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At least 19 recordsLinked to original sources
PubMed1999

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel acyloxyalkyl esters of clodronic acid.

Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P(app) ranged from -2.1 to 7. 4) than clodronate (log P(app) < or = -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and clodronic acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic acid were also synthesized, but they did not release clodronic acid due to the enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.

Animals↗
PubMed1999

Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel clodronic acid dianhydrides as bioreversible prodrugs of clodronate.

P,P'-Diacetyl, P,P'-dibutyroyl, P,P'-dipivaloyl, and P,P'-dibenzoyl (dichloromethylene)bisphosphonic acid dianhydride disodium salts (2a-d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding acid anhydride. The dianhydrides 2a-d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 degrees C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 degrees C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to formation of poorly water-soluble chelates, which may also hinder the oral absorption of clodronate. However, Ca2+ ions did not have an effect on the aqueous solubility of clodronic acid dianhydrides, and therefore, these prodrugs may improve oral absorption of the parent drug. In conclusion, these novel dianhydride derivatives may be potentially useful prodrugs of clodronate which, due to their lipophilicity and lack of Ca2+ chelating, increase its bioavailability after oral administration.

Anhydrides↗
PubMed1991

Comparative molecular field analysis of some clodronic acid esters.

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate three different types of biological activity data with physicochemical properties of some clodronate ester analogues, which act as bone-resorption regulators in cell cultures and rats. The QSAR studies show the importance of the steric properties of these new bisphosphonate derivatives for the inhibition of bone resorption in bone cell cultures and for their bioavailability in rats. This information will be used in predicting the structure of new more potent bisphosphonic compounds.

Animals↗
PubMed1994

Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Etidronic acid is an orally and intravenously active bisphosphonate, which is believed to inhibit resorption of bone via a number of cellular mechanisms, including alteration of osteoclastic activity. In studies of patients with symptomatic Paget's disease, etidronic acid 5 to 20 mg/kg/day administered orally rapidly decreased the biochemical indices of bone turnover. Mineralisation defects in forming bone may be avoided by the use of an initial dosage of 5 mg/kg/day for up to 6 months; dosages above 10 mg/kg/day should be limited to 3 months' duration, and dosages greater than 20 mg/kg/day should be avoided. Although 3-day intravenous therapy with etidronic acid 7.5 mg/kg/day has shown superior efficacy to rehydration and forced diuresis in the management of hypercalcaemia of malignancy, the efficacy of the drug is lower than that of the newer bisphosphonates, pamidronic acid and clodronic acid. Clinical studies involving postmenopausal women with established osteoporosis have indicated that oral etidronic acid 400 mg/day for 14 days as part of a 90-day cycle, repeated for up to 3 years, increases the bone mineral density (BMD) of the lumbar vertebrae and appears to reduce the incidence of vertebral fracture. Published data suggest that etidronic acid shows similar efficacy to hormone replacement therapy (HRT) in these respects. The above dosage also appears to be effective in preventing corticosteroid-induced osteoporosis when administered as part of an intermittent, cyclical regimen. Etidronic acid in higher dosages (10 to 20 mg/kg/day orally) is effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Etidronic acid is well tolerated by the majority of patients, with gastrointestinal complaints reported most commonly, but tends to delay the normal mineralisation of forming bone when administered continuously at higher dosages for prolonged periods. This is of little consequence where short term treatment is involved, but may be detrimental to those patients receiving longer courses of therapy. This effect may be minimised or avoided by using the lowest effective dosage for as short a time as possible (as in the above recommendations for Paget's disease), or by the use of intermittent cyclical therapy (as in the management of osteoporosis). Etidronic acid therefore retains a role in the management of resorptive bone disease, particularly in the treatment of Paget's disease, the prevention of heterotopic ossification, and as a second-line option in postmenopausal osteoporosis. However, the development of newer bisphosphonates requires that these compounds be continually compared and re-evaluated.

Bone Diseases↗
PubMed1991

Pamidronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Pamidronate [aminohydroxypropylidene diphosphonate disodium (APD), disodium pamidronate] is an orally and intravenously active amino-substituted bisphosphonate which produces potent and specific inhibition of bone resorption at doses devoid of any significant detrimental effect on bone growth and mineralisation. Clinical trials indicate that pamidronate is effective in a variety of conditions characterised by pathologically enhanced bone turnover, including Paget's disease, hypercalcaemia of malignancy, osteolytic bone metastasis, steroid-induced osteoporosis and idiopathic osteoporosis. Pamidronate is highly effective in restoring normocalcaemia in patients with hypercalcaemia of malignancy associated with bone metastases but, in common with other bisphosphonates, is marginally less effective against humoral hypercalcaemia of malignancy. Comparative studies in this area have suggested that, at therapeutic doses, pamidronate has a more pronounced calcium-lowering action than etidronate (etidronic acid) and clodronate (clodronic acid) and provides a longer period of normocalcaemic remission. In Paget's disease arrest and, in some patients, reversal of the progression of osteolytic lesions by pamidronate is associated with a sustained reduction in bone pain, improved mobility and a possible reduced risk of bone fracture. In patients with osteolytic bone metastasis pamidronate reduces skeletal morbidity and slows the progression of metastatic bone destruction. Long term use of low-dose pamidronate in conjunction with conventional antiosteoporotic therapy may halt bone loss in steroid-induced and idiopathic osteoporosis. Pamidronate appears to represent a valuable addition to the drugs currently available for the treatment of symptomatic Paget's disease and cancer-associated hypercalcaemia, and shows promise in the treatment of osteolytic bone metastasis and osteoporosis.

Animals↗
PubMed1996

Formulary management of drugs for cancer-associated hypercalcaemia.

Hypercalcaemia associated with cancer is seen not infrequently in hospital practice and can be a source of considerable morbidity. Over the past decade, our understanding of the pathogenesis of this syndrome has advanced, allowing improved treatment protocols. Because one of the principal abnormalities relates to an increase in bone resorption, antiresorptive agents such as calcitonin and the bisphosphonates have been shown to be of value. In the medium to longer term, the bisphosphonates -particularly pamidronic acid[pamidronate;aminohydroxypropylidene bisphosphonate (APD)] and clodronic acid [clodronate; dichloromethyl bisphosphonate (Cl2MDP)]¿ appear to be more efficacious in terms of their calcium-lowering effect than calcitonin, and also appear to be associated with fewer adverse effects than most other agents. However, the importance of energetic re-expansion of the extracellular space with 0.9% sodium chloride before bisphosphonate therapy is extremely important. Cancer-associated hypercalcaemia, especially with squamous cancer, is often associated with the production of parathyroid hormone-related protein (PTHrP). Where this is the case, it usually reflects the presence of more advanced disease with shortened life expectancy, and poorer response to calcium-lowering therapy. Multiple treatments with larger doses of bisphosphonate may be required for these patients.

Cost-Benefit Analysis↗
PubMed1990

Advances in the management of Paget's disease of bone.

The advent of potent new bisphosphonates (diphosphonates) now makes it possible to restore and maintain normal bone turnover in many patients with Paget's disease of bone (osteitis deformans). This has necessitated a reappraisal of the indications for treatment, the ways in which disease activity and response are assessed, as well as the place of existing therapies. Measurements of urinary hydroxyproline and serum alkaline phosphatase remain the most useful markers of disease activity. Pyridinium crosslinks may prove to be more specific than hydroxyproline in the assessment of bone resorption but osteocalcin has been disappointing in monitoring the effect of treatment on bone formation. Etidronic acid (disodium etidronate), the first bisphosphonate introduced for clinical use, is a potent inhibitor of osteoclastic bone resorption but its potential is limited by the development of defective mineralisation with high dosage (10 to 20 mg/kg/day). The newer bisphosphonates, clodronic acid (clodronate) and pamidronic acid (pamidronate, APD), are free from this problem and appear able to control a wide range of disease activity. A small number of patients appear resistant to the agents but the underlying mechanism is unclear. The efficacy and safety of these bisphosphonates makes it likely that the threshold for treating asymptomatic patients will fall in the hope of preventing long term complications. These developments will lead to a reappraisal of the role of calcitonin which can now be administered by both the parenteral and intranasal routes. One focus of interest will be on the quality of the bone laid down during treatment. Meticulous radiographic studies have shown that calcitonin improves bone architecture and this may have particular relevance to the treatment of lytic disease. The relative merits of the different forms of therapy for Paget's disease need further evaluation, particularly with respect to the identification of specific advantages of individual drugs.

Humans↗
PubMed1999

Clodronate: a review of its use in breast cancer.

UNLABELLED: Like other members of its class, the bisphosphonate clodronate (clodronic acid) inhibits bone resorption. The efficacy of oral clodronate 1600 mg/day in reducing the incidence of skeletal complications and metastasis development has been assessed in several clinical trials in patients with breast cancer. Long term use of oral clodronate significantly reduced the total cumulative incidence of skeletal events (including fractures, hypercalcaemia, and the need for radiotherapy for bone pain) compared with that in placebo recipients in 2 randomised double-blind placebo-controlled studies, each involving >100 patients. Significant differences in favour of clodronate were also seen in the frequency of some individual skeletal events in 1 trial. A nonblind trial in 302 patients considered to be at high risk of developing metastases found that, at a 3-year follow-up, significantly fewer patients who received clodronate for 2 years developed skeletal metastases than those in a control group. Clodronate recipients were also significantly less likely than controls to develop visceral metastases, and had significantly higher survival rates. A smaller double-blind placebo-controlled study in women with recurrent breast cancer found that clodronate significantly decreased the total number of new skeletal metastases, but not the number of patients who developed them. In a nonblind trial in 299 patients with node-positive breast cancer, however, the incidence of skeletal metastases did not differ significantly between patients who received clodronate for 3 years and those in a control group. In addition, clodronate recipients had a significantly greater incidence of nonskeletal metastases (local and visceral), and significantly lower survival rates. Intravenous or oral clodronate has been well tolerated in clinical trials. The most common adverse effects reported were mild gastrointestinal disturbances such as nausea, vomiting and diarrhoea. All these events were transient, and usually resolved without stopping treatment. CONCLUSIONS: Clodronate is a well tolerated bisphosphonate, available in both oral and intravenous forms, that significantly reduces the incidence of skeletal complications associated with breast cancer. Further research is needed to establish more clearly its efficacy in reducing metastasis development, to assess its efficacy compared with other bisphosphonates, and to determine which patients will benefit most from treatment. Currently, clodronate is probably most effective in the treatment and prevention of general skeletal complications in patients with breast cancer.

Bone Resorption↗
PubMed1998

Reduction in new metastases in breast cancer with adjuvant clodronate treatment.

BACKGROUND: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. METHODS: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy. RESULTS: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P=0.003 for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P=0.001). The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3). CONCLUSIONS: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.

Adult↗
PubMed1994

Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Clodronate (clodronic acid, dichloromethylene bisphosphonate) is a bisphosphonate which has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption including Paget's disease, hypercalcaemia of malignancy and osteolytic bone metastases. In addition, early reports demonstrating potential efficacy of clodronate in the treatment of osteoporosis suggest a possible role in this debilitating disease. Short term intravenous administration (usually 300 mg/day for 5 days) or longer courses of oral clodronate (usually 1600 mg/day for 6 months) effectively reduced bone pain and/or improved mobility in most patients with Paget's disease, and these effects persisted for up to 12 months after discontinuing clodronate. When administered intravenously (300 mg/day for up to 12 days) to patients with malignant hypercalcaemia, serum calcium levels declined significantly within 2 days of starting treatment and approximately 70 to 95% of patients became normocalcaemic. While there is less experience with oral administration, clodronate (800 to 3200 mg/day) achieved normocalcaemia in the majority of patients, usually within 1 week, and serum calcium levels remained significantly reduced from baseline for up to 6 months with continued treatment. Clodronate is clearly superior to placebo and, based on a retrospective analysis, appears to produce greater and more sustained reductions in serum calcium levels than calcitonin in patients with malignant hypercalcaemia. The few available prospective comparative trials showed that clodronate is at least as effective as etidronate, but comparisons with alendronate and pamidronate produced results of questionable clinical relevance because of low bisphosphonate dosages used in these trials. Nevertheless, single intravenous doses of clodronate 600 mg or alendronate 7.5 mg (both agents repeated on day 3 if necessary) were comparable in efficacy, whereas a single intravenous dose of pamidronate 30 mg was more effective than a single intravenous dose of clodronate 600 mg. Normocalcaemic patients with osteolytic bone metastases due to advanced breast cancer experienced significant reductions in the number of episodes of hypercalcaemia and terminal hypercalcaemia, incidence of vertebral fractures and overall rate of morbid events, including the need for radiotherapy to treat bone-related pain, following treatment with clodronate 1600 mg/day for 3 years in a large placebo-controlled study. A similar large placebo-controlled trial in patients with multiple myeloma demonstrated that clodronate 2400 mg/day orally for 2 years significantly reduced progression of osteolytic bone lesions. Follow-up data from clinical trials revealed that the effects on development of fractures and hypercalcaemia persisted for at least 12 months after the drug was discontinued.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Kupffer cell depletion by liposome-delivered drugs: comparative activity of intracellular clodronate, propamidine, and ethylenediaminetetraacetic acid.

Macrophages such as Kupffer cells in the liver are multifunctional cells. They are involved in host defense mechanisms and have a regulatory role in many biomedical processes. Their selective depletion, using liposome-encapsulated drugs, forms a widely accepted approach to studying their functional aspects in vivo. We have compared the Kupffer cell-depleting activities of liposome-encapsulated clodronate, propamidine, and ethylenediaminetetraacetic acid (EDTA) for this purpose. These molecules represent the drug families of bisphosphonates, diamidines (or aromatic polyamidines), and polyaminopolycarboxylic acid-chelating agents, respectively. The Kupffer cell-depleting activity of the liposome-encapsulated antimicrobial drug propamidine exceeded that of clodronate by about a factor of 10. EDTA appeared to be inefficacious for depletion of Kupffer cells in the rat.

Animals↗
PubMed1999

Kupffer cell-independent acute hepatocellular oxidative stress and decreased bile formation in post-cold-ischemic rat liver.

The purpose of this study was to examine distribution and time history of oxidative stress during the hyperacute period of reperfusion in the liver grafts undergoing cold ischemia and to investigate roles of Kupffer cells as a potential oxidant source. Rat livers were harvested at 4 degrees C in University of Wisconsin solution and followed by reperfusion with Krebs-Henseleit buffer under monitoring bile excretion. To investigate oxidative changes, laser-confocal microfluorography was performed in reperfused livers preloaded with dichlorodihydrofluorescein diacetate succinimidyl ester, a fluorescence precursor sensing intracellular hydroperoxide generation. Livers undergoing the 16-hour cold storage displayed an impaired recovery of bile acid-dependent bile output concurrent with a marked increase in hydroperoxide generation in hepatocytes, which occurred as early as 5 minutes after the onset of reperfusion, whereas the status of lobular perfusion was well maintained. Pretreatment with liposome-encapsulated dichloromethylene diphosphonate, a Kupffer cell-depleting reagent, did neither alter the reperfusion-induced periportal oxidative changes nor improve the recovery of bile output in the graft. On the other hand, EPCK, a hepatotropic antioxidant composed of vitamin E phosphate ester bound to vitamin C, not only diminished the oxidative changes but also improved the reduction of bile acid-dependent bile output. Furthermore, the reagent was capable of inhibiting H(2)O(2)-induced oxidative stress in cultured hepatocytes. These results suggest that hepatocytes constitute a major site of the oxidative insult triggered through Kupffer cell-independent mechanisms and serve as an important cellular component to be protected by antioxidant therapeutics.

Animals↗
PubMed1994

Modulation of hepatic sinusoidal endothelial cell function by Kupffer cells: an example of intercellular communication in the liver.

We tested the hypothesis that Kupffer cells modulate sinusoidal endothelial cell function in the liver. Rats were treated with Kupffer cell-depleting agents (gadolinium chloride and liposome-encapsulated dichloromethylene diphosphonate) or with inhibitors of phospholipase A2 or leukotriene A4 synthase (dexamethasone and diethylcarbamazine, respectively). Hyaluronan uptake by the isolated, perfused liver was measured as an index of the functional state of the sinusoidal endothelial cell. Plasma hyaluronan concentration was also determined. Three hours after Escherichia coli lipopolysaccharide administration (100 micrograms/100 gm body wt, intravenously) plasma hyaluronan levels were significantly increased (280% to 320%), whereas hepatic hyaluronan uptake was markedly decreased (approximately 76%). Pretreatment with gadolinium chloride (0.5 mg/100 gm body wt, intravenously, 21 hr before saline solution or lipopolysaccharide administration), liposome-encapsulated dichloromethylene diphosphonate (40 mumol/100 gm body wt, intravenously, 44 hr before saline solution or lipopolysaccharide injection), dexamethasone (40 micrograms/100 gm body wt, intravenously, 1 hr before saline solution or lipopolysaccharide administration) or diethylcarbamazine (repeated doses, 10 mg/100 gm body wt, intravenously, 1 hr before saline solution or lipopolysaccharide injection) counteracted the lipopolysaccharide inhibitory effect on hepatic hyaluronan uptake. With the exception of gadolinium chloride, all other agents also prevented the lipopolysaccharide-induced increase in plasma hyaluronan concentration. Gadolinium chloride only attenuated the lipopolysaccharide effect on plasma hyaluronan level. Taken together with earlier results from our laboratory, these data indicate that: (a) Kupffer cell activation by lipopolysaccharide results in suppression of hyaluronan uptake by sinusoidal endothelial cells and (b) such modulation of endothelial cell function is likely mediated by products of the lipoxygenase pathway of arachidonate metabolism.

Animals↗
PubMed1984

Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study.

Dichloromethylene diphosphonate can be used for temporary elimination of macrophages in the spleen when administered after entrapment in liposomes. No comparable effect on the macrophages of the spleen was observed with free dichloromethylene diphosphonate or in the case of empty liposomes. Marginal metallophils on the boundary between white pulp and marginal zone as well as macrophages in the marginal zone and red pulp disappeared from the spleen within one day and remained largely absent for about a week. After this time cells reappeared slowly, and at approximately four weeks after injection their presence in the spleen did not differ from that in control animals. Marginal metallophils and macrophages in the spleen were demonstrated by use of enzyme-histochemical methods and by their capacity to ingest carbon particles.

Acid Phosphatase↗
PubMed2000

Role of macrophages in restricting herpes simplex virus type 1 growth after ocular infection.

PURPOSE: To investigate the role macrophages play in controlling herpes simplex virus (HSV)-1 replication after infection of the murine cornea. METHODS: Macrophage depletion in selected tissues before or after virus infection was achieved by repeated subconjunctival (SCJ) and/or intravenous (IV) injection of liposomes containing dichloromethylene diphosphonate (L-Cl2MDP). Controls received liposomes containing phosphate-buffered saline (L-PBS). The efficiency of depletion was evaluated by histologic examination. Virus content in infected tissues was determined by standard plaque assay. Delayed-type hypersensitivity (DTH) responsiveness was assessed using the ear-swelling assay. Antibody isotype responses to virus antigens and cytokine production were monitored by enzyme-linked immunosorbent assay. RESULTS: Balb/c mice given SCJ injection of L-Cl2MDP 4 and 2 days before HSV-1 corneal infection were found to have ocular virus titers as much as 10(5)-fold higher than that seen in the L-PBS-treated controls 8 days after infection. When L-Cl2MDP treatment was delayed until 2 and 4 days after infection, virus titers in the eye were analogous to those in the control animals. Subconjunctival and submandibular lymph node macrophages in mice given local (SCJ) L-Cl2MDP pretreatment were profoundly reduced, whereas the number of corneal Langerhans' cells and lymph node dendritic cells remained unchanged. Local L-Cl2MDP pretreatment was associated with significantly reduced DTH responsiveness to HSV-1 antigen, and an alteration in selected antibody isotype production. Depletion of macrophages in the subconjunctival tissue before corneal infection was not accompanied by enhanced virus growth at early times (2 or 4 days) after infection. CONCLUSIONS: Macrophages play an important role in restricting HSV-1 growth after corneal infection. These cells appear to be required for the development of an acquired immune response, presumably by functioning in antigen processing and presentation. The hypothesis that macrophages are major participants in innate immunity to HSV-1 corneal infection was not supported.

Acid Phosphatase↗
PubMed1981

Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells.

The calvaria cells cultured for 6 days in the presence of dichloromethanediphosphonate (Cl2MDP) (0.025-250 microM), the synthesis of prostaglandin E2 (PGE2) was inhibited by up to 90%. Inhibition of PGE2 synthesis might be one mechanism whereby this diphosphonate inhibits bone resorption. This effect is not common to all diphosphates since 25 microM 3-amino-1-hydroxypropane-1,1-diphosphonate (AHPDP) stimulated the synthesis of PGE2.

Animals↗