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)

In our preliminary experiment, we found that a constant infusion of a high dose of parathyroid hormone-related protein induced both hyperphosphataemia and hypocalcaemia, secondary to renal dysfunction. Therefore, in this study, we developed two types of parathyroid hormone-related protein-induced hypercalcaemia models. One is the hypercalcaemia model, which did not show renal-dysfunction-induced hypocalcaemia. This model might be suitable for estimating hypocalcaemic activities of drugs, especially of those that act on bone resorption. The other is the model for estimating histological changes, which is associated with renal dysfunction. We then used these models to investigate the effects of three different bisphosphonates. Since the hypercalcaemic effect of parathyroid hormone-related protein infusion plateaued at 20 pmol/h, and higher doses of parathyroid hormone-related protein caused an elevation of blood urea nitrogen, the parathyroid hormone-related protein infusion rate was fixed at 20 pmol/h to avoid renal dysfunction and at 40 pmol/h to elicit renal dysfunction. The hypocalcaemic efficiencies of clodronate and etidronate were almost the same but pamidronate was 17.9 times more potent than clodronate. Additionally, both clodronate and pamidronate decreased the plasma concentrations of blood urea nitrogen and the Ca2+ times inorganic P product, whereas etidronate lacked these effects. Clodronate suppressed renal calcification and tubular dilatation in the renal-dysfunction model. These data indicated that clodronate and pamidronate not only decrease the plasma Ca2+ concentration but also improve the renal dysfunction induced by hypercalcaemia.
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PMID:Rat model of the hypercalcaemia induced by parathyroid hormone-related protein: characteristics of three bisphosphonates. 1565 23

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.
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PMID:The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications. 1577 88

Newer-generation intravenous bisphosphonates have resulted in the reduction of skeletal-related complications, i.e. skeletal-related events (SREs) such as pain, hypercalcemia, pathologic fractures and spinal cord and nerve compression, as well as improvements in the quality of life in patients with metastatic bone disease who are likely to have a prolonged clinical course. Highly potent, nitrogen-containing bisphosphonates such as zoledronic acid reduce SREs in patients with bone metastases from other solid tumors (including lung cancer). Part one of our review discussed the mechanisms of action by bisphosphonates as well as potential roles for bone markers and imaging in lung cancer. In this article, part two of our review, we examine the economic and clinical impact of bisphosphonates in lung cancer, with a focus on the potential role of newer-generation bisphosphonates in the management of advanced, metastatic bone disease of lung cancer.
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PMID:The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 2: Clinical studies and economic analyses. 1577 89

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease. Parathyroidectomy is the only curative intervention for the former condition. In the rare cases of patients with primary hyperparathyroidism who present with clinical symptoms due to their hypercalcemia, pharmacological treatment may be required. Fluid repletion and intravenous (IV) administration of bisphosphonates are recommended in the literature. Calcium receptor agonists (calcimimetic agents) are at the present time only available for use within clinical trials. Cancer patients usually present with symptoms of hypercalcemia. Rapid institution of antihypercalcemic treatment is essential in preventing life-threatening deterioration. Fluid repletion and administration of bisphosphonates are the treatment mainstays in hypercalcemia of malignancy. Five bisphosphonates are currently licensed in Europe for treatment of tumor-associated hypercalcemia: etidronate, clodronate, pamidronate, ibandronate, and zoledronate. In the US, pamidronate and zoledronate are licensed for use in this indication. Bisphosphonates containing nitrogen atoms (e.g. pamidronate, ibandronate, and zoledronate) are more potent than those without (e.g. etidronate, clodronate, and tiludronate). In patients with malignant hypercalcemia, the efficacy of the individual bisphosphonate depends on dose administered and initial serum calcium concentration. At present, pamidronate has been studied in the greatest number of investigations and in the largest number of patients. In the literature, the efficacy of pamidronate in restoring normocalcemia ranges between 40% and 100%, depending on the dose used and baseline serum calcium concentration. More recently, one study reported that pamidronate was inferior to zoledronate. In this study, the duration of response was also longer in the two zoledronate groups (30 and 40 days) than in the pamidronate group (17 days). The most serious adverse events of bisphosphonates concern renal function. Increases in serum creatinine levels have been more frequently reported following treatment of tumor-associated hypercalcemia with etidronate (8%) and clodronate (5%) than with the nitrogen-containing bisphosphonates pamidronate (2%) and ibandronate (1%). The frequency of increases in serum creatinine levels following treatment with zoledronate is difficult to estimate. Administration of the nitrogen-containing bisphosphonates has been associated with transient (usually mild) fever, lymphocytopenia, malaise, and myalgias. These events occur within 36 hours of the first dose and are self-limiting. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare. The toxicity and low efficacy of plicamycin (mithramycin) mean that use of this agent should be restricted to patients with hypercalcemia of malignancy who fail to respond to IV bisphosphonates. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect, which contrasts with the delayed but more pronounced effect of bisphosphonates. Combination calcitonin and bisphosphonate treatment may therefore be of value when rapid reduction of serum calcium is warranted. Gallium nitrate may be a valuable treatment for hypercalcemia of malignancy. It is characterized by high efficacy and few adverse events apart from renal toxicity (10% of cases). However, data are very limited and further trials are necessary.
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PMID:Current management strategies for hypercalcemia. 1596 62

Olpadronate is a nitrogenated bisphosphonate. Although it shares the therapeutic and pharmacological properties of pamidronate and alendronate, it has a greater dosage amplitude, more predictable effects and a greater digestive tolerability than other bisphosphates. Therefore, it may be more appropriate in the treatment of medical osteopathies, by both oral and parenteral routes of administration. According to various experimental and human models, the pharmacological potency of olpadronate is 5- to 10-times higher than that of pamidronate and close to that of alendronate. The two methyl groups bound to the nitrogen atom give the compound a high water solubility, which is about 8-times higher than that of the two other bisphosphonates. The lack of a terminal amino group in the side-chain of the molecule and the absence of crystallised forms of the compound in the digestive tract (due to its high water solubility) may avoid the potential for inducing oesophageal and gastrointestinal side-effects. These features may explain the high tolerability reported after the administration of doses of olpadronate (by the oral route) up to 5- to 10-times higher than the maximum tolerated dose of alendronate in Paget's bone disease and bone metastases, thus widening the possibilities for its clinical usage. In addition, initial pharmacokinetic studies suggest that olpadronate's oral bioavailability would fit into a confidence range of 2-4%, which contrasts with the erratic absorption shown by other highly potent bisphosphonates. The clinical efficacy demonstrated in preliminary studies in Paget's bone disease (including ultra-short treatments), and also in single-dose iv. therapy of hypercalcaemia of malignancies, renders olpadronate among the most promising bisphosphonate compounds, with potential use in the treatment of a variety of bone-involving diseases, such as osteoporosis, malignancies and rheumatoid arthritis.
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PMID:Olpadronate: a new amino-bisphosphonate for the treatment of medical osteopathies. 1599 50

A review of records from the AnTox database of the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center identified 43 dogs that developed increased blood urea nitrogen concentration, serum creatinine concentration, or both as well as clinical signs after ingesting grapes, raisins, or both. Clinical findings, laboratory findings, histopathological findings, treatments performed, and outcome were evaluated. All dogs vomited, and lethargy, anorexia, and diarrhea were other common clinical signs. Decreased urine output, ataxia, or weakness were associated with a negative outcome. High calcium x phosphorus product (Ca x P), hyperphosphatemia, and hypercalcemia were present in 95%, 90%, and 62% of the dogs in which these variables were evaluated. Extremely high initial total calcium concentration, peak total calcium concentration, initial Ca x P, and peak Ca x P were negative prognostic indicators. Proximal renal tubular necrosis was the most consistent finding in dogs for which histopathology was evaluated. Fifty-three percent of the 43 dogs survived, with 15 of these 23 having a complete resolution of clinical signs and azotemia. Although the mechanism of renal injury from grapes and raisins remains unclear, the findings of this study contribute to an understanding of the clinical course of acute renal failure that can occur after ingestion of grapes or raisins in dogs.
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PMID:Acute renal failure in dogs after the ingestion of grapes or raisins: a retrospective evaluation of 43 dogs (1992-2002). 1623 10

Although uremia is well known as the most common cause of pruritus, the mechanisms of pruritus in chronic hemodialysis patients remain unclear. The purpose was to characterize uremic pruritus in more detail and to investigate whether severe pruritus is a marker for poor prognosis. A total of 1773 adult hemodialysis patients were studied. A questionnaire was given to each patient to assess the intensity and frequency, as well as pruritus-related sleep disturbance. We analyzed the relationship between clinical and laboratory data and the severity of pruritus in hemodialysis patients and followed them for 24 months prospectively. In total, 453 patients had severe pruritus with a visual analogue scale (VAS) score more than or equal to 7.0. Among them, more than 70% complained of sleep disturbance, whereas the majority of patients with a VAS score of less than 7.0 had no sleep disturbance. Male gender, high levels of blood urea nitrogen, beta2-microglobulin (beta2MG), hypercalcemia, and hyperphosphatemia were identified as independent risk factors for the development of severe pruritus, whereas a low level of calcium and intact-parathyroid hormone were associated with reduced risk. During the follow-up, 171 (9.64%) patients died. The prognosis of patients with severe pruritus was significantly worse than the others. Moreover, severe pruritus was independently associated with death even after adjusting for other clinical factors including diabetes mellitus, age, beta2MG, and albumin. Severe uremic pruritus caused by multiple factors, not only affects the quality of life but may also be associated with poor outcome in chronic hemodialysis patients.
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PMID:Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. 1667 24

Multiple myeloma (MM) is a B-cell malignancy characterized by enhanced bone loss commonly associated with a diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Recent characterization of osteoclast-activating factors (OAFs), receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL)-osteoprotegerin-RANK system, and inhibitors of Wnt signaling have provided a better understanding of myeloma bone disease in molecular level. The development of minimally invasive surgical procedures such as kyphoplasty and vertebroplasty allows myeloma patients with vertebral compression fractures to have immediate improvement in quality of life and shorter hospital stays. Monthly intravenous infusion of either pamidronate or zoledronic acid have reduced the skeletal complications among MM patients and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although pre-clinical studies suggest nitrogen-containing bisphosphonates have potent anti-tumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible anti-tumor effects clinically. As our understanding of the pathophysiology of myeloma bone disease continues to increase, new target therapies will continue to emerge offering new and more advanced options for the management of myeloma bone disease.
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PMID:Myeloma bone disease and treatment options. 1679 71

Multiple myeloma disrupts calcium homeostasis by a variety of mechanisms, including bone destruction and resorption. This causes hypercalcemia. When left untreated, hypercalcemia leads to nephrocalcinosis, impairment of kidney function, and eventually renal failure. Some degree of renal dysfunction is common in myeloma patients. Here, we report case studies showing the efficacy and renal safety of the single-nitrogen bisphosphonate, ibandronate, for the treatment of hypercalcemia and/or nephrocalcinosis in multiple myeloma patients hospitalized with acute renal failure. Patients (n = 7) received either one or two intravenous infusions of ibandronate (2-6 mg). Ibandronate was well tolerated in all patients and returned elevated blood calcium levels to normal. Renal function improved for all patients and normalized in 3/7 patients. We conclude that ibandronate is involved in rapidly improving or restoring acute renal function and calcium levels to within the normal range in this patient population. To clarify the exact value of ibandronate, further investigation is warranted in randomized prospective trials.
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PMID:Ibandronate for the treatment of hypercalcemia or nephrocalcinosis in patients with multiple myeloma and acute renal failure: Case reports. 1701 34

Human Vgamma2Vdelta2 T cells recognize nonpeptide antigens derived from pathogenic microbes in a TCR-dependent manner, such as pyrophosphomonoester compounds from mycobacteria and malaria parasite and alkyl amines from Proteus, suggesting that this subset of gamma delta T cells is involved in infectious immunity. The precise recognition mechanism has been delineated using a site-directed mutagenesis strategy based on crystal structure of gamma delta TCR. On the other hand, several lines of evidence indicate that human gamma delta T cells are involved in tumor immunity. Although activated gamma delta T cells exhibit a cytolytic activity against most of tumor cells, only a small fraction of tumor cells, like Burkitt lymphoma cells and multiple myeloid cells, is recognized by human gamma delta T cells in a TCR-dependent manner. This implicates that human gamma delta T cells have two distinct pathways for anti-tumor immunity. One is a natural killer-like pathway and the other is a TCR-dependent pathway. Recently, it was shown that treatment of human tumor cells with nitrogen-containing bisphosphonates, therapeutic drugs for hypercalcemia in malignancy, generated antigenic structure on the surface of tumor cells, which could be recognized by human gamma delta T cells in a TCR-dependent manner. This tumor labeling system may lead to a novel strategy for cancer immunotherapy.
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PMID:Human gamma delta T cells and tumor immunotherapy. 1705 4


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