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)

Alendronate (aminohydroxybutylidene bisphosphonate) is a potent inhibitor of bone resorption but the role of the duration of intravenous infusion in its efficacy profile is unclear. In a two-centre, parallel, randomized, double-blind study, 20 patients with tumoral hypercalcemia received a single 10-mg i.v. infusion over either 2 h (group A, n = 10) or 24 h (group B, n = 10). Recurrences (n = 6) were retreated using the same regimen. Pretreatment plasma calcium (Ca) was 3.32 +/- 0.08 mM (mean +/- SEM) for all patients. Treatment A and B were associated with similar temporal profiles for onset, time to reach normocalcemia, (6 vs 5 days), nadir (day 6: 2.45 +/- 0.06 vs 2.43 +/- 0.08 mM) and time to relapse (day 21). Normocalcemia (2.15-2.55 mM) was achieved in seven (A) and nine (B) patients with other cases being partial responders (Ca: 2.65-2.76 mM). A significant decrease of urinary calcium and hydroxyproline excretion and a significant increase of PTH accompanied Ca normalization in both groups. Ca response was 50% lower on 2nd treatment with alendronate. Both treatments were well tolerated with transient mild fever being the most common adverse experience. In conclusion, whether infused over 2 or over 24 h, a single dose of 10 mg alendronate led to normalization of tumoral hypercalcemia in a large majority of cases.
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PMID:Comparison of a rapid (2-h) versus a slow (24-h) infusion of alendronate in the treatment of hypercalcemia of malignancy. 139 97

The inhibitory effect of murine interferon gamma (muIFN gamma) on humoral hypercalcemia in nude mice bearing lower-jaw cancer (LJC-1-JCK), in which parathyroid-hormone(PTH)-related protein is responsible for causing humoral hypercalcemia by activating bone resorption, was examined in comparison with that of a new bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). muIFN gamma was injected into tumor-bearing nude mice for 5 days before the establishment of hypercalcemia. The increase of plasma calcium concentration was delayed and this effect continued for more than 6 days even after the injection was stopped. Alendronate markedly suppressed hypercalcemia in tumor-bearing nude mice but this inhibitory effect continued for less than 6 days. Neither muIFN gamma nor alendronate affected the tumor volume or serum PTH-related protein concentration. Injection of muIFN gamma into mice for 3 days almost completely abolished the formation of multinucleated osteoclast-like cells from bone marrow cells in vitro, whereas injection of alendronate into mice had no effect. These findings suggested that muIFN gamma suppressed the formation of osteoclasts, resulting in the prolonged decrease of plasma calcium concentration in hypercalcemic tumor-bearing nude mice, whereas alendronate is cytotoxic to functionally mature osteoclasts and inhibited osteoclastic bone resorption, resulting in a marked decrease in the plasma calcium concentration in tumor-bearing hypercalcemic nude mice.
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PMID:Comparative study of inhibitory effects by murine interferon gamma and a new bisphosphonate (alendronate) in hypercalcemic, nude mice bearing human tumor (LJC-1-JCK). 752 63

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

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclosed that systemically administered alendronate is rapidly taken up by bone tissues to the extent of 60% to 70% of the dose and excreted by the kidney, 30% to 40% in 24 hr, and that renal excretion is the only route of elimination. This study was designed to explore the effect of calcium on plasma protein binding and the renal handling of alendronate. The binding of alendronate to rat plasma was concentration, pH and calcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 micrograms/ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasing pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualitatively similar. Under steady-state conditions, the binding of alendronate was substantially lower in hypocalcemic rats but unchanged in hypercalcemic rats. Although hypocalcemia caused a significant decrease in the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hypercalcemia resulted in a substantial decrease of renal secretion of all three compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of calcium in plasma protein binding and renal handling of alendronate in hypo- and hypercalcemic rats. 824 40

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

Alendronate is a powerful therapeutic agent for the treatment of hypercalcemia in malignancy and osteoporosis and has recently been developed as a treatment for hypercalcemia of malignancy. In this study, time-lapse cinemicrography was used to investigate the effects of this agent on the morphology and the motility of human osteoclast-like multinucleated cells (MNCs) from human bone marrow. Alendronate at 10(-5)M induced contraction of the cells starting 7.5 h after its addition. Contraction was markedly induced immediately after alendronate removal. However, contraction almost disappeared 18h after removal, and osteoclast-like MNCs recovered their original sizes and shape. There was only partial recovery from contraction after alendronate treatment at 10(-4)M. In contrast, untreated control cells did not change their morphology after washing with culture medium. Motility analysis showed that osteoclast-like MNCs treated with 10(-5)M alendronate moved actively after washing, but at 10(-4)M the motility locus was very narrow. At 10(-4)M, the actin ring in the cells began to break down, beginning 6h after addition. The effects of alendronate on human osteoclast-like MNCs morphology and motility were reversible at 10(-5)M, suggesting that alendronate dose not cause any cellular damages in human osteoclasts up to 10(-5)M, which is an effective dose for bone resorption.
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PMID:Reversibility of alendronate-induced contraction in human osteoclast-like cells formed from bone marrow cells in culture. 1034 Jun 36

Alendronate, a bisphosphonate compound, lowers serum calcium in patients with cancer-associated hypercalcemia through its inhibitory effect on bone resorption and as a result symptoms associated with hypercalcemia improve. This study was carried out to investigate the effects of alendronate in patients with hypercalcemia due to bone metastasis of hepatocellular carcinoma (HCC). Two patients were evaluated. Their corrected serum calcium and alpha-fetoprotein (AFP) levels and their computed tomography (CT), bone scintigraphy and magnetic resonance imaging (MRI) findings were evaluated before and during alendronate treatment. After treatment, not only the corrected serum calcium levels but also AFP levels and bone pain decreased; in addition, the regression of the metastatic focus was noted in the MRI analysis. These tumor inhibitory effects of alendronate have not been reported in HCC before; and alendronate might serve to prevent bone metastases in patients with HCC. In conclusion, two patients who developed hypercalcemia associated with bone metastasis after surgery for HCC were treated with alendronate and they experienced alleviation of the pain due to bone metastasis, improvement of their quality of life and a marked decrease in AFP levels with tumor regression.
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PMID:Effects of alendronate on bone metastases and hypercalcemia after surgery for hepatocellular carcinoma. 1109 40

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED(50) of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
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PMID:Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). 1216 45

Alendronate and other bisphosphonates are clinically efficacious in treating postmenopausal osteoporosis, Paget's disease and hypercalcemia associated with malignancy. Because bisphosphonates are being considered for use in younger patients with joint replacements to prevent osteolysis, and for stress fracture prophylaxis in military recruits, it is important to know how bisphosphonate therapy affects healthy bone. We sought to determine whether bones from healthy male dogs exhibit alterations in structural or mechanical properties following alendronate treatment for 23 weeks. We tested trabecular tissue samples in compression and determined tissue ash density. We tested whole long bones in bending and torsion. For trabecular samples, we evaluated trabecular modulus, strength, and density. For whole bone specimens, we compared structural stiffness and ultimate load. We found no significant differences in any measure, between canines treated with alendronate for 23 weeks and controls, although we found consistent trends toward higher properties in the treated group. Correlation analysis revealed significant relationships between stiffness and strength measures for each mechanical test. Our results indicate bisphosphonate treatment in healthy canines does not weaken the properties of bone. The trends indicate a slight positive overall effect of alendronate treatment on the mechanical properties of healthy canine bone.
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PMID:Mechanical evaluation of bone samples following alendronate therapy in healthy male dogs. 1604 23

A combined therapy with the strongly antiresorptive Alendronate and the pleiotropically acting D-hormone analogue Alfacalcidol may have additive effects on bone quality, falls and fracture risk in established osteoporosis. The aim of this study (Alfacalcidol Alendronate Combined-AAC) was to compare the efficacy and safety of a combined parallel therapy with Alendronate and Alfacalcidol to the treatment with either Alendronate in combination with plain vitamin D or Alfacalcidol alone in patients with established postmenopausal or male osteoporosis. Ninety patients were included as matched triplets to receive randomly either 1 microg Alfacalcidol daily + 500 mg calcium (group A, n = 30) or 70 mg Alendronate weekly + 1,000 mg calcium + 1,000 IU vitamin D daily (group B, n = 30) or 1 microg Alfacalcidol daily + 70 mg Alendronate weekly + 500 mg calcium daily (group C, n = 30). Patients were recruited in one centre and were followed up for 24 months. Analysis was intention-to-treat and the primary outcome was lumbar spine and total hip bone mineral density (measured observer blind). BMD was measured at the lumbar spine and at the proximal femur with dual energy X-ray absorptiometry (LUNAR Prodigy, GE, USA) at the beginning and after 12 and 24 months. During the 2-year-study we observed descriptively significant increases at the lumbar spine of 3.0% in group A compared to baseline, of 5.4% in group B and of 9.6% in group C, respectively. The superiority of the Alendronate + Alfacalcidol treatment group over Alfacalcidol alone and over Alendronate + vitamin D was of more than large rele-vance (both tests: MW > 0.71; CI-LB > 0.64; P < 0.001). We also observed median increases of the BMD at the total hip of 1.5% in group A, of 2.4% in group B and of 3.8% in group C, respectively. The superiority of group C over group A and over group B again was relevant and statistically significant in a descriptive sense. After 2 years there was a tendency towards higher rates of vertebral and non-vertebral fractures in group A and B as compared to C. Taking both fracture types together we observed 9, 10 and 2 "osteoporotic fractures" in groups A, B and C, respectively. The comparison of group C with pooled groups A and B and with each single group gave a relevantly lower fracture rate for the combination of Alendronate and Alfacalcidol. Furthermore a lower rate of falls was observed for the combination Alendronate plus Alfacalcidol versus Alendronate + vitamin D, but not versus Alfacalcidol alone. We found 80% of the patients in the Alendronate + Alfacalcidol group free from back pain at month 24, compared to 30% in the Alendronate + vitamin D and 43% in the Alfacalcidol monotherapy group. The superiority is relevant (both tests: MW > 0.64; CI-LB > 0.56; P < 0.003). Pain decrease also occurred more rapidly in the Alendronate + Alfacalcidol group than in the other groups. In general side effects in all groups were mild, and only four cases of moderate hypercalcuria in group A and one in group C were reported, but no case of hypercalcemia was documented. In conclusion, the combination therapy with Alendronate and Alfacalcidol exhibited superiority in terms of BMD, overall fractures, rate of falls and back pain over either Alendronate in combination with plain vitamin D or Alfacalcidol alone. The overall safety profiles of the three treatment regimens were found to be not different in this study.
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PMID:Superiority of a combined treatment of Alendronate and Alfacalcidol compared to the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial). 1721 77


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