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)

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.
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PMID:Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone. 950 93

Bisphosphonates regulate bone turnover by inhibiting osteoclastic bone resorption. Due to their pharmacodynamic and pharmacokinetic characteristics, bisphosphonates have a special pharmacotoxicological profile related to their high degree of specificity: low or non-existent distribution in soft tissues and strong affinity for calcified tissues. Some general conclusions may be drawn from the pre-clinical toxicological studies, whose main aim is to identify the toxicity target organ/s and estimate the safety margins of a "prospective therapeutic agent" in laboratory animals. They are based on our own results and on data from the available literature as regards various bisphosphonates: Alendronate, Clodronate, Etidronate, Olpadronate and Pamidronate. Generally, very high doses of bisphosphonates are required to produce in different levels and incidence various extra-skeletical toxic side effects: local reaction, hypocalcemia (and its consequences on the cardiovascular system and the possibility of tetany), affection of the dental structures and renal dysfunction. Most of side effects may be related to the low solubility in biological fluids, the formation of calcium complexes, the potent inhibitory effect of endogenous or induced bone resorption as well as to its main excretion pathway. Some other side effects (on the eye, lungs and liver), may be related to repeated excessive high doses. A safety margin of 200 to 300 : 1 between the "toxic" and "pharmacological" doses may be estimated if the total quantity of Olpadronate given to various animal species in toxicological studies and in pharmacodynamic experimental models (osteopenias due to estrogen deprivation or immobilization and retinoid-induced hypercalcemia) is considered. If the toxic doses in animals are related to the highest doses suggested for human beings, then the ratio increases from 300 to 1000 : 1 depending on the pathology and the route of administration. As regards their effect on the bone, experimental data with the new bisphosphonates suggest a significant dissociation between pharmacologically active doses and those ones producing defective mineralization. The excessive inhibition of bone remodelling, due to the use of high doses in normal animals, is the natural consequence of the pharmacological effect of this family of compounds. A bisphosphonate's toxic potential effect on bone should not be evaluated in normal animals but in particular situations with a high bone turnover. Furthermore, the doses should be adjusted in order to regulate the magnitude of bone remodelling inhibition so as to take it to a normal level without totally suppressing it. Potency, safety margins, doses and proper administration schemes, should be considered as key elements for the optimum use of the therapeutic potentiality of these compounds.
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PMID:[Preclinical toxicology of bisphosphonates]. 956 61

Bone metastases are common in patients with breast cancer and cause considerable morbidity and deterioration of the quality of life. The main pathogenetic mechanism is stimulation of osteoclastic bone resorption by factors produced by the cancer cells. Pamidronate given intravenously suppresses bone resorption and is an effective treatment of malignancy-associated hypercalcemia. Recent data indicate that it can also reduce skeletal morbidity in normocalcemic patients with breast cancer and osteolytic metastases. In a series of studies we examined the long-term efficacy of oral pamidronate in the prevention and treatment of skeletal metastases in patients with breast cancer. In patients with bone metastases oral pamidronate given for a median period of about 20 months reduced significantly skeletal morbidity and had a favourable effect on selective aspects of the quality of life of the patients. Treatment did not alter the radiological course of the disease or the overall survival of the patients. In contrast, oral pamidronate given to patients with advanced breast cancer but no demonstrable bone metastases did not prevent or delay the appearance of the first clinical or radiological manifestation of bone metastases. This treatment is therefore very effective in patients with established metastatic bone disease. More studies are needed to define the place of pamidronate (and of other bisphosphonates) in the prevention of bone metastases in patients at risk.
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PMID:Oral pamidronate in the prevention and treatment of skeletal metastases in patients with breast cancer. 956 63

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal-related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi-centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha-interferon) treatment. With a median treatment duration of about 550d, no statistically significant reduction in skeletal-related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P=0.02) and a decreased reduction of body height of 1.5 cm (P= 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.
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PMID:Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Danish-Swedish co-operative study group. 960 23

Pamidronate is an effective drug used not only in patients with tumor-associated hypercalcemia, but also in normocalcemic patients with metastatic bone disease to relieve pains. We describe a 39-year-old normocalcemic patient with subclinical hypoparathyroidism and bone metastasis due to breast carcinoma. Following parenteral administration of 60 mg pamidronate, the corrected serum level of calcium decreased from 2.12 mmol/l (=8.9 mg/dl) to 1.42 mmol/l (5.7 mg/dl), accompanied with carpal pedal spasm. The present case indicates that the hypocalcemia due to latent hypoparathyroidism was compensated by extensive osteolysis due to bone metastasis, and that overt hypocalcemia may develop after intravenous administration of pamidronate in such a patient.
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PMID:Symptomatic hypocalcemia in a patient with latent hypoparathyroidism and breast carcinoma with bone metastasis following administration of pamidronate. 963 Feb 1

Human hypercalcemia of malignancy (HHM) is generally due to the release into the circulation of parathyroid hormone-related peptide (PTHrP). PTHrP stimulates osteoclastic bone resorption and renal calcium reabsorption through the activation of a receptor similar to that of PTH (PTH-R). However, there is scarce information about the PTH-R regulation in the setting of the hypercalcemia. In the present study, we assessed the molecular basis of renal PTH-R regulation in Walker tumor-bearing rats either treated or not by a bisphosphonate, pamidronate. Twenty-seven 6-week-old rats were randomly divided into three experimental groups: WC- APD- (9 control rats), WC+ APD- (9 Walker tumor-bearing rats), and WC+ APD+ (9 Walker tumor-bearing rats receiving 15 mg/kg/day of sodium pamidronate every day for seven days). Pamidronate induced a significant decrease in the mean tumor weight (9.3+/-0.8 vs 6.3+/-0.6 g). Seven days after the subcutaneous implantation of the Walker cells, plasma total calcium was 10.8+/-0.4, 16.8+/-0.6, and 12.9+/-0.6 mg/dl in WC- APD-, WC+ APD-, and WC+ APD+, respectively. Plasma PTHrP concentration was undetectable, 15.9+/-2.6, and 7.2+/-1.4 pmol/l, respectively. Bone histomorphometric results showed high resorption in WC+ APD-, which returned below the basal level of the WC- APD- with pamidronate treatment. Densitometric analysis of Northern blots revealed that the renal PTH-R mRNA expression in WC+ WPD- rats was a quarter of the levels in the WC- APD- and WC+ APD+ groups. WC+ APD- also had a decreased PTH-stimulated cAMP production in renal membranes. The PTH-R was expressed in the Walker tumor and it was not modified by pamidronate treatment. In conclusion, the expression of PTH-R receptor mRNA is significantly reduced in the kidney of rats bearing Walker carcinoma tumor. Its regulation is tissue-specific: pamidronate, which partially corrected the hypercalcemia and elevated circulating PTHrP, normalized the PTH-R mRNA expression in the kidney but not in the tumor.
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PMID:Pamidronate corrects the down-regulation of the renal parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor mRNA in rats bearing Walker tumors. 966 83

Pamidronate constitutes a major advance in the treatment of tumor-associated hypercalcemia. However, transient electrolyte abnormalities have been reported after pamidronate administration. We describe here a patient with multiple myeloma and severe hypercalcemia who developed transient but significant electrolyte disturbances (mainly hypophosphatemia and hypomagnesemia) after a single dose of 90 mg of pamidronate, focusing on the underlying pathophysiological mechanisms.
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PMID:Multiple electrolyte abnormalities after pamidronate administration. 967 36

Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.
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PMID:The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. 987 May 69

We report four children with advanced liver disease awaiting liver transplantation who developed moderately severe hypercalcemia (range: 1.65-2.40 mmol/L) while receiving total parenteral nutrition. Hypercalcemia had been unresponsive to cessation of calcium intake and therapy with loop diuretics and calcitonin. One or two intravenous doses of disodium pamidronate (35-50 mg/m2) resulted in normalization of plasma calcium concentration within 2-4 d in all four children. Pamidronate may be useful for children with hypercalcemia associated with liver disease.
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PMID:Use of disodium pamidronate in children with hypercalcemia awaiting liver transplantation. 1008 49

Case 1: A 43-year-old woman underwent mastectomy because of locally advanced breast cancer with multiple bone metastases. She was treated with CMF therapy but developed a compression fracture of a thoracic vertebra after 10 months and received pamidronate therapy. Pamidronate administration relived her back pain after 2 months and she was able to walk again after 3 months. However, she developed a resistance to the treatment, and then refused another treatment. She was found to have hypercalcemia 6 months later and received pamidronate again, but died 9 months after the treatment. Case 2: A 52-year-old woman underwent mastectomy because of breast cancer (T2) and was diagnosed as having multiple bone metastases 24 months after the operation. She could not turn over in bed due to progressing bone pain and received pamidronate therapy with CMF therapy at home 23 months after the diagnosis. After 2 months, pamidronate administration relieved her bone pain and she was free of pain after 4 months. After 5 months, X-rays revealed that lytic lesions showed sclerosis, and the pamidronate therapy was assessed as producing a PR. Pamidronate therapy improved her quality of life and activities of daily living, and she continues to receive it this time as an outpatient. Pamidronate therapy is promising as an effective treatment for bedridden patients with bone metastasis from breast cancer.
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PMID:[Two bedridden patients with bone metastases from breast cancer effectively treated with pamidronate therapy]. 1105 29


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