Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisphosphonates have marked affinity for bone that makes them useful in both the treatment and imaging of bone lesions. Bone scintigraphy is very sensitive for the detection of bone metastases, which can cause life-threatening hypercalcemia requiring emergency treatment. This prospective study was done to determine whether intravenous administration of pamidronate, a second-generation bisphosphonate used to treat hypercalcemia, affects the affinity of the radiopharmaceutical 99m technetium-labeled hydroxymethylene bisphosphonate (99mTc-HMDP) for bone and bone lesions. Six patients with metastatic bone disease and five with Paget's disease of bone had a 99mTc-HMDP bone scan before and two to four days after an intravenous infusion of pamidronate. The number and activity of metastatic bone lesions were unchanged after pamidronate, even when the second bone scan was done only 24 hours after the pamidronate infusion. Our data suggest that emergency treatment of life-threatening hypercalcemia by intravenous pamidronate does not decrease the sensitivity of subsequent bone scanning done to detect bone metastases.
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PMID:Intravenous aminohydroxypropylidene bisphosphonate does not modify 99mTc-hydroxymethylene bisphosphonate bone scintigraphy. A prospective study. 760 79

Bisphosphonates are analogues of inorganic pyrophosphate, a naturally occurring chemical in bone. In vitro and animal experiments demonstrated that these agents were effective inhibitors of bone resorption. Subsequently they were applied to a variety of clinical problems in which increased bone resorption was an underlying feature of the pathology. In 1971 etidronate became the first bisphosphonate shown to inhibit bone resorption in humans when it was given to patients with Paget's disease. Subsequently this agent was also found to be useful in treating the hypercalcemia of malignancy. At the present time cyclic etidronate therapy is also used for the prevention of bone loss in patients with osteoporosis and for the prevention of heterotopic ossification in spinal cord-injured patients and in patients after hip replacement. Newer bisphosphonates are generally more potent than etidronate and do not produce a severe mineralization defect as do higher doses of etidronate. Pamidronate and clodronate are highly effective in the management of Paget's disease, hypercalcemia due to malignancy and immobilization, metastatic bone disease, and hematologic malignancies affecting bone. They are also promising agents for the prevention of osteoporosis. Alendronate, risedronate, and CGP 42446 are highly potent bisphosphonates that look very promising for the treatment of all disorders of bone resorption. It is fortunate that adverse reactions are not a prominent feature of bisphosphonate use. The main side effects are nausea and abdominal discomfort, mainly with oral use, a transient increase in bone pain in patients with Paget's disease, and an acute-phase reaction (fever, myalgia, mild leukopenia) in patients receiving aminobisphosphonates. The evolution of bisphosphonate therapy should be considered one of the major therapeutic events of the past 25 years. Future research should define the optimum use of these agents.
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PMID:Bisphosphonates in the treatment of disorders of mineral metabolism. 767 Oct 99

Etidronic acid is an orally and intravenously active bisphosphonate, which is believed to inhibit resorption of bone via a number of cellular mechanisms, including alteration of osteoclastic activity. In studies of patients with symptomatic Paget's disease, etidronic acid 5 to 20 mg/kg/day administered orally rapidly decreased the biochemical indices of bone turnover. Mineralisation defects in forming bone may be avoided by the use of an initial dosage of 5 mg/kg/day for up to 6 months; dosages above 10 mg/kg/day should be limited to 3 months' duration, and dosages greater than 20 mg/kg/day should be avoided. Although 3-day intravenous therapy with etidronic acid 7.5 mg/kg/day has shown superior efficacy to rehydration and forced diuresis in the management of hypercalcaemia of malignancy, the efficacy of the drug is lower than that of the newer bisphosphonates, pamidronic acid and clodronic acid. Clinical studies involving postmenopausal women with established osteoporosis have indicated that oral etidronic acid 400 mg/day for 14 days as part of a 90-day cycle, repeated for up to 3 years, increases the bone mineral density (BMD) of the lumbar vertebrae and appears to reduce the incidence of vertebral fracture. Published data suggest that etidronic acid shows similar efficacy to hormone replacement therapy (HRT) in these respects. The above dosage also appears to be effective in preventing corticosteroid-induced osteoporosis when administered as part of an intermittent, cyclical regimen. Etidronic acid in higher dosages (10 to 20 mg/kg/day orally) is effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Etidronic acid is well tolerated by the majority of patients, with gastrointestinal complaints reported most commonly, but tends to delay the normal mineralisation of forming bone when administered continuously at higher dosages for prolonged periods. This is of little consequence where short term treatment is involved, but may be detrimental to those patients receiving longer courses of therapy. This effect may be minimised or avoided by using the lowest effective dosage for as short a time as possible (as in the above recommendations for Paget's disease), or by the use of intermittent cyclical therapy (as in the management of osteoporosis). Etidronic acid therefore retains a role in the management of resorptive bone disease, particularly in the treatment of Paget's disease, the prevention of heterotopic ossification, and as a second-line option in postmenopausal osteoporosis. However, the development of newer bisphosphonates requires that these compounds be continually compared and re-evaluated.
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PMID:Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. 785 70

In 1954, when I gave a talk on calcium homeostasis at the first Gordon Conference on Bones and Teeth, it was recognized that the level of ionic calcium in the plasma and body fluids must be maintained with precision, since it is critically important for a number of vital processes. However, very little was known of the mechanisms involved and I decided to make this the focus of my research career. With the assistance of a number of first-year medical students working during the summer, we developed a precise method for measuring calcium, demonstrated the remarkable constancy of plasma calcium in normal human subjects, and found that normal calcium levels were restored quickly after being artificially raised or lowered. We focussed on parathyroid hormone (PTH), which plays a key role in controlling hypocalcemia by stimulating osteolysis. While studying the control of its secretion in 1961, we discovered a second calcium-regulating hormone (calcitonin) which was released by hypercalcemia and lowered plasma calcium by inhibiting osteolysis. It is a straight-chain peptide with 32 amino acids and a 7-membered disulfide ring at the N terminal. It is produced by C cells which arise from the neural crest and is considered a neuropeptide hormone. It is produced in the thyroid of mammals and the ultimobranchial glands of lower vertebrates. We were involved in the isolation of salmon calcitonin, which is the form most widely used in therapy because of its high potency. In addition to inhibiting bone resorption, it is a powerful analgesic agent with a potency in certain circumstances which is 30-50 times that of morphine. It is widely used clinically for the treatment of Paget's disease, hypercalcemia, osteoporosis, and relief of bone pain. World sales in 1992 exceeded US$900 million, of which 85% was for osteoporosis.
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PMID:Calcitonin: discovery, development, and clinical application. 792 3

Ciba-Geigy Central Epidemiology and Drug Safety Center has received 23 reports of suspected ocular adverse drug reactions associated with the use of intravenous pamidronate disodium, an inhibitor of bone resorption that is used primarily in the management of tumor-induced hypercalcemia and Paget's disease of the bone. Anterior uveitis, bilateral in six of seven patients, occurred within 24 to 48 hours after the drug was administered. The anterior uveitis recurred in four of the five patients who were rechallenged. Three reports involved unilateral episcleritis or scleritis occurring within one to six days after the administration of the drug. Only the episcleritis patient was rechallenged five months later, when the patient again had the episcleritis occur in the same eye. Thirteen patients reported nonspecific transitory conjunctivitis within six to 48 hours after pamidronate disodium was given intravenously. This was positive on rechallenge in six of eight patients. These data indicate that, on rare occasions, pamidronate disodium is a probable cause of anterior uveitis or nonspecific transitory conjunctivitis and is a possible cause of episcleritis or scleritis.
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PMID:Pamidronate disodium and possible ocular adverse drug reactions. 805 68

HTLV-I infection can result in adult T cell leukemia with accompanying hypercalcemia and increased bone resorption. A viral etiology has also been invoked for Paget's disease, a disease of high bone turnover. Delineation of pathogenetic mechanisms of viral-associated bone diseases has been impeded by the complexity of viral and host factors. In order to consider the relationship of HTLV-I infection to skeletal changes we have evaluated the role of a single viral gene in mice transgenic for HTLV-I tax under the control of the viral promoter. Tax mice exhibited severe skeletal abnormalities characterized by high bone turnover, increases in osteoblast and osteoclast numbers and activity, and myelofibrosis. These changes were apparent as early as two months of age. Tax mRNA and protein were highly expressed in bone but not in bone marrow nor in any other tissues except, as previously reported, salivary gland and neurofibromas when they did develop. Within bone, tax protein was detected in only two cell types, mature osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. These observations suggest that local expression of the tax gene, which encodes a viral regulatory protein known to influence host gene expression, can induce within the bone environment marked changes in bone cell activity, resulting in profound skeletal alterations.
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PMID:Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover. 821 54

Mithramycin is an mRNA synthesis inhibitor that has been used to decrease bone resorption in patients with humoral hypercalcemia and Paget's disease. During studies on the mechanism of action of mithramycin it became clear that the compound has a direct inhibitory effect on osteoclastic bone resorption in the in vitro bone slice assay. At concentrations of 0.1-100 nM mithramycin directly inhibited osteoclastic bone resorption dose-dependently up to 66 +/- 5% at 100 nM (mean +/- SEM, 3 expts.). Another mRNA synthesis inhibitor, actinomycin D (0.1-100 nM) and the protein synthesis inhibitor, cycloheximide (0.1-10 microM), also dose-dependently inhibited osteoclastic bone resorption by 78 +/- 7% at 100 nM and 76 +/- 7% at 10 microM, respectively. Mithramycin and actinomycin D at 100 nM did not affect osteoclast survival on bone slices and were therefore not cytotoxic at the concentrations used. Mithramycin (100 nM) and cycloheximide (10 microM) both slightly decreased osteoclast cytoplasmic spreading. Addition of 100 nM mithramycin 6 hr after osteoclast adhesion to bone slices still inhibited subsequent resorption by 50%, indicating a continued but lesser requirement for mRNA synthesis during bone resorption. These results show that approximately 75% of osteoclasts obtained from neonatal rat long bones are activated by adhesion to mineralized bone surfaces and require mRNA and protein synthesis in order to resorb bone in vitro.
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PMID:The majority of osteoclasts require mRNA and protein synthesis for bone resorption in vitro. 821 56

Bisphosphonates (BP) are pyrophosphate analogs, P-C-P with various carbon side-chains. The phosphate groups are responsible for the low gastrointestinal absorption (about 1%), limited penetration into cells, adsorption to bone mineral and rapid excretion in the urine. Based on the C side-chains, BPs can inhibit osteoclastic bone resorption with potencies which differ by as much as 10,000-fold among compounds. The most potent inhibitors are aminobisphosphonates. Studies of the amino-BP alendronate show preferential uptake at sites of bone resorption where they block osteoclastic activity by inhibiting ruffled border formation. BPs are the treatment of choice for hypercalcaemia of malignancy, where a single infusion with a potent BP will normalize serum calcium in 80% of the patients. Paget's disease also shows an excellent long-term response to BPs. In addition, BPs are being studied for the treatment of osteoporosis and other bone disorders which could be helped by inhibition of bone resorption.
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PMID:Bisphosphonates in the treatment of metabolic bone diseases. 821 3

Bisphosphonates have been shown to be effective in lowering serum calcium levels in patients with cancer-associated hypercalcemia. 1-Hydroxy-3-(methylpentylamino)propylidenebisphosphonate (BM 21.0955) was developed as a third generation bisphosphonate and has been recently proven effective in animals and in patients with Paget's disease or tumor osteolysis. Thirty-six patients with cancer-associated hypercalcemia were treated with increasing doses (0.2-2.0 mg) of BM 21.0955 by single i.v. infusion over 4 h in a phase I trial. Six patients were rejected from analysis due to concomitant treatment with other bisphosphonates or chemotherapy. After rehydration and infusion of BM 21.0955 the mean serum calcium levels fell significantly (P < 0.001), from 3.29 +/- 0.49 mmol/l to 3.04 +/- 0.44 mmol/l until day 2 and normalized on day 6 (2.66 +/- 0.33 mmol/l). Serum calcium was reduced in all patients and normalized in 16. No symptomatic hypocalcemia occurred. Mean serum creatinine decreased significantly (P < 0.01), from 1.25 +/- 0.58 mg/dl (day 0) to 1.05 +/- 0.37 mg/dl (day 6). The mean urinary calcium/creatinine concentration fell significantly (P < 0.001), from 1.90 +/- 1.16 mM/mM (day 0) to 0.37 +/- 0.34 mM/mM/l (day 6). There were no subjective drug-related side effects during or after the infusion. Thirteen patients had elevations of morning body temperature above 38 degrees C. This was due to confirmed infections in five patients and possibly drug- or tumor-related in the other eight. We conclude from these preliminary results that a single infusion of BM 21.0955 is an effective and safe way to treat cancer-associated hypercalcemia.
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PMID:Methylpentylaminopropylidenebisphosphonate (BM 21.0955): a new potent and safe bisphosphonate for the treatment of cancer-associated hypercalcemia. 825 67

Gallium nitrate, a group IIIa metal salt, has been found to be clinically effective for the treatment of accelerated bone resorption in cancer-related hypercalcemia and Paget's disease. Here we report the effects of gallium nitrate on osteocalcin mRNA and protein levels on the rat osteoblast-like cell line ROS 17/2.8. Gallium nitrate reduced both constitutive and vitamin D3-stimulated osteocalcin protein levels in culture medium by one-half and osteocalcin mRNA levels to one-third to one-tenth of control. Gallium nitrate also inhibited vitamin D3 stimulation of osteocalcin and osteopontin mRNA levels but did not affect constitutive osteopontin mRNA levels. Among several different metals examined, gallium was unique in its ability to reduce osteocalcin mRNA levels without decreasing levels of other mRNAs synthesized by ROS 17/2.8 cells. The effects of gallium nitrate on osteocalcin mRNA and protein synthesis mimic those seen when ROS 17/2.8 cells are exposed to transforming growth factor beta 1 (TGF beta 1); however, TGF-beta 1 was not detected in gallium nitrate-treated ROS 17/2.8 cell media. Use of the RNA polymerase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole demonstrated that gallium nitrate did not alter the stability of osteocalcin mRNA. Transient transfection assays using the rat osteocalcin promoter linked to the bacterial reporter gene chloramphenicol acetyltransferase indicated that gallium nitrate blocked reporter gene expression stimulated by the osteocalcin promoter. This is the first reported effect of gallium nitrate on isolated osteoblast cells.
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PMID:Gallium nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels. 838 Dec 50


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