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PubMed1984

Desensitization of the guinea-pig urinary bladder by the enantiomers of adenylyl 5'-(beta, gamma-methylene)-diphosphonate and by substance P.

Adenosine 5'-triphosphate (ATP), substance P (SP) and non-cholinergic nerve stimulation contracted the guinea-pig urinary bladder. SP and two poorly-degradable analogues of ATP, the enantiomers of adenylyl 5'-(beta, gamma-methylene)-diphosphonate (AMP-PCP and L-AMP-PCP), were used to desensitize the guinea-pig bladder. Desensitization of the bladder by AMP-PCP (50 microM) or by L-AMP-PCP (50 microM) abolished the responses to ATP, and inhibited the responses to non-cholinergic nerve stimulation and to SP. The responses to histamine were unaffected. Desensitization by SP (1 microM) inhibited the responses to SP itself, but not the responses to ATP, L-AMP-PCP or non-cholinergic nerve stimulation. These results suggest that SP may act partly by releasing ATP, and support the suggestion that ATP rather than SP is the non-cholinergic stimulatory transmitter.

Adenosine Triphosphate↗
PubMed1991

Direct effects of adenylyl 5'-(beta,gamma-methylene)diphosphonate, a stable ATP analogue, on relaxant P1-purinoceptors in smooth muscle.

1. Previous results obtained with the rat colon muscularis mucosae, which contracts in response to adenosine and adenosine 5'-triphosphate (ATP), had suggested that adenylyl 5'-(beta,gamma-methylene)diphosphonate (AMPPCP), a stable ATP analogue, acted on P1-purinoceptors rather than, as expected, on P2-purinoceptors. This possibility has been examined in two tissues in which adenosine and ATP both cause relaxation, the guinea-pig taenia caeci and the rat duodenum. 2. ATP, 2-methylthio-ATP (2-MeSATP), AMPPCP, adenosine 5'-(alpha,beta-methylene)triphosphonate (AMPCPP) and adenosine each relaxed the taenia caeci and the duodenum, and the order of potency of the nucleotides in each tissue was 2-MeSATP greater than ATP greater than AMPCPP greater than AMPPCP, indicating that these effects were mediated by P2Y-purinoceptors. 3. The P1 antagonist 8-(p-sulphophenyl)theophylline (8-SPT) (100 microM) did not affect the responses to ATP, 2-MeSATP or AMPCPP in either tissue, but inhibited the responses of adenosine and of AMPPCP in both tissues. In the duodenum a lower concentration of 8-SPT caused a parallel shift to the right of the concentration-response curve to adenosine and to AMPPCP but to different extents, with AMPPCP being inhibited more powerfully than adenosine. A dose-ratio of around 5 was observed for adenosine and AMPPCP at concentrations of 8-SPT of 20 microM and 2 microM respectively, but Schild analysis resulted in plots with slopes greater than unity. In the taenia caeci, however, 8-SPT inhibited adenosine more powerfully than AMPPCP, and a range of concentrations (10-20 microM) only caused a two fold shift in the concentration-response curve for AMPPCP, although the concentration-response curve to adenosine was shifted in a concentration-dependent manner and Schild analysis gave a pA2 value of 5.13 with a slope of 0.90.4. As has been shown in other tissues, including the guinea-pig taenia caeci, ATP (100 microM) was rapidly dephosphorylated by enzymes present in the rat duodenum, with less than 10% remaining after 20min incubation, whereas AMPPCP (100 microM) was resistant to degradation, with greater than 90% remaining at the same time point.5. AMPPCP therefore has pronounced but variable agonist actions on P,-purinoceptors, and appears to act entirely via these receptors on the rat duodenum although in the guinea-pig taenia caeci this action is less important and it acts largely via P2y-purinoceptors. These Pl-purinoceptor effects of AMPPCP are direct and are not due to its degradation to adenosine.

Adenosine↗
PubMed2005

Aging of red blood cells and impaired erythropoiesis following prolonged administration of dichloromethylene diphosphonate containing liposomes in rats.

OBJECTIVES: To investigate whether macrophage-depleted rats may serve as a model for studying red blood cell (RBC) aging. METHODS: Rats were macrophage-depleted by 4 weekly injections of dichloromethylene diphosphonate-containing liposomes (Cl2MDP-CL). The macrophage content of spleens and bone marrows (BMs) was investigated by immunohistochemistry and light microscopy and by flow cytometry, respectively, after staining with macrophage-specific monoclonal antibodies. In addition, the ultrastructure of residual BM macrophages and their ability to phagocytose zymosan was studied. BM was also studied for apoptosis (by the TUNEL reaction) and for erythroid progenitor cell content. Furthermore, RBC indices, morphology, life span (by 51Cr labeling) and aging features (MCV, density, 4.1a/4.1b membrane protein ratio, anti-spectrin IgG binding, microvesiculation) were investigated. Serum TNF-alpha, iron, total iron-binding capacity (TIBC) and ferritin were also determined. RESULTS: Prolonged treatment with Cl2MDP-CL caused an almost complete depletion of macrophages in the spleen and a 58% reduction of those in the BM; the residual BM macrophages were activated as judged by their ultrastructure and phagocytic capacity in vitro. These alterations were accompanied by an increase in RBC life span and age-related RBC changes, as well as by mild anemia associated with a reduced reticulocyte count, reduced BM erythroid progenitors, increased numbers of apoptotic cells in the BM, low serum iron, high TIBC and increased serum TNF-alpha levels. CONCLUSIONS: Rats subjected to prolonged macrophage depletion showed an increased prevalence of senescent RBC in the circulation due to their impaired clearance by macrophages. Hence, these animals provide a model system in which mechanisms of RBC aging can be delineated. They also showed impaired erythropoiesis, presumably related to a reduction in BM macrophages and increased production of proinflammatory cytokines by residual activated marrow macrophages and other cells.

Animals↗
PubMed1986

Effect of diphosphonate on the prevention of X-radiation-induced inhibition of bone formation in rats.

A histologic and histometric study of the effect of EHDP (ethane-1-hydroxy-1,1-diphosphonate) on the alveolar wound healing of irradiated animals is presented. This drug was selected based on its osteosclerotic effect when applied at low doses. The three left mandibular molars of 80 male Wistar rats were extracted. The rats were grouped into 4 sets of 20 rats each. Group I received no further treatment; Group II received daily intraperitoneal injections of EHDP (7.5 mg/Kg of body weight during 10 days); Group III: 15 Gy of X-radiation were applied to the head; and Group IV were irradiated and injected with EHDP as were animals of Groups III and II. Half of the animals were killed after 14 days and the other half 30 days post-extraction. Sections were made at the level of the mesial socket of the first molar in a bucco-lingual orientation, on which histometric determinations of bone activity were made. The results showed the attenuation of the inhibitory effect of radiation on bone formation when the animals were treated with EHDP.

Alveolar Process↗
PubMed1990

Fibrodysplasia ossificans progressiva. An 11-year-old boy treated with a diphosphonate.

Fibrodysplasia ossificans progressiva (FOP) is a severe, rare, autosomal dominant, ectopic ossifying condition, with primary involvement of the skeletal muscles associated with skeletal abnormalities. This report concerns an 11-year-old boy suffering from FOP, who presented significant modification of the musculoskeletal structure of the thorax and problems with articular movements. The patient showed progress after treatment with ethane-1-hydroxy-1,1-diphosphonate (EHDP). In fact, using a scintiscanner we were able to observe a significant improvement in symptoms and a recovery of some of the active sites of ossification.

Child↗
PubMed1976

Light microscopic and ultrastructural observations on the short-term effects of ethylene-1-hydroxy-1, 1-diphosphonate (EHDP) on rat tibia epiphysis.

Ethylene-1-hydroxy-1, 1-diphosphonate (EHDP) was administered intraperitoneally to one-day old rats at a concentration of 30 and 40 mg/kg body weight/injection. Two groups of animals received four doses, respectively, over a 44-hour-period and a third group received two high doses with a 15-hour interval, the total amounts corresponding to 30, 40 and 20 mg/P/kg body weight. Animals in the first two experimental groups showed increased width of the hypertrophic zone as compared with normal controls and lack of calcified septa within the zone of provisional calcification. In the calcification zone, persistent atypical chondrocytes were present and in the septa a large number of matrix vesicles which hardly ever contained any crystals. The ground substance of these septa contained fine precipitates, probably representing proteoglycan complexes which were not seen normally in this zone. In the third group, the septa of the calcification zone were calcified and the hypertrophic zone was not clearly widened. In the metaphysis, remnants of cartilage or osteoid were observed as "islands" covered with osteoblast-like cells which showed signs both of collagen and apatite formation, the latter evidenced by the appearance of crystals within the matrix vesicles. It is suggested that the complex effects observed in calcifying cartilage after administration of high doses of EHDP in vivo are not restricted solely to the stage of crystal formation.

Animals↗
PubMed1977

Calcium absorption in diphosphonate-treated rats: effect of parathyroid function, dietary calcium and phosphorus.

1. The role of parathyroid hormone (PTH) and 1, 25-dihydroxy-cholecalciferol (1,25-(OH)2D3) in modulation of intestinal Ca absorption was studied in rats, using disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP), which is known to reduce 1,25-(OH)2D3 formation. 2. EHDP decreased intestinal Ca absorption. This effect could be abolished by small amounts of 1,25-(OH)2D3, whereas even large doses of PTH were ineffective. EHDP also decreased Ca absorption in thyroparathyroidectomized (TPTX) rats. Therefore the effect of EHDP on 1,25-(OH)2D3 production is unlikely to be mediated through PTH. 3. The correction by PTH of the decreased Ca absorption in TPTX rats was inhibited by EHDP. Since EHDP inhibits formation of 1,25-(OH)2D3 the effect of PTH on Ca absorption is likely to be mediated through this vitamin D3 metabolite. 4. In normal rats both a low Ca and a low P diet stimulated Ca absorption. In EHDP-treated intact rats low Ca still stimulated Ca absorption, whereas the effect of low P abolished. This indicates that low Ca and low P diets affect Ca absorption through different mechanisms. 5. Intestinal adaptation to a low Ca diet was still observed in EHDP-treated TPTX rats. Thus, in the rat, intestinal adaptation to low Ca diet can occur without PTH.

Animals↗
PubMed1974

Parathyroid hormone effects in rats treated with diphosphonate.

The ability of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP; 40 milligrams per kilogram of body weight per day) to reduce the hypercalcemic effect of parathyroid hormone in thyroparathyroidectomized rats was confirmed. However, treatment with this large dose of EHDP enhanced the hypophosphatemic effect of a low dose of parathyroid hormone (10 international units per100 grams of body weight), apparently by promoting the renal excretion of phosphate. The data suggest that EHDP may have a direct effect on the renal action of parathyroid hormone and, in this way, may also affect vitamin D metabolism by the kidney.

Animals↗
PubMed1975

Calcium balance in children treated with diphosphonates.

Serial mineral balances have been obtained in 3 children undergoing therapy with EHDP (ethane-1-hydroxy-1, 1-diphosphonate) for diseases involving ectopic calcification. Although clinical outcome was not uniformly satisfactory, all cases showed an overall reduction in calcium balance. This was due to increased faecal excretion of calcium and was most marked after a long duration of therapy. Although these results conflict with reported experience in adults, they are in agreement with published observations of the effects of EHDP on calcium absorption in experimental animals.

Adenosine Monophosphate↗
PubMed1976

Skeletal uptake of 99mTc-diphosphonate in relation to local bone blood flow.

The right/left ratios of tibial uptake of 99mTc-diphosphonate (EHDP) and relative blood flow (based on microsphere distribution) were determined in control rats and rats with a ligated right femoral artery or a healing right tibial fracture. Correlation between 99mTc-EHDP uptake and relative blood flow was highly significant (r=0.917; P less than 0.0001) for relative flow ratios less than 1.7. When the ratio was greater than 1.7, there was little further increase in 99mTc-EHDP uptake. Ligation of the femoral artery in rats with healing fractures resulted in a more marked reduction of blood flow than of 99mTc-EHDP uptake. These results suggest that regional bone blood flow is a major determinant of 99mTc-EHDP uptake, though changes in regional tracer extraction efficiency are also important.

Animals↗
PubMed1995

Cranial osteomyelitis: diagnosis and follow-up with In-111 white blood cell and Tc-99m methylene diphosphonate bone SPECT, CT, and MR imaging.

PURPOSE: To assess the usefulness of indium-111 white blood cell and technetium-99m methylene diphosphonate bone single photon emission computed tomography (SPECT), computed tomography (CT), and magnetic resonance (MR) imaging in cranial osteomyelitis. MATERIALS AND METHODS: Twenty-six cases (25 patients: 13 male, 12 female; mean age, 55 years) of suspected osteomyelitis were evaluated. Sixteen were postoperative. Final diagnosis was established by means of bone culture in 18 cases and clinical follow-up in eight. RESULTS: Of 35 CT scans, 10 were true-positive (TP); three false-negative (FN); 13, true-negative (TN); one, false-positive (FP); and eight, equivocal. Of 36 SPECT scans, 19 were TP; 13, TN; one, FP; one, FN; and two, equivocal. Of 11 MR images four were TP; five, TN; and two, FN. CONCLUSION: CT is best for differentiation between soft-tissue and bone infection. MR imaging is best for assessment of the calvaria and skull base. SPECT is best for assessment of altered bone and may be the best technique for follow-up.

Adolescent↗
PubMed1977

Bone extraction and blood clearance of diphosphonate in the dog.

The transcapillary extraction of diphosphonate, as [99mTc]EHDP, a substance used in bone scanning and for management of certain metabolic bone diseases, has been examined. The maximum instantaneous extraction for [99mTc]EHDP was 0.27 +/- 0.05 (mean +/- SD, N = 10) and the net extraction at 5 min was 0.18 +/- 0.05 (N = 10). The permeability ratio of [99mTc]EHDP to the freely diffusible compound, sucrose, using the formula PS = -Fs loge (1 - Emax), was 0.71. This is similar to the ratio of diffusion coefficients of EHDP to sucrose, which is estimated to be 0.78. These results suggest that the mechanism by which [99mTc]EHDP passes through the capillaries in bone is passive diffusion. Tissue level estimations of EHDP confirm a rapid blood clearance associated with an increase in the rate of urinary excretion; the level of [99mTc]EHDP in bone, however, remains constant. The fractional excretion of [99mTc]EHDP was 27.3 +/- 2.0% in control dogs and was unchanged by thyroparathyroidectomy and subsequent infusion of parathyroid hormone.

Animals↗
PubMed1975

Action of 1,25-dihydroxyvitamin D3 and a diphosphonate on calcium metabolism in rats.

The effect of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) on Ca balance, 45Ca kinetics, and bone morphology has been studied in control rats and rats given disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP), 10 mg P/kg sc per day. This large dose of EHDP is known to inhibit bone mineralization and intestinal calcium absorption and to depress the endogenous production of 1,25-(OH)2D3. In conctrol rats, 1,25-(OH)2D3 increased intestinal calcium absorption. However, in contrast to the enhanced calcium absorption that results from an augmentation of dietary calcium, the 1,25(OH)2D3-induced augmentation of calcium absorption does not lead to a rise in calcium retention, the intestinal effect being matched by an increased excretion of urinary calcium. The EHDP-induced decrease of intestinal calcium absorption could be completely prevented by the concomitant administration of 1,25-(OH)2D3 but not the inhibition of bone mineralization. Therefore, in contrast to the impairment of calcium absorption, that of bone mineralization brought about by large doses of EHDP cannot be merely attributed to a decreased production of 1,25-(OH)2D3.

Animals↗
PubMed1980

Effect of diphosphonate treatment on phosphate transport by renal brush border vesicles.

Treatment with disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) given in doses of 10 mg P/kg s.c. for 7 days inhibits bone mineral retention and decreases the tubular capacity to reabsorb inorganic phosphate (Pi) in thyroparathyroidectomized (TPTX) rats. In the present work we show that pretreatment with EHDP depressed Na+-dependent Pi uptake by brush border membrane vesicles (BBMV) isolated from renal cortex of TPTX rats. The effect of EHDP was observed after feeding both high (1.2%) and low (0.2%) phosphorus diets. The EHDP-induced changes observed in vitro at the brush border level parallel the variations in the overall tubular Pi transport capacity as assessed by clearance techniques in conscious rats. Na+-dependent glucose uptake by BBMV, as well as alkaline phosphatase activity in cortical homogenates and in the BBMV were not affected by EHDP treatment. Accordingly, EHDP, given in doses that block bone mineral retention, appears to specifically affect the Na+-dependent transport of Pi across the luminal membrane of proximal tubules of renal cortex.

Animals↗
PubMed1993

Depletion of alveolar macrophages by liposome-encapsulated dichloromethylene diphosphonate.

Alveolar macrophages (AM) play an important role in lung biology. In this study, we demonstrated that tracheal insufflation of liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP-liposome) selectively depleted AMs in rats. Insufflation of a single dose of Cl2MDP-liposomes (80 microliters containing 1.34 mumol of Cl2MDP) but not liposomes containing phosphate-buffered saline resulted in > 70% depletion of AMs starting within 1 day and lasting for > 5 days after insufflation. There was a slight but significant intraalveolar inflammatory response. Insufflation of Cl2MDP also resulted in depletion of AMs; however, it caused cytoplasmic edema of alveolar epithelial cells as well. Depletion of AMs by Cl2MDP-liposomes markedly reduced the endotoxin-induced neutrophil (polymorphonuclear lymphocyte) recruitment and the release of tumor necrosis factor into the alveolar space, suggesting that endotoxin-induced neutrophil recruitment and tumor necrosis factor release were dependent on AMs. This AM-depleted animal model will be useful for studying the in vivo functions of AMs and their role in various physiological and pathological conditions.

Animals↗
PubMedDate not supplied

Detection of cardiac calcinosis in hemodialysis patients by whole-body scintigraphy with 99m-technetium methylene diphosphonate.

A noninvasive method for the diagnosis of cardiac calcinosis, a life-threatening complication in hemodialysis patients with end-stage renal disease (ESRD), has not, as yet, been firmly established. We tested whether whole body scanning with 99m-technetium methylene diphosphonate (MDP) might visualize cardiac calcinosis. In 19 consecutive chronic hemodialysis ESRD patients (13 males and 6 females, aged 40-81, mean 63 +/- 8 years) with cardiovascular disease [mitral annular calcinosis and/or calcified aortic valve (n = 4), hemodialysis cardiomyopathy (n = 1), coronary artery disease (n = 9) and peripheral artery atherosclerotic disease (n = 6)], MDP uptake in the heart was compared to that in 7 non-ESRD controls with hyperparathyroidism due to adenoma. Cardiac and lung field MDP uptake was confirmed in only 3 (16%) and 5 (26%) of the 19 ESRD subjects, respectively, but was absent in controls. Positive cardiac uptake was related to cardiac calcified complications (mobile intracardiac calcinosis, myocardial calcinosis and mitral annular calcification) and the duration of hemodialysis (p = 0.015). While it was statistically insignificant, subjects showing MDP uptake were elder and had higher serum Ca or Ca x P product and lower intact parathyroid hormone levels. These results suggest that cardiac calcinosis in ESRD patients can be detected noninvasively by myocardial scintigraphy with 99m-technetium MDP.

Adult↗