Clodronic Acid
Fractures, Spontaneous
Bone Density Conservation Agents
Diphosphonates
A high incidence of vertebral fracture in women with breast cancer. (1/352)
Because treatment for breast cancer may adversely affect skeletal metabolism, we investigated vertebral fracture risk in women with non-metastatic breast cancer. The prevalence of vertebral fracture was similar in women at the time of first diagnosis to that in an age-matched sample of the general population. The incidence of vertebral fracture, however, was nearly five times greater than normal in women from the time of first diagnosis [odds ratio (OR), 4.7; 95% confidence interval (95% CI), 2.3-9.9], and 20-fold higher in women with soft-tissue metastases without evidence of skeletal metastases (OR, 22.7; 95% CI, 9.1-57.1). We conclude that vertebral fracture risk is markedly increased in women with breast cancer. (+info)Pharmacokinetics of clodronate in haemodialysis patients. (2/352)
BACKGROUND: Clodronate is a bisphosphonate used in the treatment of hypercalcaemia of various aetiologies. The major route of elimination of clodronate is renal excretion. The aim of the study was to derive data for the adjustment of dosage in haemodialysis patients. METHODS: The pharmacokinetic parameters describing the fate of an intravenous infusion of 300 mg clodronate disodium were studied in 10 haemodialysis patients. Clodronate disodium in serum, urine and dialysate samples was analysed by capillary gas chromatography with mass-selective detection. RESULTS: Of the 300 mg clodronate infused, 159 mg (53%) was excreted into dialysate within 4 h. Clearance by haemodialysis (CLD) was 87.8+/-16.2 ml/min, accounting for 84% of total serum clearance (CLtot). Non-renal, non-dialysis clearance (CL(NRD)) represents the removal of the drug via other routes than dialysis or kidneys. The greatest CL(NRD) was observed in patients with most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH concentration. CONCLUSIONS: According to the present findings, standard haemodialysis removes clodronate effectively from the circulation, and total clearance in haemodialysis patients on a dialysis day is not very different from that in healthy subjects. The regimen of dosing intravenous clodronate in hypercalcaemia can also be used in haemodialysis patients. The portion of clodronate eliminated by routes other than via dialysate or kidneys, i.e. predominantly via skeletal deposition, was related to the severity of hyperparathyroidism. (+info)Depletion of liver and splenic macrophages reduces the lethality of Shiga toxin-2 in a mouse model. (3/352)
The haemolytic uraemic syndrome (HUS) is a clinical syndrome consisting of haemolytic anaemia, thrombocytopenia, and acute renal insufficiency. HUS is the most frequent cause of acute renal failure in childhood. It has been previously suggested that the presence of Shiga toxin (Stx) is necessary but not sufficient for HUS development, and cytokines such as tumour necrosis factor-alpha (TNF-alpha) and IL-1beta appear to be necessary to develop the syndrome. Since the mononuclear phagocytic system (MPS) is the major source of these cytokines, macrophages might be one of the relevant targets for Stx action in the pathophysiology of HUS. In this study our objective was to examine the role of the hepatic and splenic macrophages in a mouse model of HUS induced by injection of Shiga toxin type-2 (Stx2) or Stx2 plus lipopolysaccharide (LPS). For this purpose, depletion of mice macrophages by liposome-encapsulated clodronate (lip-clod), followed by injection of STx2 or Stx2 plus LPS, was assayed. In this study we show that depletion of hepatic and splenic macrophages by clodronate treatment induces a survival of 50% in animals treated with Stx2 alone or in presence of LPS. This maximal effect was observed when lip-clod was injected 48-72 h before Stx2 injection. Biochemical and histological parameters show characteristics of the lesion produced by Stx2, discarding non-specific damage due to LPS or lip-clod. In addition, we determined that the toxic action of Stx2 is similar in BALB/c and N:NIH nude mice, indicating the T cell compartment is not involved in the Stx2 toxicity. Briefly, we demonstrate that macrophages play a central role in the pathophysiology of HUS, and that the systemic production of cytokines by liver and/or spleen is for Stx2 to manifest its full cytotoxic effect. In addition, the toxicity of Stx2 alone, or in presence of LPS, is independent of the T cell compartment. (+info)Depletion of blood-borne macrophages does not reduce demyelination in mice infected with a neurotropic coronavirus. (4/352)
Mice infected with the neurotropic coronavirus mouse hepatitis virus strain JHM (MHV-JHM) develop a chronic demyelinating disease with symptoms of hindlimb paralysis. Histological examination of the brains and spinal cords of these animals reveals the presence of large numbers of activated macrophages/microglia. In two other experimental models of demyelination, experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus-induced demyelination, depletion of hematogenous macrophages abrogates the demyelinating process. In both of these diseases, early events in the demyelinating process are inhibited by macrophage depletion. From these studies, it was not possible to determine whether infiltrating macrophages were required for late steps in the process, such as myelin removal. In this study, we show that when macrophages are depleted with either unmodified or mannosylated liposomes encapsulating dichloromethylene diphosphate, the amount of demyelination detected in MHV-infected mice is not affected. At a time when these cells were completely depleted from the liver, approximately equivalent numbers of macrophages were present in the spinal cords of control and drug-treated animals. These results suggest that blood-borne macrophages are not required for MHV-induced demyelination and also suggest that other cells, such as perivascular macrophages or microglia, perform the function of these cells in the presence of drug. (+info)Effect of liposome-encapsulated clodronate pretreatment on synthetic vector-mediated gene expression in mice. (5/352)
One of the main limitations for the use of synthetic vectors in gene therapy is their relatively low in vivo efficiency when compared with viral vectors. Here, we describe a pretreatment protocol with liposome-encapsulated clodronate in mice by which gene expression levels of a luciferase reporter gene could be increased up to nine-fold in the lung, after intravenous (i.v.) injection of glycerolipoplexes. Optimal results were obtained if mice were pretreated with liposome-encapsulated clodronate 1 day before injection of lipoplexes. The enhancement effect could be observed for lipoplexes prepared with different multivalent cationic glycerolipids. Most remarkably, polyplexes behaved in the opposite way. Liposome-encapsulated clodronate pretreatment strongly reduced reporter gene expression after i.v. injection of polyethylenimine-polyplexes (ExGen500). (+info)Chromatin clearance in C57Bl/10 mice: interaction with heparan sulphate proteoglycans and receptors on Kupffer cells. (6/352)
Chromatin is an important autoantigen in the pathogenesis of systemic lupus erythematosus (SLE) as an immunogen and as a part of nephritogenic immune complexes. Earlier studies focused on clearance of DNA. However, DNA released into the circulation from dying cells is found associated with histones in nucleosomes. The liver is the major organ involved in clearance of chromatin from the circulation of mice. Heparan sulphate proteoglycans (HSPG) have been implicated in the clearance of various charged molecules. Receptor-mediated clearance of ssDNA by the liver has also been reported. Because chromatin contains positively charged histones in addition to DNA, we wished to determine if HSPG and/or DNA receptors are involved in chromatin clearance. The rate of clearance of H1-stripped chromatin from the bloodstream of C57Bl/10 mice was markedly decreased by prior treatment of mice with Heparinase I. Clearance was also inhibited by heparin, heparan sulphate, and DNA, but not by colominic acid. DNA was the most effective inhibitor of clearance and released chromatin from sites of clearance. Depletion of Kupffer cells and splenic macrophages using liposome-encapsulated Clodronate (dichloromethylene bisphosphonate) markedly inhibited chromatin clearance. These data suggest that chromatin clearance is mediated by charge interactions with cell surface HSPG and by DNA receptors. Clearance and degradation of chromatin require functional macrophages in the liver and spleen. (+info)Enhancement by galactosamine of lipopolysaccharide(LPS)-induced tumour necrosis factor production and lethality: its suppression by LPS pretreatment. (7/352)
1. D-Galactosamine (GalN) depletes UTP primarily in the liver, resulting in decreased RNA synthesis in hepatocytes. Co-injection of GalN and lipopolysaccharide (LPS) into mice produces fulminant hepatitis with severe hepatic congestion, resulting in rapid death. Although the underlying mechanism is uncertain, GalN enhances the sensitivity to tumour necrosis factor (TNF). Administration of uridine (a precursor of UTP) prior injection of either LPS itself or interleukin-1 (IL-1) reduces the lethality of GalN+LPS. The present study focused on the effects of these agents on TNF production. 2. Intraperitoneal injection of GalN+LPS into mice greatly elevated serum TNF. Although large doses of LPS alone also greatly elevated serum TNF, LPS itself induced neither hepatic congestion nor rapid death. Administration of a macrophage depletor, liposomes encapsulated with dichloromethylene bisphosphonate, reduced both the TNF production and mortality induced by GalN+LPS. 3. Uridine, when injected 0.5 h after the injection of GalN+LPS, reduced the production of TNF. Prior injection of LPS, but not of IL-1, also reduced this TNF production. 4. Serum from LPS-injected mice reduced the TNF production induced by GalN+LPS, but it was less effective at reducing the lethality. Its ability to reduce TNF production was abolished by heat-treatment. 5. We hypothesize that a factor inhibiting TNF production by macrophages is produced by hepatocytes in response to LPS. Possibly, production of this hepatocyte-derived TNF-down-regulator (TNF-DRh) may be: (i) inhibited by GalN, causing over-production of TNF by macrophages and (ii) stimulated by LPS-pretreatment (and restored by uridine), causing reduced TNF production. (+info)Liposomal clodronate eliminates synovial macrophages, reduces inflammation and ameliorates joint destruction in antigen-induced arthritis. (8/352)
OBJECTIVES: To investigate the efficacy of a single i.v. dose of clodronate encapsulated within small unilamellar vesicles in suppressing joint inflammation and the histological progression of rat antigen-induced arthritis (AIA). METHODS: Rats with AIA received a single i.v. injection of 20 mg of clodronate encapsulated within small unilamellar vesicles (SUVc) or larger multilamellar vesicles (MLVc) 7 days post-arthritis induction. Free clodronate or saline were used as negative controls. RESULTS: SUVc was shown to be more effective than MLVc, sustaining a significant reduction in knee swelling for up to 7 days after the initial systemic administration. Knee swelling in free clodronate-treated animals was not significantly affected. The increased efficacy of SUVc in reducing inflammation and joint destruction was associated with a significant depletion of resident ED1+, ED2+ and ED3+ macrophages from the synovial membrane (SM). CONCLUSIONS: SUVc is more efficient than MLVc in reducing the severity of inflammation and joint destruction in rat AIA, and is associated with the specific elimination of macrophage subpopulations from the SM. (+info)Clodronic acid is a medication that belongs to a class of drugs called bisphosphonates. It is used to treat and prevent osteoporosis in postmenopausal women and men with a high risk of fracture, as well as to treat Paget's disease of bone.
Clodronic acid works by inhibiting the activity of bone-resorbing cells called osteoclasts, which helps to slow down bone loss and increase bone density. This can help reduce the risk of fractures in people with osteoporosis.
The medication is available in several forms, including tablets and intravenous solutions. It is usually taken or administered once a day or once a week, depending on the specific formulation and the individual patient's needs.
Like all medications, clodronic acid can have side effects, including gastrointestinal symptoms such as nausea, vomiting, and diarrhea, as well as muscle pain, joint pain, and headaches. In rare cases, it can also cause more serious side effects such as esophageal ulcers and bone necrosis of the jaw. It is important for patients to follow their doctor's instructions carefully when taking this medication and to report any unusual symptoms or side effects promptly.
Spontaneous fractures are bone breaks that occur without any identifiable trauma or injury. They are typically caused by underlying medical conditions that weaken the bones, making them more susceptible to breaking under normal stress or weight. The most common cause of spontaneous fractures is osteoporosis, a condition characterized by weak and brittle bones. Other potential causes include various bone diseases, certain cancers, long-term use of corticosteroids, and genetic disorders affecting bone strength.
It's important to note that while the term "spontaneous" implies that the fracture occurred without any apparent cause, it is usually the result of an underlying medical condition. Therefore, if you experience a spontaneous fracture, seeking medical attention is crucial to diagnose and manage the underlying cause to prevent future fractures and related complications.
Bone density conservation agents, also known as anti-resorptive agents or bone-sparing drugs, are a class of medications that help to prevent the loss of bone mass and reduce the risk of fractures. They work by inhibiting the activity of osteoclasts, the cells responsible for breaking down and reabsorbing bone tissue during the natural remodeling process.
Examples of bone density conservation agents include:
1. Bisphosphonates (e.g., alendronate, risedronate, ibandronate, zoledronic acid) - These are the most commonly prescribed class of bone density conservation agents. They bind to hydroxyapatite crystals in bone tissue and inhibit osteoclast activity, thereby reducing bone resorption.
2. Denosumab (Prolia) - This is a monoclonal antibody that targets RANKL (Receptor Activator of Nuclear Factor-κB Ligand), a key signaling molecule involved in osteoclast differentiation and activation. By inhibiting RANKL, denosumab reduces osteoclast activity and bone resorption.
3. Selective estrogen receptor modulators (SERMs) (e.g., raloxifene) - These medications act as estrogen agonists or antagonists in different tissues. In bone tissue, SERMs mimic the bone-preserving effects of estrogen by inhibiting osteoclast activity and reducing bone resorption.
4. Hormone replacement therapy (HRT) - Estrogen hormone replacement therapy has been shown to preserve bone density in postmenopausal women; however, its use is limited due to increased risks of breast cancer, cardiovascular disease, and thromboembolic events.
5. Calcitonin - This hormone, secreted by the thyroid gland, inhibits osteoclast activity and reduces bone resorption. However, it has largely been replaced by other more effective bone density conservation agents.
These medications are often prescribed for individuals at high risk of fractures due to conditions such as osteoporosis or metabolic disorders that affect bone health. It is essential to follow the recommended dosage and administration guidelines to maximize their benefits while minimizing potential side effects. Regular monitoring of bone density, blood calcium levels, and other relevant parameters is also necessary during treatment with these medications.
Diphosphonates are a class of medications that are used to treat bone diseases, such as osteoporosis and Paget's disease. They work by binding to the surface of bones and inhibiting the activity of bone-resorbing cells called osteoclasts. This helps to slow down the breakdown and loss of bone tissue, which can help to reduce the risk of fractures.
Diphosphonates are typically taken orally in the form of tablets, but some forms may be given by injection. Commonly prescribed diphosphonates include alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva). Side effects of diphosphonates can include gastrointestinal symptoms such as nausea, heartburn, and abdominal pain. In rare cases, they may also cause esophageal ulcers or osteonecrosis of the jaw.
It is important to follow the instructions for taking diphosphonates carefully, as they must be taken on an empty stomach with a full glass of water and the patient must remain upright for at least 30 minutes after taking the medication to reduce the risk of esophageal irritation. Regular monitoring of bone density and kidney function is also recommended while taking these medications.
Imidazoles are a class of heterocyclic organic compounds that contain a double-bonded nitrogen atom and two additional nitrogen atoms in the ring. They have the chemical formula C3H4N2. In a medical context, imidazoles are commonly used as antifungal agents. Some examples of imidazole-derived antifungals include clotrimazole, miconazole, and ketoconazole. These medications work by inhibiting the synthesis of ergosterol, a key component of fungal cell membranes, leading to increased permeability and death of the fungal cells. Imidazoles may also have anti-inflammatory, antibacterial, and anticancer properties.