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PubMed1975

Dynamic studies with 99mTc-HEDP in normal subjects and in patients with bone tumors.

Blood clearance, urinary excretion, and spinal uptake of 99mTc-HEDP have been measured in ten normal control subjects. Blood clearance from 15 min is biexponential. Approximately 70% of the administered activity was excreted in the urine within 6 hr of injection. Spine-to-background ratios rise sequentially with time. Net normal bone uptake rises little after 2 hr and improved visualization of the normal skeleton therafter is due to reduction of blood background activity. In 13 patients with bone tumors, direct measurement of diphosphonate uptake by the tumor-involved and corresponding normal bone showed a continued rise in diphosphonate levels in the tumor-involved bone due to increased metabolic activity.

Adult↗

PubMed1994

Modulation of hepatic sinusoidal endothelial cell function by Kupffer cells: an example of intercellular communication in the liver.

We tested the hypothesis that Kupffer cells modulate sinusoidal endothelial cell function in the liver. Rats were treated with Kupffer cell-depleting agents (gadolinium chloride and liposome-encapsulated dichloromethylene diphosphonate) or with inhibitors of phospholipase A2 or leukotriene A4 synthase (dexamethasone and diethylcarbamazine, respectively). Hyaluronan uptake by the isolated, perfused liver was measured as an index of the functional state of the sinusoidal endothelial cell. Plasma hyaluronan concentration was also determined. Three hours after Escherichia coli lipopolysaccharide administration (100 micrograms/100 gm body wt, intravenously) plasma hyaluronan levels were significantly increased (280% to 320%), whereas hepatic hyaluronan uptake was markedly decreased (approximately 76%). Pretreatment with gadolinium chloride (0.5 mg/100 gm body wt, intravenously, 21 hr before saline solution or lipopolysaccharide administration), liposome-encapsulated dichloromethylene diphosphonate (40 mumol/100 gm body wt, intravenously, 44 hr before saline solution or lipopolysaccharide injection), dexamethasone (40 micrograms/100 gm body wt, intravenously, 1 hr before saline solution or lipopolysaccharide administration) or diethylcarbamazine (repeated doses, 10 mg/100 gm body wt, intravenously, 1 hr before saline solution or lipopolysaccharide injection) counteracted the lipopolysaccharide inhibitory effect on hepatic hyaluronan uptake. With the exception of gadolinium chloride, all other agents also prevented the lipopolysaccharide-induced increase in plasma hyaluronan concentration. Gadolinium chloride only attenuated the lipopolysaccharide effect on plasma hyaluronan level. Taken together with earlier results from our laboratory, these data indicate that: (a) Kupffer cell activation by lipopolysaccharide results in suppression of hyaluronan uptake by sinusoidal endothelial cells and (b) such modulation of endothelial cell function is likely mediated by products of the lipoxygenase pathway of arachidonate metabolism.

Animals↗

PubMed1996

The role of macrophages in Acanthamoeba keratitis.

PURPOSE: Macrophages are thought to be the first line of defense in many infectious diseases and are present in high numbers in corneas with Acanthamoeba keratitis. Conjunctival macrophage depletion was performed in an animal model of Acanthamoeba infection to determine the importance of macrophages in this disease. METHODS: Selective elimination of macrophages was achieved by repeated subconjunctival injection of liposomes containing dichloromethylene diphosphonate in a Chinese hamster model of Acanthamoeba keratitis. RESULTS: Macrophage depletion affected the incidence, severity, and chronicity of keratitis. The incidence of infection in normal animals was approximately 60% but rose to 100% on day 4 in animals treated with liposomes containing dichloromethylene diphosphonate (C12MDP-LIP). Moreover, the clinical appearance of the keratitis in the C12MDP-LIP group was much more severe than in animals treated with liposomes containing phosphate-buffered saline at all time points. There was also a major change in the chronicity of keratitis, with an earlier onset and a prolonged and chronic course in the C12MDP-LIP treated hamsters. CONCLUSIONS: The profound exacerbation of Acanthamoeba keratitis in hamsters treated with C12MDP-LIP strongly suggests that macrophages play an important role in corneal infection with Acanthamoeba trophozoites, probably by acting as a first line of defense and eliminating significant numbers of Acanthamoeba trophozoites.

Acanthamoeba Keratitis↗

PubMed1996

Model compounds in elucidating the structural basis of HIV retrovirus activity. Synthesis of trisodium O-monoalkyl- and O-monoaryldiphosphates.

Trisodium salts of O-methyl, O-butyl, O-phenyl, and O-(4-nitrophenyl)diphosphonic acids were prepared by reaction of sodium dimethylamido-O-(2-cyanoethyl)phosphate with O-alkyl-, and O-arylphosphonic acid. In an effort to obtain anhydrous salts of the acids, besides the conventional method using aqueous sodium hydroxide, another procedure involving reaction, of sodium methoxide in methanol was also used. The structure of the final compounds was confirmed by IR, 1H NMR and 31P NMR spectra. The prepared salts of monosubstituted diphosphonic acids are used as model compounds in studying antiviral and cytostatic activity of phosphorous derivatives of purine and pyrimidine bases.

Anti-HIV Agents↗

PubMed1997

Comparative study of monoclonal antibody scan in diagnosing orthopaedic infection.

When clinical data are insufficient to diagnose infection of bone or joints, nuclear scanning becomes crucial in making an accurate diagnosis. The efficacy of (99m)technetium antigranulocyte monoclonal antibody Fab' fragment (LeukoScan) is prospectively compared with (111)indium white blood cell and (99m)technetium methylene diphosphonate bone scans in 74 patients with suspected musculoskeletal infections. They were grouped according to site of suspected infection: 33 long bones, 23 prosthetic joints, and 18 diabetic feet. Sixty-two of these 74 patients had surgical verification with histopathology or culture. The remaining 12 patients had clinical followup as proof of absence of infection. The overall sensitivity of LeukoScan, (111)indium white blood cell, and (99m)technetium methylene diphosphonate bone scans was 93%, 85% and 92%, respectively. Specificity was 89%, 75% and 52%, and accuracy was 90%, 79% and 74%, respectively. The conclusion from this study is that LeukoScan is more accurate in detecting osteomyelitis, with better sensitivity and specificity in prosthetic joints. Compared with (111)indium white blood cell scans, LeukoScan++ gives superior images, and results are obtained in 1 to 6 hours without biohazard risk from handling blood products.

Aged↗

PubMed1978

Treatment of ectopic calcification in uremia.

Nine uremic patients on maintenance hemodialysis who showed wide arterial and/or stable periarticular calcifications in spite of a well controlled hyperphosphatemia were treated with the diphosphonate disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) in doses of 7.5 to 10 mg/kg of body wt/per day for 5 to 9 months. No clinical or biochemical side-effects were noted. A significant reduction of the extent of periarticular calcifications was observed in five patients: two of them had a complete regression of soft-tissue calcifications, and one patient showed a reduction of arterial calcification. EHDP (7.5 to 10 mg/kg of body wt/per day) induced a significant increase of the osteoid volume and osteoid surface without significant modification of the calcification front. No evident effect on bone resorption and on the mineral content of the radius has been observed.

Adult↗

PubMed1987

Clodronate. A randomized study in the treatment of cancer-related hypercalcemia.

Malignancy-associated hypercalcemia is a common and recalcitrant problem. Current modes of therapy are often ineffective or prohibitively toxic. Clodronate disodium is a diphosphonate capable of inhibiting bone resorption resulting in a hypocalcemic effect. In this randomized, placebo-controlled study, we investigated the effect of hydration only (Rx-1) vs the effect of hydration plus either intravenously administered clodronate disodium, 4 mg/kg of body weight per day for three days (Rx-2) or intravenously administered clodronate disodium, 12 mg/kg of body weight given once only (Rx-3). By the third day of observation, Rx-2 produced a significant 2.8 mg/dL (0.70 mmol/L) reduction in serum calcium levels, whereas Rx-1 and Rx-3 did not produce a significant hypocalcemic effect when compared with baseline values. There were no toxicities observed. Intravenously administered clodronate appears to be an excellent agent for the acute treatment of malignancy-associated hypercalcemia.

Adult↗

PubMed2002

Bisphosphonates for the relief of pain secondary to bone metastases.

BACKGROUND: Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain relief for bony metastases remains uncertain. OBJECTIVES: To determine the effectiveness of bisphosphonates for the relief of pain from bone metastases. SEARCH STRATEGY: MEDLINE (1966-1999), EMBASE (1980-1999), CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the Oxford Pain Database were searched using the strategy devised by the Cochrane Pain, Palliative and Supportive Care Group with additional terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'. (Last search: January 2000). SELECTION CRITERIA: Randomized trials of bisphosphonates compared with open, blinded, or different doses/types of bisphosphonates in cancer patients were included where pain and/or analgesic consumption were outcome measures. Studies where pain was reported only by observers were excluded. DATA COLLECTION AND ANALYSIS: Article eligibility, quality assessment and data extraction were undertaken by both reviewers. The proportions of patients with pain relief at 4, 8 and 12 weeks were assessed. The proportion of patients with analgesic reduction, the mean pain score, mean analgesic consumption, adverse drug reactions, and quality of life data were compared as secondary outcomes. MAIN RESULTS: Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms. REVIEWER'S CONCLUSIONS: There is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect; as first line therapy; to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases.

Analgesics, Non-Narcotic↗

PubMed1991

Insufficiency fractures of the distal tibia misdiagnosed as cellulitis in three patients with rheumatoid arthritis.

We describe 3 patients with rheumatoid arthritis who presented with diffuse pain, swelling, and erythema of the distal aspect of the lower extremity, suggestive of either cellulitis or thrombophlebitis, but were found to have insufficiency fractures of the distal tibia. The value of technetium-99m diphosphonate bone scintigraphy in the early recognition of these fractures and a possible explanation for the associated inflammatory symptoms are discussed.

Aged↗

PubMed1984

The localization of human breast carcinomas by radiolabelled monoclonal antibodies.

Immune-deprived mice bearing HX99 human breast carcinoma xenografts were injected with a radiolabelled monoclonal antibody, LICR-LON-M8 (M8), to investigate the dependence of tumour localization on (i) tumour site and (ii) antibody radiolabel. No significant difference was found in the degree of localization of radio-iodinated M8 in subcutaneous, renal or intracranial xenografts, but a highly significant improvement in HX99 localization by M8 was recorded using an 111indium-DTPA conjugate of the antibody (111In-DTPA-M8), related to its rapid tumour uptake and blood pool clearance. Radio-iodinated or 111In-labelled M8 was given to 29 patients with breast cancer, 7 with primary tumours and 22 with metastases. Tumour localization was assessed by (i) examination of surgical specimens and (ii) antibody scans, which were compared with conventional X-rays and 99mTc-methylene diphosphonate (MDP) bone scans. Radiolabelled M8 localized preferentially in all primary tumours (radioactivity tumour: normal breast = 6.2 +/- 1.4 [mean +/- s.e.]). All ten patients with skeletal metastases had positive 111In-DTPA-M8 scans, but the correlation with X-rays and MDP scans showed a regional variation. Radio-iodinated M8 failed to identify metastases in any site. The favourable biodistribution of 111In-DTPA-M8 has led to the clear localization of breast carcinomas in patients and mice. In future such reagents may rationalize the clinical management of breast cancer.

Animals↗

PubMed1986

Effect of estrogen/gestagen and 24R,25-dihydroxyvitamin D3 therapy on bone formation in postmenopausal women.

The effect of two different estrogen/gestagen regimens and 24R,25-(OH)2-cholecalciferol on bone formation was studied in a randomized trial with 144 healthy postmenopausal women. Urinary excretion (UE) of 99m-technetium-diphosphonate and serum alkaline phosphatase (AP) was determined before and then once a year for 2 years of treatment. Both estimates of bone formation showed highly significant decreases (p less than .001) to normal premenopausal levels in women receiving unopposed 17 beta-estradiol or in a sequential combination with progestagen, whereas unchanged high values were found in the groups receiving 24R,25-(OH)2D3 and placebo. The data show that bone turnover increases in early postmenopausal women concomitantly with the loss of bone mass, and that hormonal substitutional therapy normalizes the total skeletal turnover as well as preventing bone loss.

24,25-Dihydroxyvitamin D 3↗

PubMed1990

Repopulation of macrophages in popliteal lymph nodes of mice after liposome-mediated depletion.

Macrophages lining the subcapsular sinus (SCS) and those located in the medulla of popliteal lymph nodes (PLN) of mice were eliminated after subcutaneous (s.c.) injection of dichloromethylene diphosphonate (Cl2MDP)-containing liposomes. No effect of liposome-entrapped Cl2MDP could be seen on nonphagocytic cells, e.g., interdigitating cells (IDC) and B- and T-lymphocytes. One month after injection the eliminated subsets of macrophages were still absent. After 2 mo a small number of macrophages had reappeared along the SCS and in the medulla of the PLN of a few animals. Complete repopulation of the PLN with macrophages was observed only after 5 mo. This extremely long repopulation time could be shortened drastically by local administration of Freund's complete adjuvant (FCA). A small number of macrophages reappeared along the SCS and in the medulla 1 wk after FCA and after 3 wk the repopulation of the PLN with macrophages was complete. Such rapid repopulation of macrophages was not achieved after s.c. injection of paraffin oil or paratyphoid vaccine. These results indicate that the normal rate of influx of mononuclear phagocytes into the PLN is low, but that it can be sped up after administration of FCA.

Animals↗

PubMed1991

Phosphonate-modified GdDTPA complexes. I. NMRD study of the solution behavior of new tissue-specific contrast agents.

NMRD profiles, the magnetic field dependence of the water proton longitudinal relaxation rates, have been acquired for two new diphosphonate-modified GdDTPA complexes currently under evaluation as relaxation agents for the MRI detection of soft-tissue calcifications. Fresh dilute solutions show profiles identical to that of unmodified GdDTPA, which remain unchanged for up to 9 weeks. Solutions containing Gd species at MRI significant concentrations, 100 to 500 mM, show the presence of oligomers (n = 5 or more) upon aging, with much higher high-field relaxivities. Aggregation is attributed to the interactions between a gadolinium center and the phosphonate terminus of a neighboring molecule, and is prevented by esterification of the phosphonate terminus. Oligomers are also easily disrupted by dilution with phosphate-buffered saline, where the exogenous phosphate ions compete with the phosphonate. Other nucleophiles such as are present in protein side chains of bovine serum albumin also compete with the phosphonate in these associations, the result being species with even higher relaxivities.

Contrast Media↗

PubMed1993

Phosphonate-modified Gd-DTPA complexes. III: The detection of myocardial infarction by MRI.

The potential of a phosphonate-modified-Gd-DTPA for MR image enhancement of myocardial infarction has been demonstrated in imaging experiments on rats. The agent, 1-hydroxy-3-aminopropane-1,1-diphosphonate-modified-Gd-DTPA (Gd-DTPA-HPDP) accumulates in two models of myocardial infarction, (i.e., drug-induced diffusely infarcted whole hearts and in focal acute myocardial infarction from a left coronary artery ligation). The time course of the accumulation of the agent in the focal model of infarction and subsequent washout has also been followed in vitro. Results of this kinetics demonstrate that the agent first perfuses all normal fluid spaces and then slowly diffuses into the occluded zone where it is retained for a prolonged period, in sufficient quantities to be useful as an MRI contrast agent. Wash-out of the agent from normal myocardium is fast and complete with MR signal returning to background in minutes. The specificity of Gd-DTPA-HPDP for soft-tissue calcification and its retention within the infarcts permitted imaging at 1 to 2 h postinjection, (after unbound material has cleared the normal tissues). Infarcted tissue appeared as regions of increased signal intensity in T1-weighted images (> 200% enhancement), and correlated with histopathology. Unmodified Gd-DTPA was not retained under identical conditions. Gd-DTPA-HPDP permits a more accurate infarct delineation than is possible with the unmodified agent.

Animals↗

PubMed1996

Experimental topographic study of high-resolution tympanocochlear scintigraphy using the human temporal bone model.

To determine the diagnostic value of tympanocochlear scintigraphy (TCS), which is still used for the visualization of alterations of labyrinthine bone metabolism due to active otosclerosis, resolution and detection limits were examined in a normal human temporal bone model. After incubation in technetium-99m-labeled diphosphonate solution, scintigraphic imaging showed the zygomatic process and the clivus as landmarks for fine structures of the petrous bone. For further differentiation, labyrinthine fine structures were marked with radioactive tracers of 0.5-1 mm2 each. High-resolution scintigraphic imaging gave two-point discrimination for structures as small as 2.5 mm apart. Localization of the activity patterns was improved by correlating imaging with X-ray photographs or by superimposition with masks of the prepared temporal bones drawn from the X-rays. The correlation of scintigraphic findings with X-ray photographs was found to provide a powerful method for improving the accuracy of localizing temporal bone metabolic changes as it is applicable clinically for studying the occurrence of small active otosclerotic foci.

Aged↗

PubMed1979

Experiences with the measurement of inhibitory activity of urine and crystallisation inhibitors by different techniques.

The effect of urine, pyrophosphate (PPi), citrate and diphosphonate on the formation, the growth rate or the aggregation of calcium oxalate or calcium phosphate crystals was measured by 4 different methods. The degree of supersaturation and the area of crystal surface present in the test systems were found to be limiting factors for the action of inhibitors. Citrate and PPi proved to be important urinary inhibitors of the growth of calcium oxalate crystals. Comparison between stone formers and healthy controls revealed a significant lack of PPi in urine of male patients. The inhibitory effect of PPi in urine of healthy people was enhanced by unknown factors. This enhancement could not be found in about 60% of the stone patients. Problems relating to measurement and clinical importance of inhibitors are discussed.

Calcium Oxalate↗

PubMed1979

Radio-isotope bone scanning in suspected osteomyelitis in children.

The usefulness of radio-isotope bone scanning in suspected osteomyelitis has been widely acclaimed. Fourteen children had rectilinear bone scans performed three hours after injection of Tc99m methylene diphosphonate. A diagnostic accuracy of 56% was achieved, which is lower than in other series. The reasons for this are discussed and the value of bone scanning in the evaluation of osteomyelitis is questioned.

Adolescent↗

PubMed1980

Accumulation of Tx-99m phosphonate complexes in metastatic lesions from colon and lung carcinomas.

Cases are presented in which Tc-99m methylene diphosphonate accumulated in a lung metastasis from well differentiated adenocarcinoma of the colon, and in a hepatic metastasis from oat cell carcinoma of the lung. To our knowledge, this is the first report of Tc-99m phosphonate complexes concentrated in a pulmonary metastasis of colonic caecinoma or in a hepatic metastasis of oat cell lung carcinoma. The exact mechanism for this non-osseous uptake of bone scanning agents is still unknown.

Adenocarcinoma↗