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)

Ibandronate (ibandronic acid) is a third generation bisphosphonate which inhibits hone resorption in human and animal studies. It also inhibits bone formation only at high doses (10 microg/kg/day) in animal studies. In animal models, ibandronate was more potent than etidronate, clodronate, pamidronate and alendronate and equivalent in potency or more potent than risedronate in inhibiting induced hypercalcaemia and bone resorption. In clinical studies, single-dose ibandronate (0.2 to 6 mg intravenously) significantly reduced albumin-corrected serum calcium levels and urinary markers of bone resorption in patients with hypercalcaemia of malignancy, and in those with bone metastases. Serum calcium levels were normalised in 50 and 67% of ibandronate 2 mg recipients and in about 76% of 4 mg recipients. In postmenopausal women with osteoporosis or osteopenia. ibandronate (0.5 to 5 mg/day orally or 0.5 to 2 mg every 3 months intravenously) dose-dependently increased bone mineral density, with parallel reductions in the biochemical markers of bone turnover. In preliminary studies in patients with Paget's disease a single intravenous ibandronate dose (2mg) decreased serum alkaline phosphatase levels and urinary markers of bone turnover. Adverse events associated with the use of ibandronate in the management of hypercalcaemia of malignancy include increased body temperature, hypocalcaemia and hypophosphataemia. Less commonly, flu-like symptoms and gastrointestinal intolerance may occur.
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PMID:Ibandronate. 995 55

Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Osteoclasts can be activated directly by products produced by tumors or indirectly through other nonmalignant cells. By reducing osteoclastic activity, bisphosphonates inhibit bone resorption. Since these agents were shown effective in treating other diseases associated with increased bone resorption, including cancer-related hypercalcemia and Paget's disease of bone, studies have been initiated to explore the use of bisphosphonates in patients with osteolytic bone metastases. Recent large randomized double-blind studies show the efficacy of these agents in reducing skeletal complications in patients with bone metastases from both breast cancer and multiple myeloma.
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PMID:Bisphosphonates in the treatment of malignant bone disease. 1007 75

The authors review the structural, pharmacologic, and clinical aspects of bisphosphonates, a class of drugs currently used to treat several disorders of bone and calcium metabolism. Pertinent literature on the bisphosphonates was reviewed with the help of a MEDLINE search and several bibliographies, including published clinical trials, monographs, and review articles. The bisphosphonates are analogs of pyrophosphate that, when given orally or intravenously, bind avidly to exposed bone mineral and disrupt bone turnover. These agents comprise three groups or generations, based on their potency and chemical structures. All three generations are effective in treating hypercalcemia, Paget's disease of bone, osteoporosis, and other disorders of accelerated bone turnover. The third-generation agents have the greatest potency and offer the promise of a convenient way to suppress or prevent osseous metastasis in patients with certain malignancies. As a group, these agents are well tolerated and, when administered correctly, rarely cause toxicity. The bisphosphonates are safe and effective agents for the treatment of disorders of accelerated bone turnover.
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PMID:Developments in the therapeutic applications of bisphosphonates. 1039 18

Gallium nitrate, an approved antitumor drug, has found clinical application in the treatment of cancer-related hypercalcemia and of Paget's disease; the exact mechanism of its action, however, remains unknown. The present study utilized rats in a 7-day exposure to gallium at doses similar to those used clinically. Quantitative histomorphometry and ultrastructural examination of osteoclast fine structure were carried out on specimens from animals with documented hypocalcemia. Gallium exposure produced striking changes in the osteoclast. The number of nuclei/osteoclast increased, and the ruffled borders of the osteoclasts were markedly decreased along the length of the Howship's lacunar cavity. The absence of a decrease in osteoclast number and the types of changes seen in ultrastructure suggest that the mechanism of action of gallium seen here may differ from that of calcitonin, a nontoxic, reversible antiresorbing agent. Results underscore the difficulty in assessing the toxicity of agents such as gallium on the osteoclast, a mature differentiated cell which does not divide and which does not produce a characteristic extracellular matrix component.
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PMID:In vivo morphologic changes in the rat osteoclast induced by gallium nitrate: the result of toxicity or other effects? 1043 97

Bisphosphonates are pyrophosphate analogues, in which the oxygen in P-O-P has been replaced by a carbon, resulting in a P-C-P structure. They are characterised by a strong anti-osteoclastic activity and for this pharmacological property they are now considered the treatment of choice for Paget's disease of the bone, malignant hypercalcaemia and bone metastases. Etidronate, clodronate and pamidronate have been registered in several countries for these indications. Etidronate and alendronate are also extensively used for the prevention and treatment of postmenopausal and senile osteoporosis. In this article, we review the most recent findings on the newest bisphosphonates, which will become available in the near future. The aminobisphosphonate risedronate is undergoing a huge programme of clinical development for the treatment of osteoporosis. In a study of the prevention of early postmenopausal bone loss, oral risedronate 5 mg fully prevented the bone loss observed in the placebo group. Similar effects have been observed with an intermittent dosage regimen of oral risedronate 30 mg/day for 2 out of 12 weeks, which corresponds to 5 mg/day in terms of cumulative dose. With lower doses [5 mg on alternate fortnights (2 weeks)] the prevention of bone loss was half that observed with continuous 5 mg/day therapy, indicating that this might not yet be the maximum effective dose. The use of intermittent intravenous bisphosphonates for osteoporosis therapy has been pioneered by studies with clodronate, pamidronate and alendronate. This treatment regimen has been chosen for an extensive clinical development programme for ibandronate. In a phase 2 study, this new bisphosphonate was administered as an intravenous bolus (0.25, 0.5, 1 or 2 mg) every 3 months for a year, with increases in spinal bone mass of 5.2%. Tiludronate, alendronate and risedronate have been recently introduced for the treatment of Paget's disease of bone. Daily doses of tiludronate 400 mg, alendronate 40 mg and risedronate 30 mg for 3 to 6 months have been shown to be superior to etidronate 400 mg/day. The intravenous administration of ibandronate, zoledronate and alendronate (40 mg, 10 mg and 5 mg, respectively) have achieved the normalisation of serum alkaline phosphatase in more than 70% of the patients and these treatments may provide an alternative for patients intolerant oral bisphosphonates. Intravenous ibandronate has been also developed for the treatment of hypercalcaemia of malignancy. The effective doses ranged from 2 to 4 mg. Zoledronate appears to be the most powerful bisphosphonate under investigation, and the effective doses used in cancer hypercalcaemia are as low as 1 to 2 mg. The new generation of bisphosphonates are likely to increase clinical options in terms of administration regimens, but their real advantage over those already available in terms of clinical efficacy remains uncertain.
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PMID:New bisphosphonates in the treatment of bone diseases. 1058 75

Studies of the effect of parathyroidectomy (PTX) on bone turnover in patients with the combination of primary hyperparathyroidism (PHPT) and Paget's disease (PD) are largely limited to case reports. The etiology of the combination is disputed. We report 30 patients and their biochemical (n = 17) and histomorphometric (n = 4) responses to PTX in 18. All 18 patients except one had a post-PTX fall in plasma alkaline phosphatase (pAP). There was a significant positive correlation between the degree of post-PTX fall in pAP and both the preoperative plasma total corrected calcium (CaC) (P < 0.01) and serum ionized calcium (P < 0.05). For the patients with CaC levels >3.0 mmol/liter, the mean % fall in pAP was 68% of pretreatment (to 32%). For those with CaC levels >/=2.68 mmol/liter the fall in pAP was >18%. Of 12 literature cases treated by PTX and followed up, 11 had a postoperative fall in pAP (range 6-83%). Pretreatment bone biopsies (n = 6) could not be distinguished from uncomplicated PD. No significant histomorphometric changes were documented postoperatively in the four patients studied; however, % fibrotic surfaces declined in each of the four. Of the 18 patients, only one had radiologic subperiosteal erosions preoperatively; none had clinical tetany postoperatively-thus distinguishing this combination of diseases from severe PHPT bone disease-a situation easily biochemically confused with this combination. The sex distribution of 2.75:1 F/M in this series resembles reported ratios in pure PHPT of 2.37:1, unlike the ratios found in pure PD (0.49-1.01:1). The prevalence of PHPT in PD is 2.2-6.0% (mean 4.4%) in 1836 patients. In our series, 73% of patients with both diseases were females >60 years of age. In population studies >60 years, PHPT was present in 3% of women and 1% of men. Hypercalcemia in PD is frequently attributed to immobilization. As part of this study, we examined 184 patients referred with PD for the existence of, and cause of hypercalcemia. Of this group, 21 were hypercalcemic, 19 (90%) of whom had PHPT; none had immobilization hypercalcemia. In patients with both disorders, the indications for PTX should include the potential post-PTX improvement in pagetic biochemistry and symptoms. The sex distribution (resembling pure PHPT) and the similar prevalence of PHPT in Paget's, and in the elderly population, support the likelihood, in most cases, that these two common diseases are associated by chance.
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PMID:Thirty cases of concurrent Paget's disease and primary hyperparathyroidism: sex distribution, histomorphometry, and prediction of the skeletal response to parathyroidectomy. 1059 60

Bisphosphonates are synthetic analogues of pyrophosphate that inhibit bone resorption by their action on osteoclasts. Bisphosphonates have been extensively used in the elderly with primary and secondary osteoporosis, Paget's disease, and hypercalcemia of malignancy. In recent years, bisphosphonates have been used to treat children acutely for resistant hypercalcemia and chronically for various metabolic bone diseases. The theoretical concerns of possible adverse effects of these drugs on the growing skeleton have not been proven to be true. In the present review, we have critically analyzed the available literature on bisphosphonate therapy in both adult and pediatric clinical trials. Although not yet approved by the FDA for use in children, bisphosphonates, from published experience, demonstrate benefit to the child with no serious adverse effects. Based on the literature analysis the review furnishes detailed recommendations and practical guidelines regarding the use of oral and intravenous bisphosphonates in children. Bisphosphonates might be the first agents to provide the pediatrician with an opportunity to treat mineral and bone disorders of childhood, which until recently did not have satisfactory therapy.
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PMID:Bisphosphonates: from grandparents to grandchildren. 1061 61

The commercial availability of peptides and proteins and their advantages as therapeutic agents have been the basis for tremendous efforts in designing delivery systems for such agents. The protection of these agents from biological fluids and physiological interactions is crucial for the treatment efficacy. One such agent is salmon calcitonin, a 32 amino-acid polypeptide hormone used in the treatment of bone diseases such as Paget's disease, hypercalcemia and osteoporosis. Researchers have studied different routes to deliver salmon calcitonin more effectively, including nasal, oral, vaginal and rectal delivery. These systems are designed to protect the polypeptide from the biological barriers that each delivery route imposes. Oil-based and polymer-based delivery systems are discussed.
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PMID:Transmucosal delivery systems for calcitonin: a review. 1081

Bisphosphonates, analogs of pyrophosphate, bind to bone at sites of active bone remodeling. In clinical settings of rapid bone turnover and/or excessive osteolytic activity, they have been shown to have beneficial clinical effects. These settings include Paget's disease of bone, osteoporosis from a variety of clinical causes, and malignant bone disease. Bisphosphonate inhibition of osteolysis in cancer has been shown to be effective therapy for malignancy-associated hypercalcemia and as adjunctive therapy for the delay or prevention of cancer-related skeletal morbidity, including bone pain, pathologic fractures, and need for radiation therapy. Animal models of bone metastasis prevention by bisphosphonate treatment have provided the preclinical background for the adjuvant use of bisphosphonates in primary cancers. The success of these clinical trials has provided strong impetus for new research on bone disease and malignancy, as well as the development and testing of new and more potent bisphosphonates. Semin Oncol 28:284-290.
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PMID:The evolving role of bisphosphonates. 1140 38

Salmon calcitonin (sCT) is widely used therapeutically in the treatment of patients with postmenopausal osteoporosis, Paget's disease, and some forms of hypercalcemia. Preparations of synthetic calcitonin peptides of high purity and reproducibility are now routinely produced and physicochemical methods, particularly reverse-phase high-performance liquid chromatography (RP-HPLC), are replacing the in vivo biological assay for monitoring and calibration. Although the bioassay is no longer required for routine batch control in Europe, calcitonin bioassays are still required in some countries and in the development of new products. Stocks of the Second International Standard (IS) for salmon calcitonin are now depleted and, to replace it with a new calibrant, an international collaborative study was organized in which the aims were to: determine the activity of the candidate sCT by in vivo bioassay in terms of the second IS; assess the stability of the preparation after accelerated thermal degradation; estimate the purity of the ampouled candidate preparation; and determine the sCT content in gravimetric units by HPLC. The HPLC data in terms of ampoule content were in good agreement giving an estimate of 23.1 (coefficient of variation [CV] 3.8%) microg per ampoule. The HPLC chromatograms revealed a small, but detectable, degree of heterogeneity, which possibly occurred during the formulating or ampouling procedures, resulting in a reduction in monocomponent content (purity) from 96% to 92%. The biological activity of the ampoule contents in international units (IU) was calculated from the mass value and the internationally agreed-upon figure of 6000 IU/per mg for the specific activity of salmon calcitonin. This gave a value of 138 IU per ampoule, which was in good agreement with the biological assay estimate (140 IU per ampoule). The preparation of sCT was subsequently adopted as the Third International Standard by the World Health Organization with an assigned content of 138 IU per ampoule.
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PMID:Multicenter collaborative study to calibrate salmon calcitonin by bioassay and high-performance liquid chromatography: establishment of the third international standard. 1147 96


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