Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisphosphonates have demonstrated important clinical benefits for patients with malignant bone disease, metabolic bone diseases, such as Paget's disease, and postmenopausal osteoporosis. The introduction of nitrogen-containing bisphosphonates with high affinity for hydroxyapatite in bone represents an important advancement. These agents are now a standard of care for osteoporosis, Paget's disease, osteogenesis imperfecta, primary bone lesions from multiple myeloma and bone metastases from breast cancer. Moreover, the recent clinical development of zoledronic acid (4 mg by 15-minute intravenous infusion) has expanded the benefits of bisphosphonate therapy to patients with bone metastases from any solid tumour. Bisphosphonates are also being investigated at present for the prevention of bone loss resulting from cancer therapy. In addition, a variety of novel biologic agents, receptor activator of nuclear factor-kappaB (RANK) ligand antibodies, osteoprotegerin and cathepsin K inhibitors are being investigated at present for the treatment of malignant bone disease. The management of bone health is an important area of active research, and the armamentarium and role of bone-specific therapies continue to expand.
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PMID:New therapeutic agents for the treatment of bone diseases. 1595 12

Interleukin-6 (IL-6) is a 4-helical protein that binds to a specific IL-6 receptor on target cells and to two molecules of the promiscuous signal transducing protein, glycoprotein 130 (gp130). Structure-function analysis has led to the definition of molecular contacts between IL-6 and its receptor subunits. This knowledge has led to the design of competitive antagonistic proteins that retain their receptor binding capability, but fail to stimulate one or both gp130 proteins; the properties of such recombinant antagonistic proteins are compared with traditional neutralising monoclonal antibodies targeted at IL-6 or receptor subunits. Furthermore, several strategies have been employed to construct molecules with increased bioactivity. Possible therapeutic applications in putative IL-6 dependent haematologic disorders, e.g., Castleman's disease (CD), POEMS syndrome, multiple myeloma, and bone diseases, e.g., Paget's disease, osteoporosis, are outlined. IL-6 antagonists could also, in theory, suppress inflammatory activity in rheumatic and autoimmune diseases and could prevent secondary amyloidosis. This principle may prove advantageous in myocardial infarction (MI) and unstable angina pectoris. More generally, IL-6 antagonists could improve the wasting and microcytic anaemia of chronic diseases. IL-6 antagonists might slow down development of mesangio-proliferative glomerulonephritis (MPGN). Hyperagonistic variants of IL-6 have a potential use in the ex vivo expansion of haematopoietic progenitor cells and as thrombopoietic agents. They might well be the first drugs to aid liver regeneration in vivo.
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PMID:The therapeutic potential of interleukin-6 hyperagonists and antagonists. 1598 26

Interleukin-6 (IL-6) is a four-helical protein which, on target cells, binds to a specific IL-6-receptor and two molecules of the promiscuous signal transducing protein gp130. Structure-function analysis defined three molecular contact sites between IL-6 and its receptor subunits. Using this information, competitive antagonistic proteins as well as hyperagonistic proteins were developed. Possible therapeutic applications of IL-6 antagonists are in IL-6 dependent haematological disorders (Castleman's disease, POEMS syndrome, multiple myeloma) and bone diseases (Paget's disease, osteoporosis). Designer IL-6 antagonists could suppress inflammatory activity in rheumatic and autoimmune diseases and could prevent secondary amyloidosis. IL-6 antagonists could also prove advantageous in myocardial infarction and unstable angina pectoris. IL-6 antagonists might slow down development of (mesangioproliferative) glomerulonephritis. On the other hand, hyperagonistic variants of IL-6 have a potential in ex vivo expansion of bone marrow stem cells and as thrombopoietic agents. They might also be developed into drugs to support liver regeneration in vivo and to treat stress-induced cardiac insufficiency.
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PMID:New developments in IL-6 dependent biology and therapy: where do we stand and what are the options? 1599 52

Jaw bone necrosis is a clinical condition associated with defects in vascularization of the maxilla or the mandibular bone, usually present following head and neck radiotherapy and/or oral surgical interventions. Bisphosphonates are synthetic analogues of pyrophosphate used in the treatment of patients with hypercalcemia as a result of malignancy, bone metastasis and for the treatment of other disorders such as metabolic bone diseases, Paget's disease and osteoporosis. Over last 10 years, cases of jaw bone necrosis have been associated with the use of bisphosphonate therapy. In particular, Ruggiero et al. (J Oral Maxillofac Surg 2004; 62: 527-534) in 2004 described a large group of patients (63) with jaw bone necrosis probably related to the use of these drugs. It should be noted that all the patients in the group described either underwent head and neck radiotherapy or had a dental extraction while taking bisphosphonates. In the present study, we reported four cases of jawbone necrosis in patients taking pamidronate (Aredia) and zoledronate (Zometa) without having undergone any kind of radiotherapy or dental surgery. All the patients were females between the ages of 56 and 71 years; three were treated with bisphosphonates for bone metastasis and one for multiple myeloma. All the patients received surgical treatment with bone curettage, with partial and/or temporary improvement of the lesions. Although a treatment for bisphosphonate-induced bone lesions has not yet been established, we suggest careful evaluation of the patients' oral health before prescribing bisphosphonate treatment.
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PMID:Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. 1620 82

A case is presented of symptomatic hypocalcemia following treatment with bisphosphonates. This patient also had deficiency of 25 hydroxyvitamin D that was unrecognized. The use of bisphosphonates in cancer is increasing, not only in the treatment of hypercalcemia, but also for bone pain and to decrease the risk of skeletal morbidity in metastatic breast cancer, multiple myeloma, and Paget's disease in normocalcemic patients. The patient was probably vitamin D deficient because of a combination of poor oral intake, inadequate sunlight exposure, and the development of renal failure. However despite receiving both parenteral and oral calcium therapy, the serum calcium remained low until the replacement of vitamin D. With increasing use of bisphosphonate therapy in malignant disease, we believe that an assessment of vitamin D status, calcium intake, renal function, phosphate, magnesium, and albumin should be undertaken prior to initiating therapy in most palliative care patients.
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PMID:Bisphosphonate-induced hypocalcemia associated with vitamin D deficiency in a patient with advanced cancer. 1622 61

Bisphosphonates (BP) are pharmacological compounds whose the most important biological effect is the reduction of bone remodelling, explaining the reason for their use in pathological conditions characterised by an increased bone resorption, such as osteoporosis, Paget's disease, malign hypercalcemia during myeloma and osteolytic bone metastasis. Nevertheless there are several experimental evidence that BP possess different extra-skeletal biological effects, ranging from analgesic properties, anti-inflammatory and pro-inflammatory effects and the capacity of modifying the biological activity of cells other than osteoblasts and osteoclasts, such as the immune system cells and other cells of mesenchymal origin. Several data report the beneficial effects of BP as anti-inflammatory agents in different inflammatory chronic articular diseases, which make BP suitable drugs for treatment of pathologies other than bone disease.
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PMID:[The bisphosponates: chemical characteristics, skeletal biological effects and extra-skeletal effects]. 1625 98

The osteoclast (OCL) is the primary cell involved in the pathogenesis of Paget's disease (PD) and the destructive bone process in multiple myeloma (MM). Both of these diseases are characterized by increased numbers of OCLs actively resorbing bone, but they differ in that bone formation is greatly increased in PD and is suppressed in MM. The marrow microenvironment plays a critical role in both disease processes, through the increased expression of inflammatory cytokines that enhance osteoclastogenesis and, in the case of MM, also suppress osteoblast (OBL) activity. In addition, the OCLs in PD are intrinsically abnormal, are markedly increased in number and size, and are hyper-responsive to inflammatory cytokines and 1,25-(OH)2D3. This article discusses the role of immune cells and inflammatory cytokines and chemokines in the increased OCL activity in PD and MM bone disease, as well as the potential role of interleukin-3 in the suppression of OBL activity in MM.
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PMID:The role of immune cells and inflammatory cytokines in Paget's disease and multiple myeloma. 1631 53

The dye Congo red and related self-assembling compounds were found to stabilize immune complexes by binding to antibodies currently engaged in complexation to antigen. In our simulations, it was shown that the site that becomes accessible for binding the supramolecular dye ligand is located in the V domain, and is normally occupied by the N-terminal polypeptide chain fragment. The binding of the ligand disrupts the beta-structure in the domain, increasing the plasticity of the antigen-binding site. The higher fluctuation of CDR-bearing loops enhances antigen binding, and allows even low-affinity antibodies to be engaged in immune complexes. Experimental observations of the enhancement effect were supported by theoretical studies using L lambda chain (4BJL-PDB identification) and the L chain from the complex of IgM-rheumatoid factor bound to the CH3 domain of the Fc fragment (1ADQ-PDB identification) as the initial structures for theoretical studies of dye-induced changes. Commercial IgM-type rheumatoid factor (human) and sheep red blood cells with coupled IgG (human) were used for experimental tests aimed to reveal the dye-enhancement effect in this system. The specificity of antigen-antibody interaction enhanced by dye binding was studied using rabbit anti-sheep red cell antibodies to agglutinate red cells of different species. Red blood cells of hoofed mammals (horse, goat) showed weak enhancement of agglutination in the presence of Congo red. Neither agglutination nor enhancement were observed in the case of human red cells. The dye-enhancement capability in the SRBC-antiSRBC system was lost after pepsin-digestion of antibodies producing (Fab)2 fragments still agglutinating red cells. Monoclonal (myeloma) IgG, L lambda chain and ovoalbumin failed to agglutinate red cells, as expected, and showed no enhancement effect. This indicates that the enhancement effect is specific.
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PMID:The increased flexibility of CDR loops generated in antibodies by Congo red complexation favors antigen binding. 1636 76

The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating journey that is still not over. In clinical medicine, several BPs are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate, and are resistant to breakdown by enzymatic hydrolysis. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen-containing bisphosphonates (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTP-binding proteins (which are also GTPases) such as rab, rho, and rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explain the loss of osteoclast activity and induction of apoptosis. The key target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS) within osteoclasts, and the recently elucidated crystal structure of this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, and their mode of action is being unraveled. As a result their full therapeutic potential is gradually being realized.
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PMID:Bisphosphonates: from bench to bedside. 1683 38

In recent years, a growing number of reports in the literature have linked osteonecrosis of the jaw bones with intravenously administered bisphosphonates prescribed for the treatment of hypercalcemia of malignancy due to bone lesions of multiple myeloma or bone metastases in patients with breast or prostate cancer. Furthermore, an association between chronic oral bisphosphonate use in patients with osteoporosis or Paget's disease, and bone necrosis in the mandible or maxilla has been demonstrated in numerous case reports and case series in the last couple of years. Therapeutically, osteonecrosis of the jaws seems to be difficult to treat surgically, often resulting in a recurring or even progressing lesion. In the present case report of a bisphosphonate-associated osteonecrosis of the maxilla in a patient with osteoporosis, the current literature will be discussed, and open research questions and potential problems for our daily dental practice routine will be addressed.
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PMID:[Biphosphonate-associated osteonecrosis of the maxilla. Case report and review of the literature]. 1707 15


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