parathyroid carcinoma, a disorder characterized by severe hypercalcemia, very high parathyroid hormone (PTH) levels, and marked osteoclast-mediated bone resorption. All patients had biopsy-proved metastatic parathyroid carcinoma and hypercalcemia which persisted after multiple surgical procedures and other attempts at management. During a three-day observation period, each patients continued to demonstrate stable or progressive hypercalcemia despite infusion with saline solution and furosemide. Cl2MDP was administered over 2 hours at 2.5 mg/kg on day 1 and 5 mg/kg on days 2 through 7. Response was noted in all five patients; there was a gradual decline in the average serum calcium from 16.0 +/- 1.1 mg/dl (SEM) to 11.1 +/- 0.9 mg/dl by the eighth day (p less than 0.01). There were concomitant reductions in urinary calcium excretion, from 798 +/- 153 mg/g creatinine to 350 +/- 96 mg/g creatinine (p less than 0.05) and in the urinary hydroxyproline excretion, from 155 +/- 38 mg/g creatinine to 94 +/- 29 mg/g creatinine (p less than 0.02). Serum PTH levels remained markedly elevated (460 +/- 141 micrograms eq/ml to 493 +/- 169 micrograms eq/ml). In three patients, all indices returned to pretreatment levels by 10 days after the last infusion. In two of these patients there was a response to retreatment with Cl2MDP with a fall in calcium from 16.9 +/- 0.5 mg/dl to 12.4 +/- 1.5 mg/dl. There was no response in one patient. No adverse reactions to Cl2MDP were observed. The decrease in serum calcium and concomitant declines in urinary calcium and hydroxyproline suggest that Cl2MDP can effectively inhibit the excessive bone resorption associated with parathyroid carcinoma.

Aged↗
PubMed1983

The increase in vivo by electric currents of the 99mTc-methylene diphosphonate uptake and cyclic AMP content of the bone of the cat mandible.

Technetium-99-methylene diphosphonate (99mTc-MDP) bone images were obtained from live cats whose mandibles had been stimulated non-invasively and unilaterally with electric current (12 +/- 2 microA) for 1 week. The images were obtained using a gamma camera interfaced to a digital computer for quantitative comparison of the mandible. Radionuclide uptake by the stimulated sides increased by 59 +/- 26 per cent when compared with the contralateral control sites. Immunohistochemical staining of mandibular sections for adenosine 3',5'-monophosphate (cyclic AMP) showed that periosteal osteoblasts opposite the electrodes were intensely stained. Thus 99mTc-MDP scintigraphy is a sensitive non-invasive technique for determining in vivo enhanced bone remodelling activity. The immunohistochemistry indicates that the stimulation of bone cells was limited to surfaces adjacent to both cathode and anode.

Animals↗
PubMed1993

Differential sensitivity of membrane-associated pyrophosphatases to inhibition by diphosphonates and fluoride delineates two classes of enzyme.

1,1-Diphosphonate analogs of pyrophosphate, containing an amino or a hydroxyl group on the bridge carbon atom, are potent inhibitors of the H(+)-translocating pyrophosphatases of chromatophores prepared from the bacterium Rhodospirillum rubrum and vacuolar membrane vesicles prepared from the plant Vigna radiata. The inhibition constant for aminomethylenediphosphonate, which binds competitively with respect to substrate, is below 2 microM. Rat liver mitochondrial pyrophosphatase is two orders of magnitude less sensitive to this compound but extremely sensitive to imidodiphosphate. By contrast, fluoride is highly effective only against the mitochondrial pyrophosphatase. It is concluded that the mitochondrial pyrophosphatase and the H(+)-pyrophosphatases of chromatophores and vacuolar membranes belong to two different classes of enzyme.

Animals↗
PubMed1981

The uptake of 99mtechnetium diphosphonate into degenerating and regenerating muscle. A correlative histological and biochemical study.

The uptake of 99mTc-methylene diphosphonate into rat skeletal muscle has been studied. Uptake did not occur in normal or denervated muscles. Muscles damaged by exposure to the myotoxin notexin did accumulate label. The toxin causes a severe inflammatory, necrotising myopathy and regeneration normally begins 2-3 days after toxin administration. The uptake of label was maximal at 12-24 h, at which time muscle wet weight and cellular infiltration were also maximal. Label was found in the muscle mitochondria, the invading inflammatory cells and the oedema fluid. Regenerating muscles did not accumulate label. The uptake of label was positively correlated with total muscle calcium up to 24 h after the onset of necrosis, but it was suggested that the changes in the two parameters are not causally related.

Animals↗
PubMed1985

A simplified technique for quantifying 24-h whole body retention of 99mTc-labeled methylene diphosphonate (MDP).

A simple technique for measuring 24-h whole-body retention (24-h WBR) of 99mTc-labeled methylene diphosphonate (MDP) is described. We chose a standard thyroid probe-scaler system (Picker-Magna Scanner) as our counting instrument and characterized it relative to: photon saturability; optimum counting time post administration; patient positioning; and results with prostate cancer patients with positive/negative scintigram diagnoses for bone metastases. Whole body retention values of 99mTc at 24 h were easily measured with our instrumentation. Initially whole body count rates were determined at 5-min post injection and, again at 24 h. Data accumulated prior to the 5-min time period were inaccurate due to a higher sensitivity for the activity in the early circulation. Also, initial count rates obtained from patients injected with (740 MBq) (20 mCi) 99mTc-MDP usually required a correction due to detector saturation. The data observed at 24 h, representing skeletal tracer uptake, required no such correction. Patient positioning was rigorously controlled for the two time intervals to insure constant geometry. The 24 h-WBR values measured for prostate cancer patients with positive bone scintigrams was significantly different from those patients with negative scintigrams (58.8 +/- 8.7% and 29.2 +/- 9.6% respectively). Measurement of the 24 h-WBR has great potential for following various pathologies in the clinical setting.

Bone Neoplasms↗
PubMed1981

Calcitonin and diphosphonate in the treatment of Paget's disease of bone.

The ideal treatment for Paget's disease of bone should control turnover irrespective of its initial activity and produce a sustained remission once treatment is withdrawn. Unfortunately, neither the calcitonins nor the diphosphonates currently available entirely fulfil these requirements. Preliminary studies suggest that combinations of calcitonin and EHDP produce significantly better responses than those of the individual agents alone. This proposition is examined critically in terms of the optimum effects achieved with calcitonin and EHDP alone paying particular attention to variables such as disease activity, dose and duration of treatment.

Calcitonin↗
PubMed1981

Paget's disease: improvement of spinal cord dysfunction with diphosphonates and calcitonin.

The clinical and radiographic features of spinal cord dysfunction secondary to Paget's disease are described. Long-term medical management with the use of the diphosphonates, calcitonins and mithramycin resulted in marked and rapid clinical improvements in 8 of 10 of our own patients. These results are comparable to those seen in 19 other patients previously described in the literature, and are also similar to those obtained by surgical treatment. The recurrence rate and mortality (approximately 10%) of surgical treatment suggest that drug treatment now has a place in the management of paraparesis, particularly when this is of gradual onset. Medical management may also provide a valuable adjunct in those cases where surgery is required (e.g. sudden onset of paraparesis). In patients with cord dysfunction, but without significant anatomical compression of the spinal cord, it is suggested that paraparesis may be caused by a "vascular steal" syndrome, a notion which is supported by the rapidity with which drug-induced remission occurs.

Adult↗
PubMed1982

Long-term effects of dichloromethylene diphosphonate (CI2MDP) on skeletal lesions in multiple myeloma.

We report the long-term effects of dichloromethylene diphosphonate (CI2MDP), an inhibitor of bone resorption, on the skeletal lesions in multiple myeloma. Thirteen patients received either CI2MDP 1600 mg/d (seven patients) or a placebo (six patients) in addition to other chemotherapy, and the effects of treatment were followed over a period of up to 18 months in a double-blind study. CI2MDP treatment resulted in a marked reduction in bone pain, with no progression of radiologic skeletal lesions during the first year. This contrasted with a clinical deterioration and the occurrence of new fractures in half of the patients receiving the placebo. Two patients with hypercalciuria and increased excretion of hydroxyproline before treatment had normalized values following CI2MDP. Finally, iliac crest bone biopsies showed a reduction in osteoclast number after CI2MDP administration. We conclude from these results that CI2MDP could be of use in preventing the bone loss that occurs in multiple myeloma.

Biopsy↗
PubMed1984

Sequential treatment of Paget's disease with human calcitonin and dichloromethylene diphosphonate (Cl2MDP).

Dichloromethylene diphosphonate (Cl2MDP), a powerful inhibitor of bone resorption, was given (daily dose: 500 mg i.v. for 2 months and then 1600 mg p.o.) to five patients with Paget's disease after 8 months treatment with 50-100 MRC u/day of human calcitonin (CT). During treatment with CT plasma alkaline phosphatase (ALP) and urinary hydroxyproline (HOP) levels fell to about 60% of pretreatment values within the first 2 months in all the patients. Cl2MDP therapy resulted in a further drop of urinary HOP to 20% of baseline values, while serum ALP rose impressively during the first 2 weeks of therapy and then slowly fell to 25% of baseline values. We conclude that Cl2MDP can induce a further biochemical response after the so-called plateau phenomenon to CT and that it may represent the therapy of choice for severe Paget's disease.

Aged↗
PubMed1984

Dichloromethylene diphosphonate (Cl2MDP) reduces natural killer (NK) cell activity in mice.

Daily administration of dichloromethylene diphosphonate (Cl2MDP) to (C57BL/6 X DBA/2) F1 hybrid mice, from two days of age (10 mg of P/kg body weight), resulted in a marked impairment of natural killer (NK) activity of spleen cells against YAC-1 lymphoma cells. The suppressive effect increased with the duration of the treatment. Cessation of the treatment led to a rapid recovery (in 2 weeks) of NK activity while the osteopetrotic bone lesions persisted. Thus, the loss of natural killing cannot be explained by the simple reduction of bone marrow volume secondary to Cl2MDP-induced osteopetrosis. However, as NK cells are considered to be dependent on the bone marrow because they cannot be sustained by extramedullary production, a direct effect of Cl2MDP on the generation of NK cell precursors by the bone marrow was not excluded. Cl2MDP was not directly toxic to the fully differentiated splenic NK cells, since the addition of Cl2MDP to the in vitro assay (10(-5)-10 micrograms/ml) did not reduce cytotoxicity. These studies suggest that impairment of NK activity during Cl2MDP treatment may have clinical toxicologic implications since NK cells have been suggested to play an important role in natural host defenses against infection and neoplasia.

Animals↗
PubMed1989

The determination of 4-amino-1-hydroxybutane-1,1-diphosphonic acid monosodium salt trihydrate in pharmaceutical dosage forms by high-performance liquid chromatography.

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay is reported for the determination of 4-amino-1-hydroxybutane-1, 1-diphosphonic acid (AHBuDP) monosodium salt trihydrate, a new inhibitor of bone resorption. The compound does not demonstrate any intrinsic UV properties and thus pre-column derivatization of the primary amino group of the drug with 9-fluorenylmethyl chloroformate (FMOC) at pH 9 in the presence of sodium citrate is required to facilitate UV detection of the analyte. Excess derivatization reagent is extracted with methylene chloride and an aliquot of the aqueous portion is assayed on a polymeric phase (Hamilton PRP-1) at 35 degrees C by reversed-phase HPLC. A mobile phase of 0.05 M citrate and 0.05 M phosphate buffer (pH 8.0)-acetonitrile-methanol (75:20:5, v/v/v) is utilized with UV detection at 266 nm. Application of the method to the analysis of AHBuDP in I.V. solution, tablet and capsule formulations is presented.

Alendronate↗
PubMed1985

Comparative effects of an antiviral drug, inosiplex, and diphosphonates in Paget's disease of bone.

The effects of the antiviral agent, inosiplex, were assessed in four patients with Paget's disease of bone. Treatment for 6 months did not suppress disease activity as judged by serum alkaline phosphatase and hydroxyprolinuria, and viral inclusions persisted in the one patient from whom a bone biopsy was taken. These results contrasted markedly with the suppressive effects of diphosphonate treatment in these same patients.

Alkaline Phosphatase↗
PubMed2004

Release of iron from transferrin by phosphonocarboxylate and diphosphonate chelating agents.

The rates at which phosphonocarboxylate and diphosphonate ligands remove iron from the serum iron transport protein transferrin at 25 degrees C and pH 7.4 have been evaluated. These ligands show a combination of saturation and first-order kinetics with respect to the free ligand concentrations. The ability of the ligands to remove iron from transferrin appears to be subject to steric restrictions that are essentially identical to those associated with the ability of a ligand to substitute for the synergistic carbonate anion. This observation supports the hypothesis that the first-order component for iron removal involves a mechanism in which the rate-limiting step is the slow substitution of the synergistic carbonate by the incoming chelating agent. Studies on monoferric transferrins indicate that phosphonocarboxylates are unusually effective at removing iron from the C-terminal site of the protein. Difference UV spectroscopy has been used to show that the phosphonocarboxylates bind strongly to apotransferrin. It is suggested that the rapid release of iron from the C-terminal site may be due to the binding of the ligand to an allosteric anion-binding site in the C-terminal lobe of the protein.

Carboxylic Acids↗
PubMed2005

Voltammetry as a virtual potentiometric sensor in modelling of a metal-ligand system and refinement of stability constants. Part 4. An electrochemical study of NiII complexes with methylene diphosphonic acid.

The Ni(II)-MDP-OH system (MDP=methylene diphosphonic acid) and stability constants of complexes formed at ionic strength 0.15M at 298K were established by direct current polarography (DCP) and glass electrode potentiometry (GEP). The final M-L-OH model could only be arrived to by employing recent concept of virtual potentiometry (VP). VP-data were generated from non-equilibrium and dynamic DC polarographic technique. The VP and GEP data were refined simultaneously by software dedicated to potentiometric studies of metal complexes. Species distribution diagrams that were generated for different experimental conditions employed in this work assisted in making the final choice regarding the metal-ligand model. The model established contains ML, ML(2), ML(OH) and ML(OH)(2) with stability constants, as logbeta, 7.94+/-0.02, 13.75+/-0.02, 12.04 (fixed value), and 16.75+/-0.05, respectively. It has been demonstrated that virtual potential must be used in modelling operations (predictions of species formed) when a polarographic signal decreases significantly due to the formation of polarographically inactive species (or formation of inert complexes). The linear free energy relationships that included stability constant logK(1) for Ni(II)-MDP established in this work together with other available data were used to predict logK(1) values for Sm(III) and Ho(III) with MDP. The logK(1) values for Sm(III)-MDP and Ho(III)-MDP were estimated to be 9.65+/-0.10 and 9.85+/-0.10, respectively.

Bone and Bones↗