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)

Tiludronate, a potent bisphosphonate, has been extensively evaluated in the treatment of Paget's disease of bone. Its ability to normalize bone turnover without impairing mineralization suggests that tiludronate represents an important therapeutic advance in the treatment of this progressive and disabling disease. Recent attention has focused on the development of appropriate short- and long-term treatment goals: namely the control of clinical symptoms, such as bone pain, and the reduction of bone turnover to within normal range, to lessen the risk of developing later complications, such as deafness, deformity and walking difficulties. This reduction of bone turnover is the primary aim of treatment. The clinical development of tiludronate has involved large-scale international multicenter trials. To allow the comparison of results obtained in a variety of clinical settings, great emphasis was placed on the use of consistent methodology across the program. This applied to patient selection, trial design, the evaluation of clinically meaningful effects of treatment and statistical analysis of results. Strict adherence to these principles has allowed us to compare the results of treatment with tiludronate in 85 centers in six countries across Europe. This paper illustrates the importance of clinical trial design in the evaluation of tiludronate and etidronate in the treatment of Paget's disease of bone, with a brief summary of results obtained from a recent comparative, prospective, double-blind, multicenter clinical trial. Effective suppression of bone turnover was assessed by monitoring the reduction in serum alkaline phosphatase and the ratio of urinary hydroxyproline/creatinine. Reduction in bone pain was assessed using Huskisson's visual analog scale. The results clearly show that tiludronate 400 mg/day for 3 months is more effective and as equally well tolerated as etidronate 400 mg/day.
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PMID:The methodology of clinical trials of oral tiludronate in Paget's disease of bone. 857 26

A multicentre, randomised, placebo-controlled, dose-ranging study was conducted to investigate the therapeutic activity and sustained efficacy of tiludronate (200 mg, 400 mg and 600 mg once daily) taken orally for 12 weeks in patients with Paget's disease. Serum alkaline phosphatase concentrations were compared with baseline at weeks 12 and 24; treatment success was defined as a 50% reduction compared with baseline. Changes in the hydroxyproline: creatinine ratio were also measured. Pain was assessed using the Huskisson Visual Analogue Scale and by questionnaire. Patients completing at least 11 weeks of treatment were followed-up 18 months later by postal questionnaire. Significantly greater numbers of patients in the tiludronate groups successfully responded to treatment compared with the placebo group. A dose-response was observed; the percentage of patients responding to treatment being 31% (200 mg), 52% (400 mg) and 82% (600 mg) at week 12 and 45% (200 mg), 70% (400 mg) and 82% (600 mg) at week 24. Tiludronate treatment also significantly reduced hydroxyproline: creatinine ratios compared with placebo, again showing a dose response. Dose-related gastrointestinal symptoms were the commonest adverse events, occurring in 2.4%, 11.0%, 5.5% and 18.9% of patients receiving placebo and tiludronate 200, 400 and 600 mg daily, respectively. The response to oral tiludronate was sustained for more than 18 months in some patients and there was evidence of a reduction in the longer term complications of the disease. These results show that oral tiludronate is an effective, well-tolerated treatment for Paget's disease; the 400 mg once daily dose appears to offer the optimum balance of efficacy and tolerance.
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PMID:A double-blind, multicentre, placebo-controlled study of tiludronate in Paget's disease of bone. 930 42

Tiludronate, an oral bisphosphonate used to treat Paget's disease of bone, is currently being studied as a treatment for osteoporosis. A multicenter, open-label, parallel-group study was performed to compare the efficacy of two tablet formulations of tiludronate in the treatment of Paget's disease. Eighty-eight patients with active Paget's disease were recruited. The diagnosis was based on radiologic evidence of bone lesions, and all patients included in the study had serum alkaline phosphatase (SAP) levels equal to or more than twice the upper normal value of the local laboratory that assayed the sample. Each patient received treatment with oral tiludronate 400 mg/d for 84 +/- 2 days; 39 patients received the previously tested tablet formulation 3C1, and 49 patients received formulation 9O1, which is prepared using an improved manufacturing technique. The objective of this study was to determine whether the two formulations have an equivalent therapeutic effect, the primary end point being SAP levels in both groups after 3 months of treatment. This equivalence is commonly assessed by comparing pharmacokinetic data; however, in previous studies of tiludronate, large intra-individual variability prevented statistically valid comparisons of the data. Therefore, in addition to pharmacokinetic data, biochemical and clinical response data were collected during the trial. The secondary objectives of the trial were to measure the plasma levels and to assess the efficacy and safety of the two tiludronate formulations. The relative pharmacologic activities of the two formulations were assessed by comparison of the confidence intervals of levels of SAP at monthly intervals. After 3 months of treatment, the 90% confidence interval of the difference between the formulations was included in the reference confidence interval. These findings suggest that the 9O1 and 3C1 formulations did not show a significant difference in therapeutic activity. Furthermore, after 3 months of treatment, the frequency of normalization of SAP levels was 30.6% in the 9O1 treatment group and 28.2% in the 3C1 treatment group. The percentage of patients responding to treatment (defined as a decrease in SAP levels of at least 50% from baseline) was 67.3% in the 9O1 treatment group and 69.2% in the 3C1 treatment group. Statistical analyses performed on the maximum and minimum plasma concentrations of tiludronate showed no significant differences between the two formulations. In this trial, the two tablet formulations of tiludronate demonstrated therapeutic and pharmacokinetic equivalence.
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PMID:Comparison of the efficacy and bioequivalence of two oral formulations of tiludronate in the treatment of Paget's disease of bone. 938 84

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

Tiludronate ([[(4-chlorophenyl)thio]-methylene]-bis-phosphonate, ClPsMBP, Skelid, Sanofi) is a powerful inhibitor of bone resorption which has been shown to be a highly effective and safe agent for the treatment of Paget's disease of bone. Preclinical studies in vitro and in vivo have demonstrated a dose-dependent inhibitory effect on bone resorption. Unlike other bisphosphonates, tiludronate does not seem to interfere with the differentiation of osteoclasts or with their access to bone mineral. Bone tolerance studies indicate that tiludronate has an excellent therapeutic window. Thus, at the doses which induce a substantial inhibition of bone resorption it neither causes an appreciable effect on mineralisation, nor impairs biomechanical bone resistance. New formulations of tiludronate (tablets) have a bioavailability of 6% (2-11%) when ingested under optimal conditions. The pharmacokinetic profile of tiludronate is linear. Approximately 50% of the absorbed dose is bound to bone and the rate of release from this site is limited by bone turnover. Several open uncontrolled, open randomised, and double-blind, placebo-controlled studies carried out in patients with active Paget's disease have demonstrated that tiludronate reduces bone pain and produces an intense and sustained biochemical response. 3-6 months after starting tiludronate therapy, serum alkaline phosphatase levels fall far more than 50% from baseline values, reaching normal values in a percentage of the cases ranging from 35-70%. At present, tiludronate, together with pamidronate and alendronate, appear to be the drugs of choice for first-line use in the management of relatively young patients at risk of having long-term complications, when long-lasting control of disease activity is required.
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PMID:Tiludronate. A new treatment for an old ailment: Paget's disease of bone. 1124 59

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