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)

Gallium nitrate has been shown to be an effective treatment for patients with cancer-related hypercalcemia. Clinical studies have also suggested the drug may have considerably broader use in other diseases associated with accelerated bone loss including multiple myeloma, bone metastases, Paget's disease, and osteoporosis. The actions of gallium nitrate on bone are quite distinct from those of bisphosphonates. Preclinical studies show that gallium preferentially accumulates in trace amounts in metabolically active regions of bone. When present, gallium favorably alters the mineral properties to enhance hydroxyapatite crystallization and reduce mineral solubility. The drug also acts on the cellular components of bone to reduce bone resorption by decreasing acid secretion by osteoclasts. This effect appears to be mediated by inhibition of the ATPase-dependent proton pump of the osteoclast's ruffled membrane. Gallium does not inhibit the development or recruitment of osteoclasts to bone tissue, unlike many bisphosphonates that may induce osteoclast apoptosis. Together, these pharmacologic actions may yield a skeletal system with increased calcium and phosphate content and improved biomechanical strength. Gallium nitrate has potent antiresorptive effects on bone that can be achieved at considerably lower doses than are currently used for cancer-related hypercalcemia. Parenteral and oral formulations of gallium appear to have high activity in bone resorptive disorders, and thus development should be vigorously pursued in these diseases.
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PMID:The effects of gallium nitrate on bone resorption. 1277 54

Hypercalcemia is a common, life-threatening metabolic disorder that can be associated with cancer. Its pathophysiology includes enhanced osteoclastic bone resorption and decreased renal excretion of extracellular calcium. Symptoms of hypercalcemia include nausea, vomiting, bone pain, polyuria, renal insufficiency, bradycardia, and arrhythmia. The goals of medical therapy are to inhibit bone resorption and promote renal calcium excretion. Hydration is the first step in management. Treatments for hypercalcemia include phosphates, calcitonin, bisphosphonates, and gallium nitrate. Although intravenous phosphates prevent intestinal calcium absorption and inhibit mineral and bone matrix resorption, serious adverse events include renal failure, hypotension, extraskeletal calcification, and severe hypocalcemia. Calcitonin has a rapid onset of action and can lower serum calcium concentrations within hours, but its usefulness is limited by its short duration of effect and the development of tachyphylaxis. Bisphosphonates are effective inhibitors of bone resorption but appear to have decreased response rates in hypercalcemic patients with high levels of parathyroid-related protein. Gallium nitrate, an antitumor agent noncytotoxic to osteoclasts and bone cells, appears to be more effective than pamidronate, etidronate, and calcitonin in the treatment of cancer-related hypercalcemia. Importantly, unlike bisphosphonates, gallium nitrate is effective in both parathyroid-related protein-mediated and non-parathyroid-related protein-mediated hypercalcemia.
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PMID:Treatment of cancer-related hypercalcemia: the role of gallium nitrate. 1277 55

Multiple myeloma is characterized by bone destruction mediated by osteoclastic bone resorption. Skeletal complications of myeloma, including bone pain, fractures, spinal cord compression and hypercalcemia, result in significant morbidity. Gallium nitrate was shown in a small, randomized trial to attenuate the rate of bone loss in patients with myeloma treated with chemotherapy. In a retrospective analysis, we found that patients with advanced multiple myeloma treated with chemotherapy plus gallium nitrate had markedly prolonged median survival compared with similar patients treated with chemotherapy alone (87+ months v 48 months, respectively). These data suggest that gallium nitrate may have a positive, indirect benefit on survival in myeloma by decreasing the rate of bone resorption. Further evaluation of gallium nitrate to attenuate progression of disease in patients with multiple myeloma is warranted.
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PMID:Gallium nitrate in multiple myeloma: prolonged survival in a cohort of patients with advanced-stage disease. 1277 56

Gallium nitrate is effective and well tolerated for the treatment of cancer-related hypercalcemia. At somewhat higher doses, gallium nitrate also has cytotoxic activity against a variety of cancers. The probable mechanism is inhibition of both ribonucleotide reductase and a protein tyrosine phosphatase. Radioactive gallium ((67)Ga) is concentrated at sites of malignant lymphoma, Hodgkin's disease, and other tumors. Gallium nitrate has substantial single-agent activity in the treatment of patients with advanced lymphoma and has also shown activity when used in combination with other agents. Significant response rates have been observed in patients with diffuse large cell lymphoma, small lymphocytic lymphoma, and follicular lymphoma. Because of its unique mechanism of action, gallium nitrate could be non-cross-resistant with many of the cytotoxic agents used as standard chemotherapy for non-Hodgkin's lymphoma. Nephrotoxicity, the most frequent adverse event associated with gallium nitrate, can generally be minimized by ensuring adequate oral hydration and avoiding concomitant use of other nephrotoxic drugs. Gallium nitrate causes little myelosuppression and is therefore well tolerated by patients with advanced disease who have received extensive prior therapy. Given its unique mechanism of action, the high level of single-agent activity in published clinical trials, the absence of significant myelosuppression, and the potential lack of cross-resistance, further clinical study of gallium nitrate both alone and in combination with other active agents is warranted.
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PMID:Gallium nitrate in the treatment of lymphoma. 1277 57

Mortality from non-Hodgkin's lymphoma (NHL) is high, thus defining the need for additional therapeutic agents for this disease. Gallium nitrate is a metal compound that is presently approved for the treatment of hypercalcaemia associated with malignancy. In clinical trials first conducted over two decades ago, this drug was found to have antineoplastic activity in NHL. However, its development as an antineoplastic agent for the treatment of NHL was never rigorously pursued. Gallium has unique mechanisms of action that include its binding to transferrin in the circulation and targeting transferrin receptors present on lymphoma cells. As it shares chemical properties with iron, gallium can disrupt critical steps in iron homeostasis that are essential for tumour cell viability and growth and can inhibit the iron-dependent activity of ribonucleotide reductase. The drug may also target other cellular processes unrelated to iron. Phase I/II studies have shown that gallium nitrate displays the most efficacy and lowest toxicity in NHL when administered as a continuous intravenous infusion, producing response rates of 43% in patients with relapsed or refractory NHL. It does not suppress the white blood cells or platelets and does not share cross-resistance with other chemotherapeutic drugs. These characteristics make it particularly attractive for the treatment of myelosuppressed patients and for incorporation into combination therapy. Multi-institutional Phase II clinical trials are in progress to evaluate gallium nitrate as a single agent or in combination. These studies will help define its role in the current treatment of NHL.
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PMID:Gallium nitrate for the treatment of non-Hodgkin's lymphoma. 1515 28

Gallium nitrate is an approved therapy for symptomatic, cancer-related hypercalcemia unresponsive to adequate hydration, the most common life-threatening metabolic disorder of cancer. Initially developed because of its antineoplastic properties, gallium nitrate demonstrated the ability to reduce serum calcium levels in early trials. Although the mechanism by which gallium nitrate corrects hypercalcemia is not fully understood, it appears to involve multiple effects (inhibition of osteoclast-mediated bone resorption, stimulation of bone formation, and alteration of the mineral composition and properties of bone); however, gallium nitrate is not cytotoxic to bone cells. In randomized trials for moderate-to-severe cancer-related hypercalcemia, gallium nitrate was well tolerated and produced a higher rate and longer duration of normocalcemia relative to calcitonin and the bisphosphonates etidronate and pamidronate. Gallium nitrate induced normocalcemia in 72% to 82% of patients; in contrast to the comparator agents, it was effective regardless of epidermoid tumor status. Epidermoid tumors are associated with high levels of parathyroid hormone-related protein (PTHrP), the principal mediator of cancer-related hypercalcemia in solid tumors. High levels of PTHrP appear to adversely impact the calcium-lowering potential of bisphosphonates. The recommended schedule of gallium nitrate for the treatment of cancer-related hypercalcemia is 200 mg/m2 per day as a 5-day continuous intravenous infusion, administered with adequate hydration and close monitoring of renal function. Gallium nitrate is an effective treatment option for moderate-to-severe cancer-related hypercalcemia, a setting in which morbidity and mortality are high.
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PMID:Treating cancer-related hypercalcemia with gallium nitrate. 1632 18

Amongst the principal metabolic situations that can require emergency attention in the oncology patient we find: hypercalcaemia, hyponatraemia, tumoural lysis syndrome, lactic acidosis, hyperuricaemia, renal failure, hyperammonaemia, hypermpotasaemia, etc. Hypercalcaemia is the most frequent metabolic complication in oncology, appearing in 10-30% of these patients. It has two main mechanisms, tumoural lysis and humoural hypercalcaemia mediated by PTHrP (a protein related to parathormone). The principal factor for its diagnosis is suspicion, since some symptoms are non-specific and can be attributed to other causes such as somnolence, constipation, etc. Treatment will be based on intensity and is started with calciuretic measures with an intense hydration with physiological serum and on some occasions with furosemide. Anti-reabsorptive measures include calcitonin, bisphosphonates, mithramycin, gallium nitrate and on occasions corticoids. Bisphosphonates such as pamidronate and zoledronate seem to be highly useful in these cases. Hyponatraemia is classified depending on plasmatic osmorality; when this is low we find ourselves facing an authentic hyponatraemia that can develop with an extra-cellular volume that is high (cardiac insufficiency, cirrhosis, nephrotic syndrome and renal insufficiency), low (renal and extra-renal sodium losses) and normal (principally SIADH, related to a high elimination of sodium in the urine with high urinary osmolarity in spite of this being low in blood). Several types of tumour and different chemotherapy drugs can produce this SIADH. Treatment will vary according to the type and intensity, but in general this is based on hydric restriction and the replacement of the sodium deficit, either through physiological serum or through hypertonic saline serums depending on the case, and on occasions furosemide for the elimination of excess water.
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PMID:[Metabolic emergencies in the oncology patient]. 1572 5

Arthritis is inflammation in a joint often with joint damage, usually accompanied by pain, swelling and stiffness, resulting from infection, trauma, degenerative changes, metabolic disturbances, autoimmune or other causes. It occurs in various forms, including rheumatoid arthritis, osteoarthritis, bacterial arthritis and gout. Gallium III can inhibit the production of inflammatory cytokines, such as IL-1beta, produced by macrophage-like cells in vitro. A dose-dependent inhibition of IL-1beta and TPA stimulated MMP activity by gallium nitrate at increasing concentrations occurs, demonstrating that gallium nitrate can be a useful modulator of inflammation in arthritis. Gallium III is an inhibitor of bone resorption and is an effective treatment for hypercalcemia. Gallium III has been reported to be effective in the treatment of mycobacterium butycicum-induced arthritis in rats by antagonism of iron III. Long-term elimination of pain from arthritis by gallium III was first observed in horses primarily being treated for navicular disease. Several people treating their horses with gallium nitrate coincidentally found that arthritis pain in their fingers ended and did not return after soaking their hands in 14% gallium nitrate solution. Therefore, the severely arthritic hands of a 60-year-old woman were topically treated with a 14% aqueous solution of gallium nitrate for 90 min. Pain and inflammation from rheumatoid arthritis diminished rapidly, and neither pain nor inflammation returned during the following 2 years from that single treatment. A 61-year-old woman who had osteoarthritis in her left knee, shoulders and wrists was treated orally with 50 ml of a 1% gallium nitrate solution (120 mg elemental gallium) daily using a two week on and two week off protocol, resulting in almost total elimination of pain while on gallium nitrate, while pain partially returned during the two week off periods. Treatment of frozen shoulder with topical 40% gallium nitrate for 120 min resulted in greatly reduced pain and crepitus almost immediately with complete restoration of range of motion, with pain remaining essentially absent for over 1 year. Mechanisms of action are hypothesized to include anti-inflammatory, bone density improvements, antibacterial, anti-iron III and anti-aluminum III effects. Proper use of gallium III may be effective in terminating pain and inflammation of arthritis for years, often with a single treatment.
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PMID:Elimination of arthritis pain and inflammation for over 2 years with a single 90 min, topical 14% gallium nitrate treatment: case reports and review of actions of gallium III. 1612 80

Hypercalcemia is a frequently observed laboratory phenomenon in clinical practice. It can occur in several diseases, among which it is associated most frequently with neoplasms, hyperparathyroidism and disorders of vitamin D metabolism. The appearance of hypercalcemia in neoplastic diseases is related to a poor prognosis in general. In most cases, malignant hypercalcemia is related to the secretion of parathormone-related protein, but other causes have also been described. Granulomatous diseases are associated with the hypersecretion of vitamin D metabolites. Fluid volume repletion, forced diuresis can be regarded as cornerstones in the therapy of acute hypercalcemia independent of its etiology, in addition, medications including bisphosphonates, calcitonin, gallium nitrate and glucocorticoids can be applied. In this review article, the authors present a brief synopsis of the pathogenesis of hypercalcemia associated with neoplastic and granulomatous diseases along with the treatment options, underlining the practical aspects.
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PMID:[Hypercalcemia in neoplastic and granulomatous diseases: pathogenesis and treatment options]. 1615 12

In 12 of 93 hypercalcemic patients with metastatic advanced breast cancer treated with tamoxifen the most common life-threatening metabolic complication of flare hypercalcemia developed. All the hypercalcemic patients had osteolytic or mixed lytic and blastic bone metastases. In patients with advanced breast cancer, hypercalcemia develops within the first few weeks of initiation of tamoxifen therapy. In our study group, calcium levels were measured frequently in both serum and urine samples by a semi-autoanalyzer and an autoanalyzer, using standard methods. Elevation of calcium levels was noticed in the tamoxifen-receiving hypercalcemic breast cancer patients, and levels returned to normal when tamoxifen was withdrawn. The median duration of flare hypercalcemia was 9 days (range, 4-16 days). The median calcium value was 13.6 mg/dl (range, 11.7-15.8). The diagnosis of tamoxifen flare hypercalcemia was based on the normal pretreatment serum or urine calcium values and the occurrence of hypercalcemia within the first few weeks of tamoxifen initiation. There are no specific treatment recommendations for hormone flare hypercalcemia, except for tamoxifen withdrawal, which is usually temporary, and the introduction of a low dose of an antihypercalcemic drug. We evaluated the effect of such a drug, gallium nitrate, on flare hypercalcemia. All the patients were treated with hydration, and 6 patients, whose calcium level was above 13.6 mg/dl, were treated with a moderate dose of gallium nitrate (200 mg/m(2) per kg) for 5 consecutive days, they achieved normocalcemia and continued with tamoxifen. The median time from hormonal drug initiation to flare hypercalcemia was 17.5 days, and median duration was 9 days. The above result indicates that the serious metabolic complication of hypercalcemia develops due to the iatrogenic effect of tamoxifen, but it can be controlled with an antihypercalcemic drug, gallium nitrate, while continuing tamoxifen therapy. It seems that the use of gallium nitrate in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature tamoxifen discontinuance or withdrawal.
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PMID:Tamoxifen flare hypercalcemia: an additional support for gallium nitrate usage. 1662 38


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