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PubMed1979

[Evaluation of the protective action of diphosphonic compounds against a T-lymphocyte lesion by antilymphocyte serum].

Rabbit antilymphocyte serum (ALS) and complement were used in doses killing 50% of lymphocytes (staining with a 1% solution of trypan blue). In rosette-forming and blast-cell transformation reactions the counts of rosette forming and transformed cells were 60 and 24% respectively, as compared to those in controls. After adding 0.1 ml of 10 mM solution of potassium hydroxyethylene-diphosphonate belonging to a group of synthetic diphosphonates, the protective effect was observed shown by that the counts of rosette-forming and transformed lymphocytes did not differ from the control ones, wherein the reactions were produced with intact cells.

Animals↗
PubMedDate not supplied

Radionuclide imaging of the heart in myocardial infarction and acute ischemia by 99mtechnetium diphosphonate.

99mtechnetium diphosphonate was used in 81 patients for myocardial imaging. 46 of the patients suffered, 2-6 days prior to the test, from an acute transmural infarction provided by clinical, ECG, and enzymatic evidence; the scintigram was definitely positive in 43, equivocal in 2, and negative in 1. In 16 patients with subendocardial infarctions, in 9 the scintigram showed a positive result, in 1 it was equivocal, and in6 patients negative. In 6 other patients who suffered from acute chest pain, followed by enzyme changes, but no ECG evidence of infarction throughout the hospitalization period, the scan was positive in all. In 13 patients with acute ischemia (unstable 'crescendo' angina), 9 had a positive, 1 an equivocal, and 3 a negative scan. We conclude that radionuclide imaging is a valuable addition to the methods already available for diagnosis of myocardial infarction. With the use of diphosphonate as the tracer, we found that acutely ischemic myocardium that later may recover, gives also positive imaging.

Adult↗
PubMed1983

[Treatment of hypercalcemia of myelomatous origin with intravenous diphosphonates].

Diphosphonates were administered intravenously to 4 patients with myeloma-induced hypercalcaemia. All patients received EHDP 4.3 mg/kg/day for 3 to 8 days. One of them, whose hypercalcaemia recurred, was later treated with Cl 2 MDP 5 mg/kg i.v. for 8 days. In 2 patients EHDP infusions were followed by EHDP administered orally (5 mg/kg/d) for 3 weeks, after which transiliac bone biopsy was performed. In all patients calcemia fell from 130 +/- 14 to 99 +/- 4 mg/l at the end of the intravenous treatment, with parallel decrease in calciuria. Histomorphometric analysis of the bone biopsies showed few osteoclasts but massive infiltration with plasmocytes. In one case, EHDP probably induced a deficit in mineralization. Intravenous diphosphonates therefore proved to be rapidly effective in the treatment of hypercalcaemia due to malignancy. However prolonged administration of EHDP in high doses is not recommended, as it may result in osteomalacia.

Aged↗
PubMed1984

Effect of dichloromethylene diphosphonate (Cl2-MDP) on bone resorption induced by PHA-stimulated human mononuclear cells in organ culture.

Human mononuclear cells stimulated by PHA caused resorption of fetal rat bones in tissue culture. Non-adherent cells alone failed to produce substantial bone resorbing activity. The mixed culture of adherent and non-adherent cells (1:40) produced significant bone mineral resorption in vitro. The bone resorption induced by human mononuclear cells stimulated by PHA required the presence of living bone tissue in culture. The bone resorbing effect caused by PHA-stimulated cells was blocked by dichloromethylene diphosphonate at 10(-5) M concentration, but mononuclear cells preincubated in diphosphonate containing media were capable to resorb fetal rat bone in tissue culture.

Animals↗
PubMed1981

Effects of dissolved oxygen on Tc-99m methylene diphosphonate: concise communication.

Tc-99m methylene diphosphonate (MDP) was prepared using stannous methylene diphosphonate (ligand) kits of similar formula from either of two manufacturers (A or B), and physiologic saline of either regular dissolved oxygen content (RDO, 6.7 mg O2/l) or low (LDO, 3.8 mg O2/l). A resulting Tc-99m MDP dose was administered to each of 70 patients for bone imaging. The A + RDO combination led to greater film density in the bone image than did the B + RDO (p less than 0.05). However, use of LDO saline to reconstitute B improved bone-image density to equal that from A + RDO. Overall image quality with A + RDO was judged to be superior to that with either B + RDO (p less than 0.05) or B + LDO (p less than 0.01) by an investigator unaware of the particular DO and ligand combination injected. However, neither bone delineation nor soft-tissue radioactivity on images was judged to be different among the four combinations (p greater than or equal to 0.05). There was also no difference in soft-tissue radioactivity among the four combinations as revealed by image densitometry. Under the conditions of this study, the major differences in clinical performance between products A and B were only minimally affected by the O2 content of the saline used for reconstitution.

Bone and Bones↗
PubMed1977

Pharmacokinetics of technetium-99m diphosphonate.

Increased diagnostic information may be derived with Tc-99m diphosphonate from a detailed kinetic analysis of blood disappearance, urinary excretion, and quantitative assessment of skeletal uptake. Blood and urine determinations were studied in three populations: normal volunteers, patients with negative bone scans, and patients with positive bone scans. Quantitative imaging studies were performed in normal volunteers and patients with a scintillation camera interfaced to a computer. All subjects were scanned in the lower lumbar region up to 1 hr after Tc-99m diphosphonate administration. Blood levels exhibited a triexponential clearance pattern. Significant (p less than 0.05) differences were observed for the 5-min blood and 0-1 hr urine values among the various groups. The computer-generated images showed an initial early uptake in bone, kidneys and soft tissue. Thereafter, a parallel fall-off in activity was observed in kidney and soft tissue, with a concomitant increase in bone. Skeletal uptake was different for normal and diseased bone.

Adult↗
PubMed1997

Interaction of Alkyl/Arylphosphonates, phosphonocarboxylates and diphosphonates with different anion transport systems in the proximal renal tubule.

Luminal and contraluminal stop-flow microperfusion was applied, and the apparent Ki values (mmol/l) against the luminal phosphate and the contraluminal p-aminohippurate (PAH), sulfate and dicarboxylate transport systems were evaluated. Luminal phosphate transporter: Among the 20 compounds tested only phosphonoformate (foscarnet), etidronate, and clodronate have a good affinity (app.Ki < 1 mmol/l), whereas the 2-naphthylphosphonates, phosphonoacetate, pamidronate, alendronate and aminomethanediphosphonates have a moderate affinity (app.Ki, 1.6-6.0 mmol/l). The other compounds tested had a low (app. Ki > 6 mmol/l) or no affinity. Contraluminal PAH transporter: The hydrophobic phenyl-, benzyl- or 2-naphthylphosphonates have good to moderate affinity, whereas the less hydrophobic alkylphosphonates, the phosphonocarboxylates (except 4-phosphonobutyrate) and all tested diphosphonates show no interaction. Sulfate transporter: 2-Naphthylmethylphosphonate and 2-naphthylmethyldifluorophosphonate have a good affinity (app.Ki </= 0.5 mmol/l), whereas Cl-F-methylphosphonate, 2OH-5NO2-benzyl-phosphonate, 2-naphthylhydroxymethylphosphonate, phosphonoacetate etidonate and clodronate have only a moderate affinity (app.Ki approximately 3 mmol/l). The other tested compounds have a low or no affinity. Dicarboxylate transporter: Among the tested compounds only 3-phosphonopropionate (app.Ki, 4.2 mmol/l) and 4 phosphonobutyrate (app.Ki, 7.0 mmol/l) interact with this transporter. Thus, we might conclude that in the submillimolar range only phosphonoformate (foscarnet), etidronate and clodronate inhibit luminal phosphate transport. As predictable from previous structure-activity studies for the contraluminal PAH, sulfate and dicarboxylate transporters the alkyl/arylphosphonates and the phosphonocarboxylates interact with these transporters according to their hydrophobicity and charge distribution. Among the seven diphosphonates tested, only etidronate and clodronate have a moderate affinity to the sulfate transporter, whereas the aminodiphosphonates have no (or low) affinity to any of the contraluminal anion transporters.

Animals↗
PubMed1975

Effect of hydrochlorothiazide on phosphorus during treatment with diphosphonate.

The effects of probenecid and hydrochlorothiazide on renal handling of phosphorus during hyperphosphatemia induced by diphosphonate (ethane-1-hydroxy-1, 1-diphosphonate, EHDP) was studied. Measurements of calcium, phosphorus, and creatinine clearance were performed in 2 sessions on each of 3 consecutive days in 10 normal fasting volunteers during the morning hours from 8 A.M. to 12 noon. During 2 to 3 wk thereafter, each subject was treated with EHDP, 30 mg/kg/day. The second group of studies were performed in the same manner as the first except the EHDP administration was continued throughout. EHDP caused elevation of serum phosphorus in all cases. Probenecid did not affect urine phosphorus. Hydrochlorothiazide caused a transient phosphaturia of similar magnitude in the EHDP treated and untreated states. Creatinine clearance was not affected by any of the treatments and urine calcium was decreased by EHDP. It was concluded that hydrochlorothiazide inhibits tubular reabsorption of phosphorus but that it does not affect the mechanism whereby EHDP causes increased tubular reabsorption of phosphorus. Chronic administration of hydrochlorothiazide along with EHDP may inhibit hyperphosphatemia and may change the bone effects of EHDP.

Adult↗
PubMed1977

Metabolic effects of diphosphonate in primary hyperparathyroidism.

Six patients with primary hyperparathyroidism (PHPT) and one with squamous cell carcinoma of the esophagus with parathyroid hormone excess received disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) at a daily dose of 20 mg/kg orally. During treatment, the decrease in urinary calcium, total urinary hydroxyproline, and fasting urinary calcium suggested an inhibition of bone resorption. Serum calcium intestinal absorption of calcium and urinary cyclic adenosine monophosphate (cAMP) did not change significantly. This preliminary study indicates a possible role of diphosphonates in the management of inoperable cases of primary hyperparathyroidism or pseudohyperparathyroidism.

Adult↗
PubMed1983

The effect of diphosphonates on heterotopic ossification in regenerating Achilles tendon of the mouse.

Midpoint tenotomy of the mouse Achilles tendon is followed by regeneration with heterotopic ossification at the junction of tendon stump and the regenerated segment. This heterotopic bone formation occurs through a process of endochondral ossification and the cartilage cells appear to arise by a process of fibroblast transformation. Five weeks after tenotomy 60 per cent. of specimens show cartilage and bone formation whilst the remaining 40 per cent. show chondrification only. After 10 weeks all specimens showed bone formation with trabecular bone and haemopoietic marrow. The treatment of tenotomised animals with either disodium ethane-1, 1-diphosphonate (EHDP) or disodium dichloromethylene diphosphonate (Cl2MDP) has no effect on the process of heterotopic ossification which can be detected at the radiological or light microscopical level.

Achilles Tendon↗
PubMed1990

Scintigraphic evaluation of tumor regression during preoperative chemotherapy of osteosarcoma. Correlation of 99mTc-methylene diphosphonate parametric imaging with surgical histopathology.

The effect of preoperative chemotherapy (PCT) on the uptake of 99mTc-labeled diphosphonates into tumor bone was quantitatively assessed from serial scan studies of 30 osteosarcomas and correlated with the histomorphological changes determined from the surgical specimens. The parametric images of the tumor blood pool and labeled methylene diphosphonate (99mTc-MDP) plasma clearance by the tumor bone enabled a sensitive distinction to be made preoperatively between a good (greater than 90% tumor cell destruction) and a poor (less than 90% tumor cell destruction) tumor response. Overall accuracy in presurgical prediction of tumor regression was found to be 88% and 96% for the blood pool and 99mTc-MDP clearance measurements, respectively (P less than or equal to 0.0004). In addition, it proved possible to localize resisting areas of viable tumor up to 1.0 cm in diameter. Even at the half-way stage of PCT, a poor response could be reliably predicted (overall accuracy 91% and 100%, respectively; P less than or equal to 0.011). Therefore, 99mTc-MDP parametric imaging is a highly sensitive and specific modality for an objective and accurate assessment of tumor regression during PCT of osteosarcoma.

Adolescent↗
PubMed1993

Influence of dichloromethylene diphosphonate on reactive oxygen species production by human neutrophils.

Biphosphonates suppress bone destruction in various diseases. Several studies have demonstrated the potential use of biphosphonate in arthritis. The results of these studies indicate that the effectiveness of the biphosphonates, for inhibiting the arthritic process, is related to their antiresorptive properties. It has been shown that the generation of reactive oxygen species is associated with the formation of new osteoclasts and enhanced bone resorption. We studied the effects of the dichloromethylene diphosphonate on the reactive oxygen species production by activated polymorphonuclear leucocytes, measured by chemiluminescence. Our results indicate a dose-dependent inhibitory effect of dichloromethylene diphosphonate on reactive oxygen species production by polymorphonuclear leucocytes stimulated with N-formil-methionyl-leucyl-phenylalanine, the calcium ionophore A23187 and phorbol myristate acetate. The mechanisms by which this biphosphonate inhibits the reactive oxygen species production by activated polymorphonuclear leucocytes are discussed.

Bone Resorption↗
PubMed1997

Rhenium-188 hydroxyethylidene diphosphonate: a new generator-produced radiotherapeutic drug of potential value for the treatment of bone metastases.

The search for an ideal radioisotope for systemic radiotherapy continues. As a generator-produced radioisotope emitting both beta and gamma rays and having a short physical half-life of 16.9 h, rhenium-188 is a very good potential candidate for systemic radiotherapy. In this study, we labeled hydroxyethylidene diphosphonate (HEDP) with 188Re and analyzed the biodistribution and bone uptake following intravenous injection in rats to assess its potential for clinical use. The rats were injected with approximately 14.8 MBq (0.4 mCi) 188Re-HEDP in a volume of 0.1 ml intravenously and then sacrificed at 1 h, 24 h, or 48 h (four rats at each time). Samples (about 0.1 g) of lung, liver, kidney, spleen, testis, muscle, stool, and bone (thoracic vertebra) were taken and weighed carefully. In addition, a 1-ml sample of blood was drawn from the heart and 1 ml of urine was taken from the urinary bladder immediately after killing. Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (% ID/g or ml). Bone lesions were created in the right tibial bone in three rabbits to calculate the lesion to normal uptake ratio (L/N ratio). The biodistribution data showed that the radioactivity in the bone tissue was as high as 1.877% ID/g at 1 h and that it climbed to 2.017% ID/g at 4 h. The activity level in the kidney was highest at 1 h but declined rapidly throughout the study. The radioactivities in the lung, liver, muscle, spleen, testis, blood, and stool were all lower than 0.3% ID/g at 1 h and also declined rapidly. The biological half-life in bone was the longest (60.86 h). In contrast, the biological half-lives in muscle and blood were short (2.99 h and 6.21 h respectively). The concentrations of radioactivity in muscle, spleen, testis, and stool were quite low throughout the study. Most of the radiotracer was excreted by the urinary system. The L/N ratio was 4.23+/-0.21 in rabbits injected with 188Re-HEDP and 4.25+/-0.23 in those injected with technetium-99m methylene diphosphonate. In conclusion, we would suggest that 188Re-HEDP is a very good potential candidate for the treatment of bone metastases because of the following characteristics: (1) it is generator produced; (2) it has a short half-life; (3) it emits gamma rays suitable for imaging; (4) there is highly selective uptake in the skeletal system and bone lesions; and (5) it has a low non-target uptake and rapid clearance in nonosseous tissue.

Animals↗
PubMed1982

Blood: bone disequilibrium. V. Effects of a diphosphonate (EHDP) on phosphate fluxes in rat calvaria.

Calvaria taken from rats (normal or thyroparathyroidectomized) given a diphosphonate (EHDP 10 mg/kg daily for 7 days) were placed in special Ussing chambers for the measurement of phosphate fluxes to and from bone. When compared with appropriate controls, the experimental calvaria showed a marked decrease in influx, K, a significant increase in the projected equilibrium concentration, E/K, where E is the efflux and a significant increase in the calcium concentration in the medium. It is concluded that this large increase in passive "solubility" is caused by the diphosphonate's ability to stabilize the small amount of regulator phase (brushite or brushite-apatite mixture) present in bone.

Animals↗
PubMed1976

Factors affecting uptake and retention of technetium-99m-diphosphonate and 99m-pertechnetate in osseous, connective and soft tissues.

The bone scanning complex, 99mTc-Sn-EHDP, consisting of the nuclide technetium-99m, stannous ion and ethane-1-hydroxy-1,1-diphosphonate, administered intravenously is retained in soft tissues in proportion to increasing calcium content of the tissues. Within bone tissue, the retention is proportional to vascularity and to surface area of calcium phosphate in bones and not necessarily to calcium and phosphate concentration. The nuclidic agent 99mTcO4-BUT NOT THE 99MTc-diphosphonate is selectively taken up by the thyroid and this uptake can be blocked by administering sodium perchlorate. Among the connective tissues studied, the tracheal cartilage seems to have the greatest potential to calcify with increasing age of the animal and man. Soft tissue does not retain the bone scanning complex 99mTc-Sn-EHDP but does retain 99mTcO4-.

Age Factors↗