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PubMedDate not supplied

Comparison of 99mTc phosphate and diphosphonate complexes in experimental renal infarcts.

The 3-hour biodistribution of 99mTc complexes of five diphosphonates (HMDP, NMMDP, DMAD, DPD, and APD), imidodiphosphonate (IDP), and pyrophosphate (PYP) was compared in rats with segmental renal infarction induced by a 1-hour occlusion of a renal artery branch. 95mTc labeled MDP was a reference substance in all animals. Three agents (APD, HMDP and IDP) had a higher infarct/normal kidney concentration ratio than MDP, the latter two by virtue of a lower content in normal kidney. HMDP, DPD, and IDP had very high liver concentrations. DPD showed relatively high concentrations in soft tissues and blood. The blood and kidney levels of PYP were higher than those of MDP but the infarct/normal kidney ratios were similar. None of the agents had a higher uptake in bone than MDP: four had a significantly lower uptake. The increased concentration of 99mTc MDP in the infarcts was readily seen in camera images one day after renal artery occlusion, but not at three or seven days. Increased diphosphonate uptake was accompanied by an influx of calcium in both cortex and medulla. The accumulation of diphosphonate in areas of infarction was not modified by infusions of verapamil or Captopril.

Animals↗
PubMed2002

[Hydroxy(aryl)methylene]diphosphonic acids, a class of drugs in bone pathology treatments, crystallize as head-to-head dimers.

Two [hydroxy(aryl)methylene]diphosphonic acids have been crystallized as dimers. The first compound, [hydroxy(phenyl)methylene]diphosphonic acid monohydrate, C(7)H(10)O(7)P(2).H(2)O, crystallizes in the non-centrosymmetric space group P2(1), with the two enantiomers related by a non-crystallographic centre of inversion, while the second compound, [hydroxy(4-nitrophenyl)methylene]diphosphonic acid tetrahydrofuran disolvate, C(7)H(9)NO(9)P(2).2C(4)H(8)O, crystallizes in the centrosymmetric space group P2(1)/c and uses the centre of symmetry to form the same dimer.

Bone Diseases↗
PubMed1986

The effect of clodronate (dichloromethylene diphosphonate) on the mineral concentration of dental enamel and bone of the miniature swine.

Diphosphonates are compounds which prevent the crystallisation of calcium phosphates from solution. Our aim was to study the effects of clodronate (dichloromethylene diphosphonate), one of the diphosphonates, on the mineral concentrations of dental enamel and bone. In a subchronic experiment the effects of this compound were investigated. The drug was administered orally in three doses (100, 300, 1000 mg/kg) per day to 32 Göttingen miniature swines for six months. From the acid etch biopsy of enamel the amount of dissolved hydroxyapatite and the concentrations of fluoride and magnesium were measured. The calcium, phosphorus, fluoride, magnesium, carbonate and citrate concentrations were determined from the cancellous bone sample. All values were calculated for dry bone. Calcium/phosphorus and calcium/magnesium ratios were calculated for both enamel and bone. In tooth enamel the magnesium concentration showed a significant dose dependent decrease and calcium/magnesium ratio a significant dose dependent rise. Calcium phosphorus/ratio exhibited a dose dependent increase in surface enamel. Bone fluoride concentration showed a highly significant and calcium/magnesium ratio a significant dose dependent rise. Clodronate seems to interfere with the remineralization process of tooth enamel, through its effect on magnesium. Incorporation of the drug also appears to exhibit a marked action on the fluoride metabolism of bone. This may require attention in certain long term treatment situations with clodronate in high fluoride areas.

Animals↗
PubMed1986

Treatment of cancer associated hypercalcaemia with combined aminohydroxypropylidene diphosphonate and calcitonin.

Eight patients with cancer associated hypercalcaemia were treated with the combination of aminohydroxypropylidene diphosphonate and salmon calcitonin for six days. Serum calcium concentration fell significantly within 24 hours of starting treatment due to a reduction in bone resorption and renal tubular calcium reabsorption. In the longer term hypercalcaemia was controlled by a further progressive reduction in bone resorption, which persisted for six days after treatment was stopped. Renal tubular calcium reabsorption, however, remained suppressed only during drug treatment. The rapid fall in serum calcium was attributable to the acute renal and skeletal effects of calcitonin, whereas in the longer term control of hypercalcaemia was due to diphosphonate mediated suppression of bone resorption. In view of the rapid effect and lack of toxicity, combined treatment with aminohydroxypropylidene diphosphonate and calcitonin would be of particular value in patients with severe hypercalcaemia in whom a quick but sustained reduction in the serum calcium concentration is desired.

Bone Resorption↗
PubMed1982

Long term effects of dichloromethylene diphosphonate in Paget's disease of bone.

Dichloromethylene diphosphonate (Cl2MDP) is a diphosphonate which markedly inhibits bone resorption. We have tested Cl2MDP in Paget's disease, a disorder characterized by increased bone remodeling. Sixty-three patients with progressive Paget's disease were treated for 6 months with Cl2MDP at daily oral doses of 400, 800, 1600, or 2400 mg. Thirty-nine patients received calcium and vitamin D supplements during treatment. patients in all treatment groups had significant reduction in serum alkaline phosphatase, urinary hydroxyproline, skeletal uptake of 99mtechnetium-diphosphonate scintiscans, and resorption parameters on iliac crest biopsy samples as assessed by quantitative histomorphometry. Treatment was well tolerated and did not induce a skeletal mineralization defect. The reduction in alkaline phosphatase and urinary hydroxyproline persisted 1 yr after withdrawal of treatment. The biochemical remission was sustained in half of the patients 2 yr after the end of treatment and was accompanied by a marked reduction of bone pain. a daily dose of 800 mg is recommended as the best of control of clinical and biochemical symptoms. The transient increase in iPTH levels observed in patients treated with Cl2MDP alone did not occur when calcium and vitamin D were added. We conclude that Cl2MDP is effective in the treatment of Paget's disease of bone and provides a prolonged response. Dietary supplementation with calcium and vitamin D is desirable to prevent secondary hyperparathyroidism.

Alkaline Phosphatase↗
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↗
PubMed1984

Urinary 99m-Tc-diphosphonate excretion as a simple method to quantify bone metabolism.

Twenty-four-hour whole-body retention (WBR) of 99m-Tc-methylene-diphosphonate (an index of bone turnover) was determined by whole-body counting (WBRs) and complementarily by urine counting (WBRu) in nineteen subjects with normal to highly increased bone turnover. WBRs and WBRu correlated well (r = 0.94, P less than 0.001), and gave almost the same results. Both WBRs correlated equally well with serum alkaline phosphatase and urine hydroxyproline/creatinine (r = 0.82-0.93). Coefficient of variation in WBRu was 7.0%, determined by duplicate measurements in sixteen normals. The injected dose of diphosphonate did not influence WBRu. However, since almost 50% of the diphosphonate excreted in urine appeared during the first few hours after the i.v. injection, the method of WBRu requires careful urine collection. Thus, the simple WBRu determination provides the same information on bone metabolism as does the more cumbersome and expensive WBRs technique.

Adult↗
PubMed1989

A new class of calcium entry blockers defined by 1,3-diphosphonates. Interactions of SR-7037 (belfosdil) with receptors for calcium channel ligands.

Tetrabutyl-2(2-phenoxyethyl)-1,3-propylidene diphosphonate (SR-7037) completely displaced dihydropyridine [( 3H]PN200-110), phenylalkylamine [( 3H]D888), and benzothiazepine [( 3H]diltiazem) ligands from brain L-type calcium channels. Half-maximal inhibition of [3H]PN200-110 binding occurred at 19 nM with a Hill coefficient of 0.96. SR-7037 primarily decreased the affinity for [3H]PN200-110 with a small, but significantly, effect on the maximal binding capacity. Kinetic studies showed that this was due to an increased radioligand dissociation rate from 0.04 min-1 to 0.43 min-1 in the presence of the diphosphonate. Displacement of [3H]D888 by SR-7037 was biphasic with respective IC50 of 44 and 8400 nM. Likewise, unlabeled (-)-D888 identified two sites with IC50 values of 0.9 and 27 nM. Both SR-7037 (1000 nM) and D888 (200 nM) accelerated radioligand dissociation about 2-fold. [3H]Diltiazem binding was inhibited by SR-7037 with an IC50 value of 29 nM. The inhibition of dihydropyridine binding by SR-7037 is enhanced by most divalent cations at millimolar concentrations with the following potency: Mn2+ greater than Mg2+ greater than Ca2+ greater than Co2+. Barium has the opposite effect. The half-maximal effect of calcium occurred at 6 microM free ion. Specific binding of [3H]D888 was antagonized in the presence of 1 mM CaCl2. It is concluded that SR-7037 has allosteric interactions with the dihydropyridine receptor of the L-type calcium channel. The differential effect of Ca2+ on the potency of D888 and diltiazem relative to that of SR-7037 indicates that the three drugs may bind to nonequivalent sites. These results support specific calcium channel inhibition, possibly at a novel site, as the primary mechanism of the diphosphonate's pharmacological actions.

Animals↗
PubMed1988

Localization of 99mTc-diphosphonates in newly formed bone matrix as a measure of bone lesion detectability.

The lesion-to-normal-bone ratios of DBA-MDP (dibutylamino-methylene-diphosphonate), DPD (dicarboxypropane-diphosphonate) and MDP (methylene-diphosphonate) each labeled with 99mTc, were evaluated in experimental bone lesions. In 3-day old lesions this ratio was increased twofold for DBA-MDP in comparison with MDP and DPD which showed nearly equal ratios. Later on these differences became negligibly small. It is concluded that 99mTc-DBA-MDP is fixed more strongly in the immature bone matrix and that this will lead to an improvement in the detectability of lesions containing larger amounts of immature bone matrix.

Animals↗
PubMed1982

The effect of long-term low-dose diphosphonate treatment on rat bone.

Weaning, male rats were given ethane-1-hydroxy 1,1-diphosphonate (EHDP) or dichloromethylene diphosphonate (Cl2MDP) 0.5 mgP/kg/day for 140 days. Samples prepared after sacrifice were: (1) thin ground (30 micrometers) transverse tibial sections, (2) methacrylate-embedded 5 micrometers sections of the proximal tibial metaphysis, and (3) ultrathin calcified metaphyseal sections for electron microscopy. Cl2MDP reduced the diaphyseal medullary cavity, and EHDP increased the osteoid width. Both drugs increased endosteal bone apposition (possible secondarily to the impaired resorption) and, perhaps as a result, periosteal apposition was increased. Consequently, diaphyseal bone area was unchanged. Metaphyseal bone area was increased and osteoclast numbers reduced, in contrast to the increased osteoclast numbers reported previously in animal experiments with diphosphonates. Acid phosphatase activity within osteoclasts was markedly reduced with EDHP and unchanged with Cl2MDP. The ultrastructural changes in osteoclasts, i.e., a deficiency of ruffled borders, reduced numbers of cytoplasmic vacuoles and the presence of crystals between bone and the osteoclastic plasmalemma, were more marked with EHDP than Cl2MDP.

Animals↗
PubMed1981

[Myocardial scintigraphy using technetium-99m labelled methylene diphosphonate in coronary care units. 82 cases].

Many isotopic methods have been proposed recently for the investigation of normal and diseased myocardium in ischaemic heart disease. The results of myocardial scintigraphy with Technetium 99 m marked methylene diphosphonate in the supine, left lateral and 30 degrees or 45 degrees right anterior oblique incidences are reported. A preliminary study of the tracer's fixation on diseased myocardium was performed in 18 patients. Scintigraphy every 30 minutes over a five hour period showed the optimal time for investigation to be situated between the third and fourth hour after the injection of the tracer. Seventy eight patients were then investigated; 82 scintigraphies were performed, 58 in patients with acute myocardial infarctions confirmed by the usual biological and electrocardiographic changes. A 74% sensitivity and 67% specificity were obtained with the methylene diphosphonate method. These figures varied according to the type of necrosis, subendocardial or transmural and with its extent, chronicity and degree of CPK elevation. Methylene diphosphonate scintigraphy would appear to be less sensitive and more specific for diseased myocardium than other isotopic methods. It may be carried out at the bedside and could improve the diagnosis of acute myocardial infarction when the clinical history and electrocardiographic changes are difficult to interpret.

Adult↗
PubMed1981

[Diphosphonates in the treatment of bone metastases].

The diphosphonates are a group of phosphate compounds which inhibit the growth and dissolution of apatite crystals. These drugs have similar biological effects on bone by inhibiting the osteoclasts, and are also active in preventing pathological calcifications. The diphosphonates have been used successfully in various bone diseases and are now currently used for bone scanning. They are also considered one of the best treatments for Paget's disease. Several experiments in vitro and in vivo have suggested that the diphosphonates are active against bone metastases. Clinical trials have been undertaken and have shown that these compounds are active against malignant hypercalcemia. Further, they may delay the extension of bone destruction due to malignancy.

Animals↗
PubMed1980

[Treatment of hypercalcemia of tumoral origin with two diphosphonates].

Two diphosphonates, EHDP (disodium etidronate, or ethane-hydroxy-diphosphonate) and Cl2MDP (disodium clodronate, or dichloromethylene-diphosphonate) were injected in various doses in 8 patients who had had one or more episodes of malignant hypercalcemia. All patients responded well to the drugs after a time lapse of 2-10 days. Tolerance of the drugs was excellent. EHDP, and especially Cl2MDP, are promising agents for the treatment of hypercalcemia and the inhibition of bone resorption in malignant disorders.

Adult↗
PubMed1980

[The effect of various diphosphonate compounds on macro- and micromorphologic details of golden hamster incisors].

Five different diphosphonates have been parenterally applied to Syrian golden hamsters. Microscopic-metric and histological examinations revealed changes in size and structure in the incisors of those experimental animals which had received n-butylaminomethane diphosphonate. It is warned against the uncontrolled use of the tested diphosphonates for stomatological purposes.

Animals↗
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↗
PubMed1980

Evaluation of femoral neck fracture healing in man by serial 99mTc-diphosphonate scintimetry.

99mTc-diphosphonate uptake was measured in thirty-four patients with intracapsular fractures of femoral neck and in sixteen patients with trochanteric fractures during their healing process. A peak value in count ratio was recorded in all patients 4 to 6 weeks after fractures. Fifty patients were classified into a normal healing group and a delayed or non-union group. Namely, 99mTc-diphosphonate uptake was significantly higher in the delayed or non-union group than in the normal healing union group 10 weeks after injury. The application of 99mTc-diphosphonate scintimetry seems to make it possible to differentiate objectively the normal healing union from the delayed or non-union.

Adult↗
PubMed1993

Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates.

Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Several DP have also been shown to exert significant antiarthritic effects in the rat adjuvant-induced polyarthritis model; however, there is no direct evidence for the anti-inflammatory effects of these compounds. We therefore tested the effects of dichloromethylene diphosphonate on delayed-type hypersensitivity granuloma elicited by s.c. implantation of antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dichloromethylene diphosphonate induced a dose-related inhibition of the delayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/kg/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 were also effective in the same dose range. In contrast, all DP failed to suppress 24-hr delayed-type hypersensitivity paw edema in mice. In addition to rat adjuvant-induced polyarthritis, mouse antigen-induced erosive arthritis was also significantly suppressed by s.c. administration of all four DP. Toxicity was minimal for each DP (> 600 mg/kg p.o. or s.c.). We conclude that DP represent a novel class of anti-inflammatory agents with excellent therapeutic potential for chronic inflammatory diseases including rheumatoid arthritis.

Animals↗