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PubMed1998

Cytochemical and biochemical studies on adenylate cyclase activity in preneoplastic and neoplastic liver tissue and cultured liver cells.

The ATP-analogue adenylyl(beta,gamma-methylene)diphosphonate was chosen as substrate for the cytochemical localization of adenylate cyclase (AC) activity. The tissues investigated covered normal rat liver and liver from carcinogen-treated animals with preneoplastic lesions and hepatocellular neoplasms, as well as cultured liver cells. The AC reaction product methylene diphosphonate was precipitated with Pb2+ immediately at the place of production. This approach permitted a precise localization of AC activity by light and electron microscopy. The specificity of the AC reaction was demonstrated by control reactions, including inhibition of AC with 2'5'-dideoxyadenosine and activation with forskolin, glucagon, and cholera toxin. Endogenous phosphatases were inhibited with tetramisole and NAD. In normal liver, AC activity was mainly localized in the sinusoidal membrane of hepatocytes. A distinct gradient in activity was observed within the liver lobule. Hepatocytes localized around the terminal hepatic venule showed a significant higher AC activity compared to hepatocytes near the portal tract. AC was clearly decreased in focal preneoplastic liver lesions of the glycogenotic-basophilic cell lineage leading to hepatocellular carcinomas. Cytochemically detected intensity of AC activity corresponded to data obtained by microbiochemical assays in laser-dissected tissue samples. A remarkable interdependence of AC activity and degree of differentiation was also seen in epithelial rat liver cell lines: Highly differentiated cells show high enzyme activity and vice versa, as shown by both cytochemical and biochemical examinations. It is concluded that alterations in cellular signal transduction caused by alterations in AC activity play an important role in hepatocarcinogenesis.

Adenosine Triphosphate↗
PubMed1996

Liposome-mediated monocyte depletion during wallerian degeneration defines the role of hematogenous phagocytes in myelin removal.

Newly recruited hematogenous mononuclear cells of the monocyte/macrophage system are suggested to be important effector cells in myelin removal during Wallerian degeneration. Their role has extensively been studied in various in vitro and in vivo models. However, there has been much controversy concerning the role of hematogenous vs. resident cells of the peripheral nervous system in Wallerian degeneration. The present study used a recently established technique to deplete the hematogenous monocyte population by application of dichloromethylene diphosphonate-containing liposomes. Intravenously injected liposomes containing dichloromethylene diphosphonate (Cl2MDP) are ingested by macrophages and monocytes and cause temporary and selective depletion of these cells. The number of LFA-1- and Mac-1- positive macrophages within the nerves was significantly reduced when liposomes were injected shortly after nerve transsection. In these nerves, myelin degradation was significantly less, indicating an essential role of newly recruited phagocytes in this process. Macrophage invasion of degenerating nerves occurred within the first 2 days after transsection. Resident cells of the peripheral nerve participate in myelin removal since macrophage depletion did not completely abolish myelin degradation. These results confirm the important role of hematogenous phagocytes in myelin removal during Wallerian degeneration.

Animals↗
PubMed1994

Small animal imaging with pinhole single-photon emission computed tomography.

BACKGROUND: High resolution spatial details of the distribution of activity in three dimensions is required to evaluate the localization and dosimetric properties of radiolabelled monoclonal antibodies in tumors and normal tissues. Planar imaging of small animals with a resolution of 5-10 mm is usually the imaging modality of choice. The authors investigated high resolution single-photon emission computed tomographic (SPECT) imaging, based on a rotating pinhole scintillation camera. Although the sensitivity of the pinhole collimator is low, several radionuclides offer suitable decay properties to perform pinhole SPECT, especially in conjunction with high activity levels used in radioimmunotherapy. METHODS: Transverse, sagittal, and coronal sections were reconstructed using a three-dimensional cone-beam algorithm, which is a generalization of the two-dimensional fan-beam filtered backprojection algorithm. Before reconstruction, the pinhole projections were corrected for the decay of the radionuclide, geometric and intrinsic efficiency variations of the camera system, and center of rotation shift. RESULTS: The spatial resolution at 50 mm from the pinhole collimator with 3.3 mm aperture was 3.4 mm, and the sensitivity 7.2 c/s microCi for technetium-99m. With the 2 mm collimator the resolution was 2.2 mm, and the sensitivity was 2.6 c/s/microCi. To show the spatial resolution in vivo, a rat was injected with 185 MBq of technetium-99m-methylene diphosphonate or with 5 mCi technetium-99m-hexamethylpropylene amine oxime. The bone structures were well delineated in the methylene diphosphonate image, and in the hexamethylpropylene amine oxime image, the brain was nicely shown. For comparison a magnetic resonance image for the same section was done. CONCLUSIONS: High resolution SPECT imaging with the pinhole collimator provides mapping of the activity in three-dimensions, needed for more detailed biodistribution data and to perform more accurate dosimetry.

Algorithms↗
PubMed1995

Immunogenic role of Kupffer cells in a rat model of acute liver allograft rejection.

Kupffer cells (KCs) are of bone-marrow origin. After liver transplantation, recipient KCs are supposed to replace donor KCs. On the other hand, KCs are currently hypothesized to play a major immunogenic role in acute liver allograft rejection. In the present study, we investigated the immunogenic role of KCs in acute rat liver allograft rejection. For this purpose, we depleted the donor KCs using intravenous injection of liposome-encapsulated dichloromethylene diphosphonate (DMDP) in the fully allogenic ACI-to-LEW rat liver transplantation model. Kupffer cell depletion was confirmed using monoclonal antibodies ED2. In a first set of experiments, graft survival was evaluated, as were body weight and serum bilirubin changes, after the transplantation. Graft survival time showed no difference between the groups (treated, 12.5 +/- 0.92 days; control, 11.9 +/- 0.80 days). Body weight and serum bilirubin changes were similarly affected in both groups. In a second set of experiments, recipients were killed on day 6 after the transplantation, and rejection was histologically graded from 0 to 4. All grafted livers were judged as grade 3 regardless of treatment. ED2 staining showed KCs repopulation in both untreated and the dichloromethylene diphosphonate treated livers. The results of the present study provide evidence that KCs do not play an important immunogenic role in acute liver allograft rejection of the rat.

Acute Disease↗
PubMed1982

Skeletal muscle calcergy.

The subcutaneous injection of mast cell degranulators in the mouse is followed by calcification of fibres of the Panniculus Carnosus muscle. This reaction is seen in damaged fibres adjacent to a central zone of complete necrosis. Calcification of muscle fibres is also seen after the injection of KMnO4 but this uniformly affects the fibres at the site of reaction. Quantitative studies of the latter model and qualitative studies of the former show that treatments with the diphosphonates EHDP and Cl2MDP do not influence the calcific responses. It is suggested that the inducing chemicals interact with the muscle fibre membrane causing membrane dysfunction and a resultant influx of calcium ions. It has been proposed that this is a pathogenetic mechanism in various myopathies and that prevention of net calcium ion influx might form a basis for treatment. In this context, the results of the present experiments suggest that the diphosphonates would be unlikely to efficacious in this regard.

Animals↗
PubMed1985

Clinical comparison of 99mTc-HMDP and 99mTc-MDP. A multicenter study.

99mTc-Hydroxymethylene diphosphonate (HMDP) was compared to 99mTc-methylene diphosphonate (MDP) with respect to image quality, lesion detectability, and the uptake ratios of normal bone to soft tissue (B/S), metastatic bone to soft tissue (M/S) and bone metastases to normal bone (M/B) at 2 and 3 h after injection in the same subjects. Thirty-three patients with bone metastases were examined in six nuclear-medicine departments, with each center using its usual bone-scanning protocol which was identical for both compounds in the same patient. The uptake of 99mTc-HMDP in normal bone (B/S) was significantly higher than that of MDP at 2 and 3 h, but there were no significant differences between the two compounds with regard to the M/S or M/B ratios. The M/B of HMDP at 2 h was not significantly different from that of MDP at 3 h, the latter showing a significantly higher B/S and M/S ratio. All lesions were detected with both compounds, even at 2 h. The image quality was rated as follows (in decreasing order): HMDP (3 h), MDP (3 h), HMDP (2 h), and MDP (2 h). HMDP was shown to be a useful bone-imaging agent, especially when shorter intervals between injection and recording are required.

Adult↗
PubMed1984

Effectiveness of phosphocitrate and N-sulpho-2-amino tricarballylate, a new analogue of phosphocitrate, in blocking hydroxyapatite induced crystal growth and calcium accumulation by matrix vesicles.

Phosphocitrate and its analogue N-sulpho-2-amino tricarballylate were compared with ethane-1-hydroxy-1,1-diphosphonate for inhibition of calcium phosphate crystallization in hydroxyapatite induced crystal growth and 45Ca uptake by matrix vesicles. Phosphocitrate (1 microM) was the most potent inhibitor followed by ethane-1-hydroxy-1,1-diphosphonate and N-sulpho-2-amino tricarballylate, the latter requiring a high concentration (100 microM) to be equally effective as an inhibitor.

Animals↗
PubMed1988

A clinical and biochemical assessment of etidronate disodium in patients with active rheumatoid arthritis.

Diphosphonates reduce the rate of bone turnover. They have additional pharmacological properties improving adjuvant arthritis in rats and lowering ESR in this condition. We have evaluated etidronate disodium, a diphosphonate commonly prescribed in the United Kingdom for Paget's disease in patients with rheumatoid arthritis. Apart from an early improvement in articular index, perhaps reflecting anti-inflammatory activity, no significant change occurred in clinical variables or in laboratory indices of 'secondline' action at a dose of 5 mg/kg/day.

Adult↗
PubMed1985

Fibrodysplasia ossificans progressiva: current concepts and the role of CT in acute changes.

Fibrodysplasia ossificans progressiva (FOP) may be treated with diphosphonate in an attempt to control the deposition of calcium phosphate. Amounts of calcium deposition may be assayed by plain radiographs and CT. In a sporadic case of FOP treated for 6 years with a diphosphonate (EHDP) we have analyzed the findings from CT. This modality presents a suitable means of monitoring response to new therapeutic agents, but CT also gives insights into the pathogenesis of the disorder.

Child↗
PubMed1981

Studies of diffusion in calvaria.

The rates of diffusion of small ions and neutral molecules through isolated calvaria have been determined. Compared with data published on self-diffusion and diffusion through cartilage, H2O, 3-O-methylglucose, lactate, sulfate, and methylamine diffuse at approximately 2/3 the expected rate. Diffusion of H2O and sulfate was unaffected by the administration of the diphosphonate 1-hydroxyethane-1,1-diphosphonate (EHDP), although phosphate fluxes are markedly diminished. Diffusion of water was nearly doubled by vitamin D deficiency. A 1-week treatment with 1,25(OH)2D3 had no effect on H2O diffusion while returning calcium influx to normal. It is concluded that bone matrix permits a flow of small neutral and ionized molecules nearly comparable to that in cartilage. When changes in calcium and phosphate influx are observed, they can be ascribed to the exchange properties of bone mineral and not to changes in matrix permeability.

3-O-Methylglucose↗
PubMedDate not supplied

The 24-h urinary cyclic adenosine 3', 5' monophosphate/creatinine ratio: an useful approach to the diagnosis of parathyroid disorders and function.

24-h urinary cyclic adenosine 3', 5'-monophosphate/creatinine (cAMP/Cr) ratio was assessed in 10 patients with hypoparathyroidism, 6 with primary hyperparathyroidism, 7 with normocalcemic hypercalciuria and recurrent nephrolithiasis, 14 with osteomalacia, 25 with Paget's disease and 53 with symptomatic postmenopausal osteoporosis. In hypoparathyroid subjects the mean values of 24 h cAMP/Cr ratio were significantly lower than the control values, whereas in patients with parathyroid adenoma the mean values were higher and fell after parathyroid surgery. Patients with nephrolithiasis due to absorptive hypercalciuria showed low or normal cAMP/Cr ratio, whereas in those with osteomalacia and mean values of cAMP/Cr ratio were significantly higher than the control values and decreased after vitamin D treatment. The mean value of the 24 h urine cAMP/Cr ratio was normal in patients with Paget's disease or postmenopausal osteoporosis and increased significantly after long term treatment with calcitonin or diphosphonate. This increase paralleled a significant decrease of calcium plasma level. A significant improvement of fractional calcium absorption was observed in women with postmenopausal osteoporosis at the end of treatment with calcitonin or diphosphonate.

Adolescent↗
PubMed1987

Therapy of hypercalcemia of malignancy.

An appreciation of the pathogenesis of the hypercalcemia of malignancy is essential to its management. At the outset, since most patients with symptomatic hypercalcemia of malignancy are dehydrated, infusion of 2 to 3 liters of saline per day will at least partially reduce serum calcium levels. Induction of calciuresis by infusing larger volumes of saline simultaneously with parenteral administration of furosemide may reduce the serum calcium concentration to normal in the short term. Of major importance in long-term therapy, however, are drugs that inhibit bone resorption, a major cause of hypercalcemia. These include calcitonin, plicamycin, glucocorticoids, prostaglandin synthetase inhibitors, and the diphosphonates. These agents may provide long-term control of hypercalcemia in many patients. Reduction of intestinal calcium absorption by dietary means or by glucocorticoid therapy is often effective in the rare subset of patients with increased serum levels of 1,25-dihydroxyvitamin D. Oral and intravenous phosphorus therapy may be effective via unknown mechanisms in some patients. The diphosphonates, in particular, should greatly facilitate management of both acute and chronic hypercalcemia of malignancy. Daily intravenous infusion of etidronate disodium (etidronate) with saline over a period of three to six days, for example, appears to be a safe and effective means of restoring serum calcium concentrations to the normal range. Study results have shown that more than 90 percent of patients have a response to etidronate. Oral administration of the drug has been demonstrated to maintain normal serum calcium concentrations.

Bone Resorption↗
PubMed1991

ATP-dependent DNA aggregation is a novel function of rat serum albumin.

An ATP-dependent DNA aggregating activity was purified from rat liver by DEAE-cellulose, phosphocellulose, and novobiocin-Sepharose column chromatography. The protein aggregated superhelical, relaxed, single-, or double-stranded DNA in a divalent cation- and ATP-dependent reaction. The DNA aggregating activity was detected by retardation of a DNA-protein complex at the origin on a 1% agarose gel. The protein appeared to exist in solution as a monomer of molecular weight 66,000, and had no DNA polymerase, topoisomerase, recombinase, or ligase activity. The DNA aggregating activity was inhibited by 10 mM nalidixic acid or 1 mM novobiocin but not by 20 mM N-ethylmaleimide or camptothecin. Adenylyl(beta,gamma-methylene)-diphosphonate, adenylyl-imidodiphosphate, or adenosine-5'-O(3-thiotriphosphate) did not substitute for ATP whereas CTP, dTTP, or the ATP analog adenylyl(alpha,beta-methylene)-diphosphonate could replace ATP. The aggregated DNA was only partially dissociated by restriction endonuclease digestion but was completely dissociated by deproteinization with SDS, proteinase K, or chloroform/octanol extraction. On the basis of the molecular weight, thermostability, antigenic property, and amino acid sequence homology in the first 12 positions, we conclude that the rat liver protein is serum albumin and that the ATP-dependent DNA aggregation is a novel function of rat serum albumin.

Adenosine Triphosphate↗
PubMed1990

A new method for removal of mononuclear phagocytes from heterogeneous cell populations in vitro, using the liposome-mediated macrophage 'suicide' technique.

In this study we present a new method for the elimination of mononuclear phagocytic cells from cell suspensions. By making use of liposome-encapsulated dichloromethylene diphosphonate we were able to effectively remove macrophages from spleen cell suspensions. This effect was not observed when using the free drug or control (PBS) liposomes. The use of this procedure has no effect on other cell types, as measured by growth, protein production, antigen presentation and antigen specific T cell proliferation, though PBS liposomes in very high doses were able to inhibit antigen presentation. The finding that lymphocytes are not affected by the liposome encapsulated drug suggests that the observed loss of lymphocytes in vivo, after intravenous dichloromethylene diphosphonate liposome treatment, may be due to damage inflicted by lysosomal enzymes released from dying macrophages. This method permits the removal of both macrophages and monocytes from heterogeneous cell populations (i.e., blood, lymphoid tissue suspension) in vitro with a very high rate of reliability. With the concentrations and incubation time used, no negative effects on other cell types were observed.

Animals↗
PubMed1988

Treatment of painful prostatic bone metastases with oral etidronate disodium.

A class of drugs called diphosphonates have been used for several years in benign disorders of ossification such as Paget disease. Recently, these compounds have been applied to treating hypercalcemia of malignancy and painful bone metastases. We have used one of the oral diphosphonates, etidronate disodium, to palliate pain in 12 patients suffering from multiple bone metastases from prostate cancer. All of the patients had progressive metastatic disease following earlier endocrine therapy. Ten of 12 (83%) patients had a positive subjective and clinical response to treatment with oral etidronate disodium. Daily narcotic usage and pain intensity (measured by a zero to 10 pain scale) both decreased significantly on the etidronate protocol. There were no side effects associated with the drug in our patients.

Administration, Oral↗
PubMed1976

Disaggregation of hydroxyapatite crystals.

A system has been developed to measure quantitatively the disaggregation of hydroxyapatite crystals. Disaggregation was induced by pyrophosphate, ethane-1-hydroxy-1,1-diphosphonate, dichloromethylene diphosphonate, haparin and citrate. Hyaluronic acid stimulated aggregation at low concentrations and disaggregation at high concentrations. Lactate had no effect. The possible role disaggregation might play in the resorption of calcified tissues in vivo id discussed.

Binding Sites↗
PubMed1986

The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine.

The beta emitting isotopes 186Re and 188Re are logical choices on which to base therapeutic radiopharmaceuticals that might be expected to be analogous to diagnostic radiopharmaceuticals based on 99mTc. However, the chemistry of rhenium is sufficiently different from that of technetium so that the development of Re radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of 99mTc radiopharmaceuticals. The relevant chemical differences involve the greater stability of the higher oxidation states of Re (and thus the greater tendency of reduced Re radiopharmaceuticals to undergo re-oxidation to perrhenate), and the greater substitution inertness of reduced Re complexes. These differences are illustrated in the preparation and use of 186Re (Sn)-HEDP and 99mTc(Sn)-HEDP diphosphonate radiopharmaceuticals designed, respectively, for palliative therapy and diagnosis of metastatic cancer to bone, and in the preparation and biodistribution of tr[186Re(DMPE)2Cl2]+ and [186Re(DMPE)3]+, analogs to the potential myocardial perfusion imaging agents tr-[99mTc(DMPE)2Cl2]+ and [99mTc(DMPE)3]+. [HEDP = (1-hydroxyethylidene)diphosphonate; DMPE = 1,2-bis(dimethylphosphino)ethane].

Animals↗