Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zoledronate (CGP 42446) is a third generation imidazole ring containing bisphosphonate that has been found in animal studies to be up to 850 times more potent than pamidronate. In this first study reporting the effects of this drug in humans, 16 patients with active Paget's disease of bone [baseline serum alkaline phosphatase activity (SAP) at least twice the upper limit of normal] were treated in a fixed ascending dose-ranging protocol with a single 1-hour infusion of either 24, 72, 216, or 400 microg of zoledronate (four patients per dose). SAP and two markers of bone resorption, 24-hour urinary hydroxyproline/creatinine excretion (OHP) and 24-hour urinary calcium/creatinine excretion, were measured at baseline, 24 hours postinfusion (day 1) and on postinfusion days 3, 7, 10, and 14. Safety parameters including vital signs, hemogram, and chemistries were measured at the same time points. At the 24- and 72-microg doses there were no consistent or meaningful changes in the bone resorption markers. However, with the 216 microg dose, urinary OHP decreased from baseline by a mean of 16-19% on days 3, 7, 10, and 14; with the 400 microg dose, OHP decreased by a mean of 33-48% at days 1, 7, and 10 and by 16% at day 14. Urinary calcium/creatinine decreased from baseline with the 216 microg dose by a mean of 15-40% on days 1, 3, 7, 10, and 14 and with the 400 microg dose by a mean of 55-71% on days 3, 7, 10, and 14. As expected, there was no reduction in SAP during the 14-day postinfusion period. There was no evidence of an acute phase reaction (pyrexia, myalgia, or arthralgia), leukopenia, or renal or hepatic toxicity. We conclude that single infusions of microgram amounts of zoledronate were capable of inhibiting bone resorption in patients with active Paget's disease during a 2-week study interval. This anti-bone resorbing effect was not associated with any clinically or biochemically observed toxicity. This potent new bisphosphonate appears to be a promising compound for the management of skeletal disorders characterized by increased bone resorption.
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PMID:Antiresorptive effect of a single infusion of microgram quantities of zoledronate in Paget's disease of bone. 911 57

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

In an attempt to increase the life of cementless prostheses, an hydroxyapatite-coated implant which releases a bisphosphonate has been suggested as a drug-delivery system. Our in vitro study was designed to determine the maximum dose to which osteoblasts could be safely exposed. Our findings demonstrated that zoledronate did not impair the proliferation of human osteoblasts when used at concentrations below 1 microm. Murine cells can be exposed to concentrations as high as 10 microm.A concentration of 0.01% of titanium particles did not impair the proliferation of either cell line. Zoledronate affected the alkaline phosphatase activity of murine osteoblasts through a chelation phenomenon. The presence of titanium particles strongly decreased the alkaline phosphatase activity of murine osteoblasts. We did not detect any synergic effect of zoledronate and titanium particles on the behaviour of both human and murine osteoblasts.
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PMID:The effect of bisphosphonates and titanium particles on osteoblasts: an in vitro study. 1604 57

Zoledronate, an aminobisphosphonate with potent antiresorptive activity in bone, has the potential for treatment of malignant osteolysis and hypercalcemia in dogs. The purpose of this study was to evaluate the bone metabolic effects of a single dose of zoledronate in healthy dogs. Four skeletally mature, male, intact dogs received a 15-minute i.v. infusion of zoledronate at a dosage of 0.25 mg/kg. Urine N-telopeptide of type I collagen (NTx) excretion decreased significantly from baseline by 76, 63, 77, and 73% on days 7, 14, 21, and 28, respectively (P < .0125). Serum bone-specific alkaline phosphatase (bALP) decreased significantly from baseline by 36 and 42% on days 21 and 28, respectively (P < .0125). No changes were detected in indices of calcium homeostasis (ionized calcium, intact PTH, or urine calcium excretion). Single-dose i.v. zoledronate at 0.25 mg/kg appears to inhibit homeostatic osteolytic activity in healthy, skeletally mature dogs. Prospective studies should assess repeated-dose safety and activity in healthy and diseased animals of various age groups.
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PMID:Bone metabolic effects of single-dose zoledronate in healthy dogs. 1635 93

Paget's disease is a relatively common high-turnover metabolic bone disease that can serve as a model for osteoporosis and other metabolic bone diseases in investigation of therapeutic strategies to normalize bone turnover. Aims of treatment include rapid normalization of bone formation and resorption to prevent loss of mechanical integrity. Treatment will also reduce pain, while long-term maintenance of normal turnover may prevent long-term complications. Newer bisphosphonates have high antiresorptive potency and increased retention in bone, permitting a strategy of intermittent intravenous (IV) administration in achieving and maintaining normal bone turnover. In pivotal zoledronic acid Paget's disease trials, patients received a single 15-min IV infusion of zoledronic acid 5 mg (ZOL 5 mg) or risedronate 30 mg/day orally for 2 months. Treatment with ZOL 5 mg was associated with significant improvement in serum alkaline phosphatase, normalization in both the short and long term, and significant prolongation of biochemical therapeutic response in long-term follow-up. No changes in serum creatinine levels were observed with either treatment, and no clinically significant renal abnormalities were reported. Intermittent IV administration of potent bisphosphonates constitutes an intriguing strategy for treatment of Paget's disease and other metabolic bone diseases.
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PMID:Pharmacological therapy of Paget's and other metabolic bone diseases. 1640 63

Bone pain and bone deformities are the most common manifestations of Paget's disease of bone, even if the diagnosis is nowadays most often made by chance following a routine measurement of serum alkaline phosphatase. Woven bone is formed following a marked increase in bone resorption due to a stimulation of osteoclast activity. Biphosphonates constitute the modern treatment of Paget's disease of bone. Tiludronate (Skelid), or better risedronate (Actonel), are administered orally every day during at least 2 months. Zoledronic acid (Aclasta), as a single 15-min 5 mg infusion, has been recently compared to risedronate, 30 mg/d orally for 2 months, in two randomized studies including 357 patients. Zoledronic acid had a superior therapeutic efficacy, as judged by its rapidity of action, the duration of the biochemical response and the percentage of responders. Thus, at 6 months, alkaline phosphatase levels were normalized in 89% of the patients in the zoledronic acid group as compared to 58% in the risedronate group. The most frequent side effect was a flu-like syndrome, observed in 10% of the patients. An adequate intake of calcium and vitamin D is recommended to avoid posttreatment hypocalcemia. The introduction of Aclasta should simplify and improve the therapeutic management of Paget's disease of bone.
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PMID:[Treatment of Paget's disease of bone with zoledronic acid]. 1645 55

Zoledronic acid inhibits bone resorption for up to 12 months. It is not known whether the duration of this antiresorptive effect extends beyond this period of time. The aim of this study was to evaluate the changes in bone turnover at 12 months (T12) and 18 months (T18) after a single injection of 4 mg of zoledronic acid. It is a prospective, longitudinal study, with a follow-up for 18 months. We studied male and female patients (60.5 +/- 11.0 years old), with low bone mineral density (BMD) coming from the outpatient clinic in a metabolic bone unit of a tertiary care hospital. All patients received a single intravenous dose of 4 mg of zoledronic acid, bone turnover markers [serum carboxyterminal telopeptide of type I collagen (CTX-I), bone-specific alkaline phosphatase (BSAP)] and BMD [lumbar spine (LS) and total hip (TH)] were measured at baseline, and after 12 months (T12) and 18 months (T18). Median serum CTX-I and BSAP levels were suppressed at T12 in comparison with baseline values: 0.183 to 0.039 ng/ml for CTX-I (p = 0.0002) and 16.95 to 13.96 U/l for BSAP (p = 0.005). At T18, both CTX-I and BSAP continued to be suppressed below baseline at 0.108 ng/ml and 12.23 U/l (p = 0.009 and p = 0.02, vs. T0). Significant increases in BMD at T18 as compared with T12 were observed in patients (median increase 6.1% for LS and 2.0% for TH). Zoledronic acid inhibits bone turnover effectively for 12 months, with evidence for continued suppression and gains in BMD even after 18 months.
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PMID:Bone turnover 18 months after a single intravenous dose of zoledronic acid. 1750 70

Paget's bone disease is a disorder in which bone regions with high turnover are replaced by new, vascular, but disorganized and immature bone with excessive fibrosis, high tendency of deformity and diminished mechanical resistance. Treatment aims at the suppression of osteoclast activity and is achieved with bisphosphonates, which represent the treatment of choice for Paget's disease. Zoledronic acid, a relatively new member of this class, normalizes alkaline phosphatase in the majority of patients and has a favorable safety profile. We report the case of an asymptomatic patient who was diagnosed with Paget's disease based on typical biochemical, radiological and histological findings and was treated with a single intravenous infusion of 4 mg of zoledronic acid. No side effects were observed. Alkaline phosphatase levels normalized within four months. At the last follow up examination, three years after treatment, the patient remains asymptomatic, without significant changes in radiology imaging, and alkaline phosphatase levels are still within the normal range. In conclusion, zoledronic acid, apart from being safe and effective in Paget's disease, also appears to be able to achieve significantly prolonged remissions.
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PMID:Persistent effect of zoledronic acid in Paget's disease. 1763 47

Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There was a decrease in cell migration at >or=10 micromol/L concentrations, but invasion was inhibited at a much lower dose of 0.1 micromol/L. Reverse transcription-PCR showed that ZOL overall caused an increased expression of osteocalcin and decreased expression of alkaline phosphatase, osteopontin, osteonectin, and vascular endothelial growth factor, with no change in expression of osteoprotegerin. ZOL administration s.c. twice weekly at 0.12 mg/kg to SaOS-2 tumor-bearing mice resulted in primary tumor growth inhibition, reduction in lung metastases, and dramatic decrease in osteolysis. Furthermore, in the ZOL cohort, there was a clear reduction in the number of osteoclasts in bone exposed to tumor and a lower tumor vessel density. These data point to the adjuvant potential of ZOL in the management of osteosarcoma not only for its antiosteolytic properties but also for its ability to directly halt tumor cell growth and metastasis via its effects on viability, invasion, differentiation, and angiogenesis.
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PMID:Zoledronic acid inhibits osteosarcoma growth in an orthotopic model. 1808 20

Zoledronic acid (ZA) delays the onset or reduces the incidence of skeletal complications in breast cancer patients with bone metastases. However, there are few data on the long-term renal safety of ZA. We retrospectively evaluated 43 breast cancer patients with bone metastases who received ZA more than 24 months. The following parameters measured prior to first ZA use and after the last dose of ZA administration were compared: serum creatinine (SCr), blood urea nitrogen (BUN), alkaline phosphatase (ALP), calcium (Ca), and phosphorous (P). Forty-three breast cancer patients with documented bone metastases were evaluated. Median age at the start of treatment was 53 years (range 37-77). Median overall duration of ZA administration was 36 months (25-62). There were no statistically significant differences in the pre- and post-treatment levels of SCr, BUN, Ca and P. However, ALP levels after long-term ZA administration were decreased significantly (P<0.05). More than 24 months of ZA administration did not adversely affect the renal function. ZA can be used safely in breast cancer patients with bone metastases beyond 2 years.
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PMID:Renal safety of zoledronic acid administration beyond 24 months in breast cancer patients with bone metastases. 1819 80


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