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PubMed1979

A rabbit model to study the biokinetics of radiopharmaceuticals in bone.

A technique is described using the rabbit as the 'animal model' to measure the rate of extraction of the bone-seeking agent, technetium labelled ethane-1-hydroxy-1, 1-diphosphonate (99Tcm-EHDP) following constant-rate infusion into the femoral nutrient artery. The extraction is shown to be approximately linear for a period of 60 min. Washout of the tracer from bone was followed for a further 60 min period and graphical analysis shows that each curve could be resolved into two distinct exponential functions. The 2-h residue of 99Tcm-EHDP in bone has been examined and is found to be dependent upon its route of administration. A high residue (43.7 +/- 5.1%) results when the infusate is delivered directly into the nutrient artery and the single muscular branch is tied off. Retrograde infusion via the femoral artery results in a lower residue (7.8 +/- 2.3%). The close correlation of these results in the rabbit with our previous findings in the dog suggested that the rabbit model described can be used to study the kinetics of other radiopharmaceuticals during their passage through bone.

Animals↗
PubMed1993

Characterization of the bisphosphonate recognition site on hydroxyapatite using radioligand binding techniques with [14C]citric acid.

The present studies characterize the binding of [14C]citric acid to synthetic hydroxyapatite (HA) crystals. [14C]Citric acid specifically bound to HA and was dependent upon the concentration of HA in the assay. The binding of [14C] citric acid to HA reached equilibrium within 20 min and remained stable for at least 90 min. Dissociation of bound [14C]citric acid was biphasic in nature since both rapid and more slowly reversible binding components were detected. Saturation experiments also indicated that [14C]citric acid labeled two recognition sites with different affinity (KdH = 42 nM and KdL = 24,000 nM) and density (BmaxH = 161 fmol/micrograms HA and BmaxL = 8.8 pmol/micrograms HA). Ligand competition experiments revealed that compounds that are known to readily bind bone (e.g., sodium pyrophosphate, methylene diphosphonic acid, etidronate) potently inhibited the binding of [14C]citric acid to HA, whereas compounds known to have poorer affinity for bone (e.g., oxalic acid and GABA) did not. Computer analysis of these inhibition curves revealed specific ligand interactions at two different affinity recognition sites. The present results indicate that [14C]citric acid binds discrete sites on synthetic HA in a fashion consistent with a specific labeling of the bisphosphonate recognition site. Analysis of the binding of [14C]citric acid to HA provides a useful method to further explore the structure activity relationships of novel compounds that have binding affinity for bone.

Binding Sites↗
PubMed1991

Changes in calcium homoeostasis and bone formation in patients recovering from acute myocardial infarction: effect of verapamil treatment. Danish Study Group on Verapamil in Myocardial Infarction.

The effect of the calcium antagonist verapamil on calcium homoeostasis and bone metabolism has been investigated in a double-blind randomized placebo-controlled study. Ten patients randomized to verapamil 120 mg t.i.d. and 9 patients randomized to placebo in The Danish Verapamil Infarction Trial II took part in the study. Bone formation, estimated by 24-h whole body retention of diphosphonate (WBR), osteocalcin, alkaline phosphatase and calcium metabolic indices, was recorded before the start of medication and after 1 and 6 months of treatment. Baseline calcium metabolic variables were not significantly different between the two study groups. There were no significant differences in WBR (0.38 vs 0.37), osteocalcin level (8.2 vs 8.0 micrograms/l) or alkaline phosphatase (218 vs 200 U/l) after treatment for 6 months with verapamil compared to placebo. Serum PTH, calcium and phosphate levels were also not affected by verapamil. The results suggest that prolonged treatment with clinical doses of verapamil does not affect indices of calcium and bone metabolism in humans.

Alkaline Phosphatase↗
PubMed1984

Bone infarction in children with sickle cell disease: early diagnosis and differentiation from osteomyelitis.

An early differential diagnosis between bone infarction and osteomyelitis in sickle cell patients is practically impossible using routine laboratory methods. Twenty radioisotope studies in sickle cell patients during vaso-occlusive crises, were analyzed. A three stage process can be described. In the first stage a decreased uptake can be demonstrated by Tc 99m methylene diphosphonate (MDP) bone scanning. In osteomyelitis, an increased uptake area is usually seen at this early stage, corresponding to increased uptake in Ga-67 citrate scanning. At the second stage, approximately a week later, normal uptake can be seen. Two to four weeks later an area of increased uptake is recorded that corresponds to the healing process, stage three. We recommend therefore Tc 99m MDP bone scanning in the early stages if clinical signs and symptoms suggest a vaso occlusive crisis or osteomyelitis in a sickle cell patient. This study can be followed by a Ga-67 citrate scintigraphy in doubtful cases. Later studies should be used for the assessment of the healing process. Two illustrative case reports are included.

Anemia, Sickle Cell↗
PubMed1980

99mTc-MDP extraction in relation to 81mKr perfusion following a partial osteotomy in the dog tibia.

The bone mineral extraction of technetium-99m-methylene diphosphonate (99mTc-MDP), and blood supply of Krypton-81m (81mKr) have been compared in normal and osteotomy regions of the canine tibia. A partial osteotomy was carried out under aseptic conditions, and isotopic measurements made over a period of 123 days. Both blood flow and bone mineral extraction increase after a partial osteotomy.

Animals↗
PubMed1991

The "whisker sign" as an indicator of ochronosis in skeletal scintigraphy.

A patient with alkaptonuria and ochronotic arthrosis was imaged twice with technetium-99m dicarboxypropane diphosphonate (99mTc-DPD)--once during a bout of arthritic knee pain and once when symptom-free. There was a marked accumulation of radioactivity in the large joints. During the episode of arthritis the knee joints had a higher uptake than when the patient was without symptoms. The intervertebral discs showed a high uptake which extended laterally from the axial vertebral column; the finding gave an impression of whiskers, and this "whisker sign" may be characteristic of ochronosis.

Alkaptonuria↗
PubMed1988

A comparison of the pharmacokinetics of 14C-labelled APD and 99mTc-labelled APD in the mouse.

The disposition of 14C-labelled and 99mTc-labelled APD has been investigated in the Balb/c mouse following a single ip injection containing APD (total dose 5 mg/kg) labelled partly with carbon-14 and partly with technetium-99m. The plasma clearance of carbon-14 was twice that for technetium-99m and the accumulation of carbon-14 in bone was twice as great as that of technetium-99m. All other tissues assayed (liver, lung, kidney and muscle) contained higher concentrations of technetium-99m than carbon-14. There was a particularly marked accumulation of technetium-99m in the liver. We conclude that pharmacokinetic studies of diphosphonates cannot be conducted reliably with 99mTc-labelled compounds.

Animals↗
PubMed2003

Signal enhancement through heteronuclear polarisation transfer in in-vivo 31P MR spectroscopy of the human brain.

Significant (31)P NMR signal enhancement through heteronuclear polarisation transfer was obtained in model solutions and in vivo on a 1.5-T whole-body MR scanner equipped with two RF channels. The much higher population differences involved in proton Zeeman energy levels can be transferred to the (31)P levels with the refocused INEPT (insensitive nucleus enhancement by polarisation transfer) double-resonance experiment by means of a series of simultaneously applied broadband RF pulses. INEPT achieves a polarisation transfer from (1)H to (31)P spin states by directly reordering the populations in spin systems with heteronuclear scalar coupling. Thus, only the (31)P NMR signal of metabolites with scalar (1)H-(31)P coupling is amplified, while the other metabolite signals in the spectra are suppressed. Compared to Ernst-angle excitation, a repetition-time-dependent signal enhancement of eta=(29+/-3)% for methylene diphosphonic acid (MDPA) and eta=(56+/-1)% for phosphorylethanolamine (PE) was obtained on model solutions through optimisation of the temporal parameters of the pulse experiment. The results are in good agreement with numerical calculations of the theoretical model for the studied spin systems. With optimised echo times, in-vivo (31)P signal enhancement of the same order was obtained in studies of the human brain.

Brain↗
PubMed2005

Inhibition of family II pyrophosphatases by analogs of pyrophosphate and phosphate.

Imidodiphosphate (the pyrophosphate analog containing a nitrogen atom in the bridge position instead of oxygen) is a potent inhibitor of family II pyrophosphatases from Streptococcus mutans and Streptococcus gordonii (inhibition constant Ki approximately 10 microM), which is slowly hydrolyzed by these enzymes with a catalytic constant of approximately 1 min(-1). Diphosphonates with different substituents at the bridge carbon atom are much less effective (Ki = 1-6 mM). The value of Ki for sulfate (a phosphate analog) is only 12 mM. The inhibitory effect of the pyrophosphate analogs exhibits only a weak dependence on the nature of the metal ion (Mn, Mg, or Co) bound in the active site.

Cobalt↗
PubMed1987

Dose/response study of aminohydroxypropylidene bisphosphonate in tumor-associated hypercalcemia.

Bisphosphonates (or diphosphonates) constitute a major advance in the treatment of tumor-associated hypercalcemia and also have the potential to prevent or reverse osteolysis in normocalcemic patients. Available information on adequate therapeutic doses and potential toxicity is, however, very fragmentary. This report describes a phase I study of one of the most promising bisphosphonates currently available, aminohydroxypropylidene bisphosphonate (AHPrBP or APD), in tumor-associated hypercalcemia. Only patients remaining hypercalcemic after 48 hours of rehydration were evaluated, and antineoplastic therapy was delayed at least until a normal serum calcium level was reached. AHPrBP was given as two-hour daily infusions for three days, and three different patients were treated at each of the six following dosage levels: 0.01, 0.05, 0.25, 0.75, 1.5, and 3.0 mg/kg per day. The two lowest dosages levels were insufficient to normalize serum and urinary calcium levels, but the efficacy of the four other dosages was very similar. Plasma immunoreactive parathyroid hormone levels increased as a function of calcium levels, whereas urinary hydroxyproline levels did not prove to be a very useful measure of AHPrBP's effects on bone resorption. The drug was generally very well tolerated: only six patients had transient fever and/or decreases in lymphocyte count that were not clearly related to AHPrBP dosage. The only real problem was observed at the highest dosage of 3.0 mg/kg per day in an obese woman in whom high fever and hypotension developed. Efficacy and tolerance in dehydrated patients were verified by treating seven other patients, not previously rehydrated, at 1.0 mg/kg per day for three days. In summary, the therapeutic range of AHPrBP, given for three days as a two-hour infusion daily, lies between 0.25 and 1.5 mg/kg per day. Fasting urinary calcium levels are probably the most reliable and easily measured parameter to monitor AHPrBP's inhibition of bone resorption in normocalcemic patients.

Adult↗
PubMed1987

Bone metastases: pathogenesis, treatment, and rationale for use of resorption inhibitors.

Tumors in bone are usually metastatic, with breast, prostate, and lung tumors accounting for more than 80 percent of clinically manifest lesions. Untreated, such metastases can produce the symptoms that most concern cancer patients--pain, pathologic fractures, and paralysis through epidural cord compression. Recent advances in the understanding of the metastatic cascade and the regulation of bone formation and resorption provide unique therapeutic approaches for prevention and treatment of these lesions. This article reviews the prevalence, distribution, diagnosis, and treatment of metastatic cancer in the skeleton, as well as the processes involved in the development of such metastases, the local mediators responsible for some of the destructive changes in bone, and their pathologic results. In addition to considering some of the conventional therapeutic approaches, a rationale for the use of bone resorption inhibitors, such as the diphosphonates (bisphosphonates), is presented for the prevention and amelioration of the pathologic consequences of skeletal metastases.

Bone Neoplasms↗
PubMed1978

Purification and properties of guanylate cyclase from the synaptosomal soluble fraction of rat brain.

Guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) was purified 2250-fold from the synaptosomal soluble fraction of rat brain. The specific activity of the purified enzyme reached 41 nmol cyclic GMP formed per min per mg protein at 37 degrees C. In the purified preparation, GTPase activity was not detected and cyclic GMP phosphodiesterase activity was less than 4% of guanylate cyclase activity. The molecular weight was approx. 480 000. Lubrol PX, hydroxylamine, or NaN3 activated the guanylate cyclase in crude preparations, but had no effect on the purified enzyme. In contrast, NaN3 plus catalase, N-methyl-N'-nitro-N-nitrosoguanidine or sodium nitroprusside activated the purified enzyme. The purified enzyme required Mn2+ for its activity; the maximum activity was observed at 3-5 mM. Cyclic GMP activated guanylate cyclase activity 1.4-fold at 2 mM, whereas inorganic pyrophosphate inhibited it by about 50% at 0.2 mM. Guanylyl-(beta,gamma-methylene)-diphosphonate and guanylyl-imidodiphosphate, analogues of GTP, served as substrates of guanylate cyclase in the purified enzyme preparation. NaN3 plus catalase or N-methyl-N'-nitro-N-nitrosoguanidine also remarkably activated guanylate cyclase activity when the analogues of GTP were used as substrates.

Animals↗
PubMed1983

A radio-isotope study of the healing of mandibular bone grafts in patients.

Radionucleotide scanning is now accepted as a reliable method of visualising the metabolic activity of the skeletal system. Its application to the maxillo-facial region is reviewed, and its possible role in monitoring the healing of bone grafts is discussed. The radio-isotope 99m technetium-methylene diphosphonate was used to study the revascularisation and healing of large autogenous bone grafts to the mandible in eight patients. The scans demonstrated the dynamic activity in the grafts and showed varying patterns in different types of grafts.

Bone Transplantation↗
PubMed1984

Electrolytically labeled [99mTc]MDP: chromatographic pattern, stability and biodistribution in rats.

The labeling of methylene diphosphonate with 99mTc is possible after reduction of pertechnetate by means of controlled potential electrolysis. This results in a [99mTc]MDP complex which differs slightly from 99mTc(Sn)-MDP in paper and gel chromatography. The scintigraphic images of both preparations are comparable in quality. Biodistribution in rats shows a higher bone uptake for the 99mTc(Sn)-MDP complex, whereas [99mTc]MDP shows a higher uptake in the gastric wall.

Animals↗
PubMed1989

The liposome-mediated macrophage 'suicide' technique.

Macrophages form an important cell population involved in numerous immunological processes. Techniques which eliminate these cells, in order to permit 'in vivo' studies of their function are generally imperfect and for that reason we have developed a method using the liposome encapsulated drug dichloromethylene diphosphonate (Cl2MDP). The liposomes are ingested by the macrophages which are then destroyed following phospholipase-mediated disruption of the liposomal bilayers and release of the Cl2MDP. In the present review, technical details of the preparation of liposome encapsulated Cl2MDP are given, and applications of the technique are discussed.

Animals↗
PubMed1977

Medical therapy of experimental infection stones.

Struvite bladder calculi were induced in rats with an intrarenal injection of urease-producing human T mycoplasma strain T960. Acetohydroxamic acid was effective in inhibiting calculous formation. Methylene blue, tetracycline, orthophosphate, diphosphonate, and hydrochlorothiazide had no inhibitory effect.

Animals↗