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Heller A, Senwitz C, Foerstendorf H, Tsushima S, Holtmann L, Drobot B, Kretzschmar J. Europium(III) Meets Etidronic Acid (HEDP): A Coordination Study Combining Spectroscopic, Spectrometric, and Quantum Chemical Methods. Molecules 2023; 28:molecules28114469. [PMID: 37298946 DOI: 10.3390/molecules28114469] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Etidronic acid (1-Hydroxyethylidene-1,1-diphosphonic acid, HEDP, H4L) is a proposed decorporation agent for U(VI). This paper studied its complex formation with Eu(III), an inactive analog of trivalent actinides, over a wide pH range, at varying metal-to-ligand ratios (M:L) and total concentrations. Combining spectroscopic, spectrometric, and quantum chemical methods, five distinct Eu(III)-HEDP complexes were found, four of which were characterized. The readily soluble EuH2L+ and Eu(H2L)2- species with log β values of 23.7 ± 0.1 and 45.1 ± 0.9 are formed at acidic pH. At near-neutral pH, EuHL0s forms with a log β of ~23.6 and, additionally, a most probably polynuclear complex. The readily dissolved EuL- species with a log β of ~11.2 is formed at alkaline pH. A six-membered chelate ring is the key motif in all solution structures. The equilibrium between the Eu(III)-HEDP species is influenced by several parameters, i.e., pH, M:L, total Eu(III) and HEDP concentrations, and time. Overall, the present work sheds light on the very complex speciation in the HEDP-Eu(III) system and indicates that, for risk assessment of potential decorporation scenarios, side reactions of HEDP with trivalent actinides and lanthanides should also be taken into account.
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Affiliation(s)
- Anne Heller
- Chair of Radiochemistry/Radioecology, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany
- Central Radionuclide Laboratory, Radiation Protection Office, Technische Universität Dresden, 01062 Dresden, Germany
| | - Christian Senwitz
- Chair of Radiochemistry/Radioecology, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany
- Central Radionuclide Laboratory, Radiation Protection Office, Technische Universität Dresden, 01062 Dresden, Germany
| | - Harald Foerstendorf
- Institute of Resource Ecology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Satoru Tsushima
- Institute of Resource Ecology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
- International Research Frontiers Initiative (IRFI), Institute of Innovative Research, Tokyo Institute of Technology, Tokyo 152-8550, Japan
| | - Linus Holtmann
- Institute of Radioecology and Radiation Protection, Leibniz Universität Hannover, 30419 Hannover, Germany
| | - Björn Drobot
- Institute of Resource Ecology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
| | - Jerome Kretzschmar
- Institute of Resource Ecology, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany
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Rajani P, Sachin AR, Nagarajan S, Brahmananda Rao CVS, Gopakumar G. Insights into the Coordination Behavior of Methyl-Substituted Phosphinic Acids with Actinides. Inorg Chem 2022; 61:13047-13057. [PMID: 35942987 DOI: 10.1021/acs.inorgchem.2c01287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The electronic structure and complexation behavior of methyl-substituted phosphinic acids with U(VI) and Pu(IV) were explored by applying quantum chemical methods. In contrast to Ingold's classification, our results indicate that the methyl group is electron-withdrawing, reducing the phosphoryl group electron density in substituted phosphinic acids. The magnitude of the computed complexation energy values increases along with the series, PA → MPA → DMPA, and MP → MMP → MDMP, implying an increasing complexation tendency upon methyl group substitution for both U(VI) and Pu(IV) complexes. One of the nitrate groups in UO2(NO3)2•2L complexes (L = PA, MPA, and DMPA) is in monodentate coordination mode due to the additional stability gained from O2N-O···H hydrogen bonding interactions with the acidic H atoms of respective ligands. The calculation indicates marginally stronger metal-ligand interactions in Pu(IV) complexes compared to that in U(VI), which is supported by the computed complexation energies, M-OP bond lengths, ν(P═O), the extent of metal-ligand charge transfer, and properties of M-OP bond critical points. The energy landscape of substituted phosphinic acid ligands is further analyzed within the framework of the activation strain model to explain the energetic preference of certain conformers.
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Affiliation(s)
- Puchakayala Rajani
- Indira Gandhi Centre for Atomic Research, Kalpakkam, Tamil Nadu 603102, India.,Homi Bhabha National Institute, Training School Complex, Anushakthinagar, Mumbai 400094, India
| | - Aditya Ramesh Sachin
- Indira Gandhi Centre for Atomic Research, Kalpakkam, Tamil Nadu 603102, India.,Homi Bhabha National Institute, Training School Complex, Anushakthinagar, Mumbai 400094, India
| | - Sivaraman Nagarajan
- Indira Gandhi Centre for Atomic Research, Kalpakkam, Tamil Nadu 603102, India.,Homi Bhabha National Institute, Training School Complex, Anushakthinagar, Mumbai 400094, India
| | - Cherukuri Venkata Siva Brahmananda Rao
- Indira Gandhi Centre for Atomic Research, Kalpakkam, Tamil Nadu 603102, India.,Homi Bhabha National Institute, Training School Complex, Anushakthinagar, Mumbai 400094, India
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Nguyen THV, Yekwa E, Selisko B, Canard B, Alvarez K, Ferron F. Inhibition of Arenaviridae nucleoprotein exonuclease by bisphosphonate. IUCRJ 2022; 9:468-479. [PMID: 35844481 PMCID: PMC9252148 DOI: 10.1107/s2052252522005061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/11/2022] [Indexed: 06/15/2023]
Abstract
Arenaviruses are emerging enveloped negative-sense RNA viruses that cause neurological and hemorrhagic diseases in humans. Currently, no FDA-approved vaccine or therapeutic agent is available except for ribavirin, which must be administered early during infection for optimum efficacy. A hallmark of arenavirus infection is rapid and efficient immune suppression mediated by the exonuclease domain encoded by the nucleoprotein. This exonuclease is therefore an attractive target for the design of novel antiviral drugs since exonuclease inhibitors might not only have a direct effect on the enzyme but could also boost viral clearance through stimulation of the innate immune system of the host cell. Here, in silico screening and an enzymatic assay were used to identify a novel, specific but weak inhibitor of the arenavirus exonuclease, with IC50 values of 65.9 and 68.6 µM for Mopeia virus and Lymphocytic choriomeningitis virus, respectively. This finding was further characterized using crystallographic and docking approaches. This study serves as a proof of concept and may have assigned a new therapeutic purpose for the bisphosphonate family, therefore paving the way for the development of inhibitors against Arenaviridae.
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Affiliation(s)
- Thi Hong Van Nguyen
- Aix-Marseille Université and Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS – UMR-7257, 13288 Marseille, France
| | - Elsie Yekwa
- Aix-Marseille Université and Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS – UMR-7257, 13288 Marseille, France
| | - Barbara Selisko
- Aix-Marseille Université and Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS – UMR-7257, 13288 Marseille, France
| | - Bruno Canard
- Aix-Marseille Université and Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS – UMR-7257, 13288 Marseille, France
- European Virus Bioinformatics Center, Leutragraben 1, 07743 Jena, Germany
| | - Karine Alvarez
- Aix-Marseille Université and Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS – UMR-7257, 13288 Marseille, France
| | - François Ferron
- Aix-Marseille Université and Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), CNRS – UMR-7257, 13288 Marseille, France
- European Virus Bioinformatics Center, Leutragraben 1, 07743 Jena, Germany
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Accumulation of zoledronic acid in rabbit intervertebral discs. J Chromatogr B Analyt Technol Biomed Life Sci 2022; 1197:123229. [DOI: 10.1016/j.jchromb.2022.123229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 11/19/2022]
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Sabel BO, Brand K, Rueckel J, Hoppe B, Fink N, Bartling S. Macrophage ablation significantly reduces uptake of imaging probe into organs of the reticuloendothelial system. Acta Radiol 2021; 62:882-889. [PMID: 32772706 DOI: 10.1177/0284185120943048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Macrophages engulf particulate contrast media, which is pivotal for biomedical imaging. PURPOSE To introduce a macrophage ablation animal model by showing its power to manipulate the kinetics of imaging probes. MATERIAL AND METHODS The kinetics of a particulate computed tomography (CT) contrast media was compared in macrophage ablative mice and normal mice. Liposomes (size 220 µg), loaded with clodronate, were injected into the peritoneum of three C57BL/6 mice. On the third day, 200 µL of the particulate agent ExiTron nano 6000 were injected into three macrophage-ablative mice and three control mice. CT scans were acquired before and 3 min, 1 h, 6 h, and 24 h after the ExiTron application. The animals were sacrificed, and their spleens and livers removed. Relative CT values (CTV) were measured and analyzed. RESULTS Liver and spleen enhancement of treated mice and controls were increasing over time. The median peak values were different with 225 CTV for treated mice and 582 CTV for controls in the liver (P = 0.032) and 431 CTV for treated and 974 CTV in controls in the spleen (P = 0.016). CONCLUSION Macrophage ablation leads to a decrease of enhancement in organs containing high numbers of macrophages, but only marginal changes in macrophage-poor organs. Macrophage ablation can influence the phagocytic activity and thus opens new potentials to investigate and manipulate the uptake of imaging probes.
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Affiliation(s)
- Bastian O Sabel
- Department of Radiology, German Cancer Research Center, Heidelberg, Germany
- Institute for Clinical Radiology, University Hospital Munich, Munich, Germany
| | | | - Johannes Rueckel
- Institute for Clinical Radiology, University Hospital Munich, Munich, Germany
| | - Boj Hoppe
- Institute for Clinical Radiology, University Hospital Munich, Munich, Germany
| | - Nicola Fink
- Institute for Clinical Radiology, University Hospital Munich, Munich, Germany
| | - Soenke Bartling
- Department of Radiology, German Cancer Research Center, Heidelberg, Germany
- Department of Clinical Radiology and Nuclear Medicine, Mannheim University Medical Center, Mannheim, Germany
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Cheviet T, Peyrottes S. Synthesis of Aminomethylene- gem-bisphosphonates Containing an Aziridine Motif: Studies of the Reaction Scope and Insight into the Mechanism. J Org Chem 2021; 86:3107-3119. [PMID: 33476157 DOI: 10.1021/acs.joc.0c02434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A broad range of N-carbamoylaziridines were obtained and then treated by the diethyl phosphonate anion to afford α-methylene-gem-bisphosphonate aziridines. Study of the reaction's scope and additional experiments indicates that the transformation proceeds via a new mechanism involving the chelation of lithium ion. This last step is crucial for the reaction to occur and disfavors the aziridine ring-opening. A phosphonate-phosphate rearrangement from a α-hydroxybisphosphonate aziridine intermediate is also proposed for the first time. This reaction provides a simple and convenient method for the synthesis of a highly functionalized phosphonylated aziridine motif.
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Affiliation(s)
- Thomas Cheviet
- Team Nucleosides & Phosphorylated Effectors, Institute for Biomolecules Max Mousseron (IBMM), UMR 5247 CNRS, ENSCM, Univ. Montpellier, Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier, France
| | - Suzanne Peyrottes
- Team Nucleosides & Phosphorylated Effectors, Institute for Biomolecules Max Mousseron (IBMM), UMR 5247 CNRS, ENSCM, Univ. Montpellier, Campus Triolet, cc1705, Place Eugène Bataillon, 34095 Montpellier, France
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Wang L, Fang D, Xu J, Luo R. Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review. BMC Cancer 2020; 20:1059. [PMID: 33143662 PMCID: PMC7607850 DOI: 10.1186/s12885-020-07568-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/26/2020] [Indexed: 12/19/2022] Open
Abstract
Zoledronic acid (ZA) is one of the most important and effective class of anti-resorptive drug available among bisphosphonate (BP), which could effectively reduce the risk of skeletal-related events, and lead to a treatment paradigm for patients with skeletal involvement from advanced cancers. However, the exact molecular mechanisms of its anticancer effects have only recently been identified. In this review, we elaborate the detail mechanisms of ZA through inhibiting osteoclasts and cancer cells, which include the inhibition of differentiation of osteoclasts via suppressing receptor activator of nuclear factor κB ligand (RANKL)/receptor activator of nuclear factor κB (RANK) pathway, non-canonical Wnt/Ca2+/calmodulin dependent protein kinase II (CaMKII) pathway, and preventing of macrophage differentiation into osteoclasts, in addition, induction of apoptosis of osteoclasts through inhibiting farnesyl pyrophosphate synthase (FPPS)-mediated mevalonate pathway, and activation of reactive oxygen species (ROS)-induced pathway. Furthermore, ZA also inhibits cancer cells proliferation, viability, motility, invasion and angiogenesis; induces cancer cell apoptosis; reverts chemoresistance and stimulates immune response; and acts in synergy with other anti-cancer drugs. In addition, some new ways for delivering ZA against cancer is introduced. We hope this review will provide more information in support of future studies of ZA in the treatment of cancers and bone cancer metastasis.
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Affiliation(s)
- Lianwei Wang
- Department of General Surgery, Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Dengyang Fang
- Department of General Surgery, Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Jinming Xu
- Department of General Surgery, Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Runlan Luo
- Department of Ultrasound, Fuling Central Hospital of Chongqing City, Chongqing, 408300, China.
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Liu C, Pang Q, Jiang Y, Xia Y, Fang L, Wang O, Li M, Xing X, Gong Y, Xia W. Defective O-glycosylation of novel FGF23 mutations in a Chinese family with hyperphosphatemic familial tumoral calcinosis. Bone 2020; 137:115401. [PMID: 32360901 DOI: 10.1016/j.bone.2020.115401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/25/2020] [Accepted: 04/28/2020] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Hyperphosphatemic familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome (HFTC/HHS) is a rare disorder caused by deficiency or resistance of fibroblast growth factor 23 (FGF23). Here we reported a Chinese family with HFTC/HHS, aiming at clarifying the clinical features, bone microarchitectures and molecular mechanisms of the disease. METHODS Clinical manifestations, laboratory examinations and genetic analyses were collected from two HFTC patients. Bone microarchitectures were detected by HR-pQCT. In vitro expression and glycosylation of mutant and wild-type FGF23 proteins were analyzed by western blotting and wheat germ agglutinin affinity chromatography. Subcellular localizations of FGF23 proteins were detected by immunocytochemistry. RESULTS The two brothers carried previously unreported c.413T > G, p.Leu138Arg and c.491T > A, p.Ile164Asn compound heterozygous variants in the FGF23 gene, which was "likely pathogenic" according to American College of Medical Genetics (ACMG) Standards and Guidelines. Both patients had severe hyperphosphatemia and significantly elevated C-terminal FGF23. With HHS, patient 1 presented with lower extremity pain and widespread cardiovascular calcification. HR-pQCT of his distal radius and tibia revealed decreased volume BMD and cortical thickness, which were inconsistent with hyperostosis manifestations in X-ray. He received etidronate treatment, which improved his BMD and the ectopic calcification. His brother exhibited less bone involvement but had experienced recurrent painful calcified mass from a young age and undergone several resections. In vitro experiments showed that the mutant FGF23 proteins had defective O-glycosylation and impaired secretion. However, no difference in subcellular localization was found between the wild-type and mutant FGF23 proteins. CONCLUSION We have presented a Chinese HFTC/HHS family with novel FGF23 c.413T > G, p.Leu138Arg and c.491T > A, p.Ile164Asn variants. We clarified the bone microarchitectures of HFTC/HHS patients by HR-pQCT, and expanded the genotype-phenotype spectrum of the disease. In vivo studies suggested that O-glycosylation of FGF23 plays an important role in the pathogenesis of HFTC/HHS, providing further understanding of the disease mechanism.
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Affiliation(s)
- Chang Liu
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Qianqian Pang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Musculoskeletal Research Laboratory and Bone Quality and Health Assessment Centre, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong
| | - Yan Jiang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yu Xia
- Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Ligang Fang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Ou Wang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mei Li
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiaoping Xing
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yiyi Gong
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
| | - Weibo Xia
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
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Wang J, Wu Y, Jiang J, Liu G, Zhu P. Analysis of bisphosphonate using ultraviolet-visible spectroscopy based on modified phosphorus determination reagent. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2020; 235:118308. [PMID: 32251892 DOI: 10.1016/j.saa.2020.118308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/16/2020] [Accepted: 03/25/2020] [Indexed: 06/11/2023]
Abstract
An improved phosphorous determination was developed using ethanol, phosphorus determination reagent (PDR) and Ultraviolet-visible spectroscopy (UV-Vis) for analyzing the bisphosphonates (BPs). The method was carried out under mild conditions without digestion, high temperature, high pressure, and other extreme conditions. Alcohols played an important role in this method. Without alcohol, this reaction system did not have a color reaction. Alendronate (ALN) and risedronate (RIS) were used to demonstrate the reliability of the improved phosphorous determination under different reaction conditions. The absorbance had an equal ratio of increase as well as a good trend line when the content of BPs increased. The improved phosphorous determination could be a new method to measure the drug content of BPs.
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Affiliation(s)
- Jinyu Wang
- Institution of Biomedicine and Tissue Engineering, School of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu 225002, PR China
| | - Yaping Wu
- Institution of Biomedicine and Tissue Engineering, School of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu 225002, PR China
| | - Jiawei Jiang
- Institution of Biomedicine and Tissue Engineering, School of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu 225002, PR China
| | - Guanxiong Liu
- Institution of Biomedicine and Tissue Engineering, School of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu 225002, PR China
| | - Peizhi Zhu
- Institution of Biomedicine and Tissue Engineering, School of Chemistry and Chemical Engineering, Yangzhou University, Jiangsu 225002, PR China.
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Robinson TE, Hughes EAB, Wiseman OJ, Stapley SA, Cox SC, Grover LM. Hexametaphosphate as a potential therapy for the dissolution and prevention of kidney stones. J Mater Chem B 2020; 8:5215-5224. [PMID: 32436557 DOI: 10.1039/d0tb00343c] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The incidence of kidney stones is increasing worldwide, and recurrence is common (50% within 5 years). Citrate, the current gold standard therapy, which is usually given as potassium or sodium salts, is used because it raises urine pH and chelates calcium, the primary component of up to 94% of stones. In this study hexametaphosphate (HMP), a potent calcium chelator, was found to be 12 times more effective at dissolving calcium oxalate, the primary component of kidney stones, than citrate. HMP was also observed to be effective against other common kidney stone components, namely calcium phosphate and struvite (magnesium ammonium phosphate). Interestingly, HMP was capable of raising the zeta potential of calcium oxalate particles from -15.4 to -34.6 mV, which may prevent stone growth by aggregation, the most rapid growth mechanism, and thus avert occlusion. Notably, HMP was shown to be up to 16 times as effective as citrate at dissolving human kidney stones under simulated physiological conditions. It may thus be concluded that HMP is a promising potential therapy for calcium and struvite kidney stones.
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Affiliation(s)
- Thomas E Robinson
- School of Chemical Engineering, University of Birmingham, Edgbaston, B15 2TT, UK. and Royal Centre for Defence Medicine, Birmingham Research Park, Vincent Drive, Edgbaston, B15 2SQ, UK
| | - Erik A B Hughes
- School of Chemical Engineering, University of Birmingham, Edgbaston, B15 2TT, UK.
| | - Oliver J Wiseman
- Department of Urology, Cambridge University Hospital, Cambridge, CB2 0QQ, UK
| | - Sarah A Stapley
- Royal Centre for Defence Medicine, Birmingham Research Park, Vincent Drive, Edgbaston, B15 2SQ, UK
| | - Sophie C Cox
- School of Chemical Engineering, University of Birmingham, Edgbaston, B15 2TT, UK.
| | - Liam M Grover
- School of Chemical Engineering, University of Birmingham, Edgbaston, B15 2TT, UK.
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New insights into molecular and cellular mechanisms of zoledronate in human osteosarcoma. Pharmacol Ther 2020; 214:107611. [PMID: 32565177 DOI: 10.1016/j.pharmthera.2020.107611] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
Osteosarcoma is the most common primary malignant tumor of the skeleton in teenagers and young adults and continues to confer a generally poor prognosis in patients who do not respond to chemotherapy or who present with metastatic diseases at diagnosis. The nitrogen-containing zoledronate, the third generation bisphosphonate (BP), effectively inhibits osteoclastic bone resorption and is widely utilized in the treatment of metabolic and metastatic bone diseases nowadays. Owing to an acceptable safety profile and tolerability, zoledronate is the only BP currently approved for the prevention and treatment of skeletal relevant events in patients with metastatic bone lesions, especially bone metastases from advanced renal cell carcinoma and prostate cancer, and breast cancer, due to all solid malignancy. Moreover, zoledronate possesses diverse anti-osteosarcoma properties and may have potential to become an adjunctive treatment for high-grade osteosarcoma to enhance survival rates and to obliterate complications of the chemotherapy. Herein we highlighted the pharmacology of BPs and its underlying molecular mechanisms in osteoclasts and various cancer cells. We further provided the available literature on in vitro studies to illustrate the new insights into the intracellular molecular mechanisms of zoledronate in human osteosarcoma cell lines and in vivo animal models that led to the development and regulatory approval of zoledronate in patients with human osteosarcoma. This review also addresses clinical trials to focus on the efficacy of zoledronate on human osteosarcoma.
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Kovacevic L, Lu H, Kovacevic N, Lakshmanan Y. Effect of bisphosphonates on the crystallization of stone-forming salts in synthetic urine. Investig Clin Urol 2020; 61:310-315. [PMID: 32377608 PMCID: PMC7189110 DOI: 10.4111/icu.2020.61.3.310] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 01/01/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose We investigated the inhibitory effect of bisphosphonates (BPs) on the crystallization of calcium oxalate monohydrate (COM), calcium phosphate (CaP), and magnesium ammonium phosphate (MAP) in synthetic urine, aiming to see 1) which specific BPs work best on a particular type of crystal and 2) what is the lowest concentration of BPs that inhibits crystal formation. Materials and Methods Crystals from synthetic urine were exposed to different concentrations of BPs. Urinary turbidity was used as a marker of crystallization and was measured by spectrophotometry by use of a validated method in our laboratory. The percent inhibitory activity (IA) was calculated by using the formula: (a−b )/a×100, where a is baseline maximal turbidity and b is maximal turbidity with various concentrations of medication. Potassium citrate and magnesium citrate were used as positive controls. Results At the lowest dose of 0.001 mg/mL, risedronate induced the highest IA of 37% on CaP, whereas ibandronate had the strongest IA on COM (24%). To initiate the inhibition of MAP crystallization, risedronate required a two-fold higher concentration (0.002 mg/mL) to reach 30% IA, whereas etidronate required a four-fold higher concentration (0.004 mg/mL) to reach 42% IA. Conclusions BPs are good inhibitors of crystallization in synthetic urine, with risedronate and ibandronate being the most potent. At a low clinically acceptable dose, their highest inhibitory action was on CaP and COM crystals. Higher doses were needed to prevent MAP crystallization. Further investigation of the use of BPs in kidney stone prevention is warranted.
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Affiliation(s)
- Larisa Kovacevic
- Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI, USA
| | - Hong Lu
- Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI, USA
| | - Natalija Kovacevic
- Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI, USA.,Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA
| | - Yegappan Lakshmanan
- Department of Pediatric Urology, Children's Hospital of Michigan, Detroit, MI, USA
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Saha HH, Ala-Houhala IO, Liukko-Sipi SH, Ylitalo P, Pasternack AI. Pharmacokinetics of Clodronate in Peritoneal Dialysis Patients. Perit Dial Int 2020. [DOI: 10.1177/089686089801800210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective To study the pharmacokinetics of clodronate in patients on continuous ambulatory peritoneal dialysis (CAPD). Design A single intravenous dose pharmacokinetic study. Setting University hospital. Patients Ten CAPD patients (3 female, 7 male, age 39 79 year, median 55). Methods Clodronate disodium in serum, urine, and dialysate was collected for 24 hours and analyzed by capillary gas chromatography with mass-selective detection. Results Only 7% of the infused dose of clodronate was eliminated through peritoneal dialysis during 24 hours. Clearance via CAPD (CLCAPD) was 2.4 ± 0.6 mL/min, which was less than 10% of the total serum clearance (CLtot’ 26.0 ± 19.3 mL/min). Even the kidneys were a more important route of elimination than CAPD in those patients with residual diuresis of more than 500 mL/24 hr. However, in all patients most of the clodronate serum clearance (77% ± 13%) took place via routes other than peritoneal dialysis or kidneys, that is, via nonrenal-non-CAPD clearance (CLNRD). CLNRD most likely represents the part of the drug deposited in the skeleton. There was a positive correlation between CLNRD and the plasma intact parathyroid hormone concentration. Conclusions CAPD removed clodronate poorly from the circulation. Most clearance took place via routes other than CAPD or kidneys. This CLNRD most likely represents the skeletal deposition of the drug, and this is related to the severity of hyperparathyroidism. When treating CAPD patients with hyperparathyroid bone disease, the administration of clodronate should be adjusted as in those subjects with severe renal failure.
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Affiliation(s)
- Heikki H.T. Saha
- University of Tampere, Medical School, Turku, Finland
- Tampere University Hospital, Tampere, Turku, Finland
| | | | | | - Pauli Ylitalo
- University of Tampere, Medical School, Turku, Finland
- Tampere University Hospital, Tampere, Turku, Finland
| | - Amos I. Pasternack
- University of Tampere, Medical School, Turku, Finland
- Tampere University Hospital, Tampere, Turku, Finland
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Parwin A, Najmi AK, Ismail MV, Kaundal M, Akhtar M. Protective effects of alendronate in Triton X-100-induced hyperlipidemia in rats. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:557-564. [PMID: 31144662 DOI: 10.5152/tjg.2019.18076] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS The aim of the present study was to evaluate the protective effects of alendronate (used in osteoporosis disease) in Triton X-100 (a polyethylene glycol-based non-ionic surfactant)-induced hyperlipidemia in rats. MATERIALS AND METHODS The animals were randomized into seven groups receiving different treatments for 21 days, and alendronate was administered (1.5 and 3 mg/kg body weight, per orally (p.o.) by oral gavage). On day 21, the rats were anesthetized and decapitated, blood samples were extracted, and the livers were dissected for various biochemical tests and histopathological examinations. RESULTS The biochemical parameters, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein-cholesterol (LDL-C), very low-density lipoprotein-cholesterol (VLDL-C), thiobarbituric acid reactive substances (TBARS), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and atherogenic index, were increased, and reduction in high-density lipoprotein-cholesterol (HDL-C) levels was observed following Triton X-100 treatment to rats. Alendronate (1.5 and 3 mg/kg) produced a dose-dependent reduction in serum TC, VLDL-C, TGs, ratio of TC/HDL-C, ALT, AST, and TBARS. It significantly increased the HDL-C and superoxide dismutase levels but did not cause a significant decrease in serum LDL-C and/or an increase in catalase levels. Histopathological examinations of alendronate showed beneficial effects with lower capsular thickening, slight enlargement of the hepatocytes at the margin, and lower inflammatory cell infiltration. CONCLUSION Alendronate showed dose-dependent antihyperlipidemic and hepatoprotective effects. It may serve a dual purpose as anti-osteoporotic and hypolipidemic by reducing blood cholesterol and TG synthesis and offering hepatic protection.
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Affiliation(s)
- Ashiyana Parwin
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mohd Vasim Ismail
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Madhu Kaundal
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Mohd Akhtar
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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15
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Tzschentke TM. Pharmacology of bisphosphonates in pain. Br J Pharmacol 2019; 178:1973-1994. [PMID: 31347149 DOI: 10.1111/bph.14799] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/11/2019] [Accepted: 07/19/2019] [Indexed: 01/15/2023] Open
Abstract
The treatment of pain, in particular, chronic pain, remains a clinical challenge. This is particularly true for pain associated with severe or rare conditions, such as bone cancer pain, vulvodynia, or complex regional pain syndrome. Over the recent years, there is an increasing interest in the potential of bisphosphonates in the treatment of pain, although there are few papers describing antinociceptive and anti-hypersensitizing effects of bisphosphonates in various animal models of pain. There is also increasing evidence for clinical efficacy of bisphosphonates in chronic pain states, although the number of well-controlled studies is still limited. However, the mechanisms underlying the analgesic effects of bisphosphonates are still largely elusive. This review provides an overview of preclinical and clinical studies of bisphosphonates in pain and discusses various pharmacological mechanisms that have been postulated to explain their analgesic effects. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
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16
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Terzopoulou Z, Baciu D, Gounari E, Steriotis T, Charalambopoulou G, Tzetzis D, Bikiaris D. Composite Membranes of Poly(ε-caprolactone) with Bisphosphonate-Loaded Bioactive Glasses for Potential Bone Tissue Engineering Applications. Molecules 2019; 24:E3067. [PMID: 31450742 PMCID: PMC6749304 DOI: 10.3390/molecules24173067] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/16/2019] [Accepted: 08/21/2019] [Indexed: 12/11/2022] Open
Abstract
Poly(ε-caprolactone) (PCL) is a bioresorbable synthetic polyester with numerous biomedical applications. PCL membranes show great potential in guided tissue regeneration because they are biocompatible, occlusive and space maintaining, but lack osteoconductivity. Therefore, two different types of mesoporous bioactive glasses (SiO2-CaO-P2O5 and SiO2-SrO-P2O5) were synthesized and incorporated in PCL thin membranes by spin coating. To enhance the osteogenic effect of resulting membranes, the bioglasses were loaded with the bisphosphonate drug ibandronate prior to their incorporation in the polymeric matrix. The effect of the composition of the bioglasses as well as the presence of absorbed ibandronate on the physicochemical, cell attachment and differentiation properties of the PCL membranes was evaluated. Both fillers led to a decrease of the crystallinity of PCL, along with an increase in its hydrophilicity and a noticeable increase in its bioactivity. Bioactivity was further increased in the presence of a Sr substituted bioglass loaded with ibandronate. The membranes exhibited excellent biocompatibility upon estimation of their cytotoxicity on Wharton's Jelly Mesenchymal Stromal Cells (WJ-SCs), while they presented higher osteogenic potential in comparison with neat PCL after WJ-SCs induced differentiation towards bone cells, which was enhanced by a possible synergistic effect of Sr and ibandronate.
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Affiliation(s)
- Zoi Terzopoulou
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, GR54124 Thessaloniki, Central Macedonia, Greece.
| | - Diana Baciu
- National Center for Scientific Research "Demokritos", GR15341 Athens, Ag. Paraskevi Attikis, Greece
| | - Eleni Gounari
- Biohellenika Biotechnology Company, Leoforos Georgikis Scholis 65, GR57001 Thessaloniki, Central Macedonia, Greece
| | - Theodore Steriotis
- National Center for Scientific Research "Demokritos", GR15341 Athens, Ag. Paraskevi Attikis, Greece
| | - Georgia Charalambopoulou
- National Center for Scientific Research "Demokritos", GR15341 Athens, Ag. Paraskevi Attikis, Greece
| | - Dimitrios Tzetzis
- School of Science and Technology, International Hellenic University, GR57001 Thermi, Central Macedonia, Greece
| | - Dimitrios Bikiaris
- Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, GR54124 Thessaloniki, Central Macedonia, Greece
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17
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Salin AV, Il'in AV, Faskhutdinov RI, Fayzullin RR. Phosphine-catalyzed bishydrophosphorylation of electron-deficient alkynes. Tetrahedron 2019. [DOI: 10.1016/j.tet.2019.03.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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18
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Rojek T, Goldeman W, Ślepokura K, Zierkiewicz W, Matczak-Jon E. Deciphering preferred solid-state conformations in nitrogen-containing bisphosphonates and their coordination compounds. A case study of discrete Cu( ii) complexes based on C α-substituted analogues of zoledronic acid: crystal structures and solid-state characterization. CrystEngComm 2019. [DOI: 10.1039/c9ce00614a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Conformation diversity of N-containing bisphosphonic acids and related anions within their metal complexes and salts.
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Affiliation(s)
- Tomasz Rojek
- Department of Chemistry
- Wrocław University of Science and Technology
- 50-370 Wrocław
- Poland
| | - Waldemar Goldeman
- Department of Chemistry
- Wrocław University of Science and Technology
- 50-370 Wrocław
- Poland
| | | | - Wiktor Zierkiewicz
- Department of Chemistry
- Wrocław University of Science and Technology
- 50-370 Wrocław
- Poland
| | - Ewa Matczak-Jon
- Department of Chemistry
- Wrocław University of Science and Technology
- 50-370 Wrocław
- Poland
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19
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Rousseau M, Retrouvey JM. Osteogenesis imperfecta: potential therapeutic approaches. PeerJ 2018; 6:e5464. [PMID: 30128210 PMCID: PMC6100848 DOI: 10.7717/peerj.5464] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/27/2018] [Indexed: 11/20/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a genetic disorder that is usually caused by disturbed production of collagen type I. Depending on its severity in the patient, this disorder may create difficulties and challenges for the dental practitioner. The goal of this article is to provide guidelines based on scientific evidence found in the current literature for practitioners who are or will be involved in the care of these patients. A prudent approach is recommended, as individuals affected by OI present with specific dentoalveolar problems that may prove very difficult to address. Recommended treatments for damaged/decayed teeth in the primary dentition are full-coverage restorations, including stainless steel crowns or zirconia crowns. Full-coverage restorations are also recommended in the permanent dentition. Intracoronal restorations should be avoided, as they promote structural tooth loss. Simple extractions can also be performed, but not immediately before or after intravenous bisphosphonate infusions. Clear aligners are a promising option for orthodontic treatment. In severe OI types, such as III or IV, orthognathic surgery is discouraged, despite the significant skeletal dysplasia present. Given the great variations in the severity of OI and the limited quantity of information available, the best treatment option relies heavily on the practitioner’s preliminary examination and judgment. A multidisciplinary team approach is encouraged and favored in more severe cases, in order to optimize diagnosis and treatment.
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Affiliation(s)
- Maxime Rousseau
- Faculty of Dentistry, McGill University, Montreal, QC, Canada
| | - Jean-Marc Retrouvey
- Faculty of Dentistry, Department of Orthodontics, McGill University, Montreal, QC, Canada
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20
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Ipshita S, Kurian IG, Dileep P, Kumar S, Singh P, Pradeep AR. One percent alendronate and aloe vera gel local host modulating agents in chronic periodontitis patients with class II furcation defects: A randomized, controlled clinical trial. ACTA ACUST UNITED AC 2018; 9:e12334. [PMID: 29722166 DOI: 10.1111/jicd.12334] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 01/19/2018] [Indexed: 12/14/2022]
Abstract
AIM Alendronate (ALN) has antiresorptive and osteostimulative properties. The major component of aloe vera (AV) gel is acemannan, which has been found to have osteogenic properties. The aim of the present study is to explore the effectiveness of 1% ALN and AV gel as an adjunct to scaling and root planing (SRP) in chronic periodontitis patients with class II furcation defects. METHODS Ninety volunteers were randomly assigned to three treatment groups: (a) SRP plus placebo gel; (b) SRP plus 1% ALN gel; and (c) SRP plus AV gel. Clinical and radiographic parameters were recorded at baseline and at 6 and 12 months. RESULTS The mean probing depth reduction and relative horizontal clinical attachment level (CAL) and relative vertical CAL gains were greater in the ALN group than in the AV and placebo groups at 6 and 12 months. Furthermore, a significantly greater mean percentage of defect depth reduction (DDR) was found in the ALN group (38.09 ± 9.53, 44.86 ± 6.29) than the AV groups (11.94 ± 15.10, 14.59 ± 25.49) at 6 and 12 months, respectively. CONCLUSION ALN showed significant improvement in all clinical parameters, along with greater DDR, compared to AV in the treatment of class II furcation defects as an adjunct to SRP.
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Affiliation(s)
- Sahu Ipshita
- Department of Periodontology, Government Dental College and Research Institute, Bangalore, Karnataka, India
| | - Ida G Kurian
- Department of Periodontology, Government Dental College and Research Institute, Bangalore, Karnataka, India
| | - Pankaj Dileep
- Department of Periodontology, Government Dental College and Research Institute, Bangalore, Karnataka, India
| | - Shatrughan Kumar
- Department of Medicine, Employee's State Insurance Postgraduate Institute of Medical Science and Research, Bangalore, Karnataka, India
| | - Priyanka Singh
- Department of Opthalmology, Grant Medical College and JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Avani R Pradeep
- Department of Periodontology, Government Dental College and Research Institute, Bangalore, Karnataka, India
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21
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Mashiba T, Saito M, Yamagami Y, Tanaka M, Iwata K, Yamamoto T. Effects of suppressed bone remodeling by minodronic acid and alendronate on bone mass, microdamage accumulation, collagen crosslinks and bone mechanical properties in the lumbar vertebra of ovariectomized cynomolgus monkeys. Bone 2017; 97:184-191. [PMID: 28082077 DOI: 10.1016/j.bone.2017.01.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 12/16/2016] [Accepted: 01/06/2017] [Indexed: 01/22/2023]
Abstract
Collagen crosslinking is an important determinant of the quality of bone material. We have previously shown that suppressed bone turnover by high doses of minodronic acid and alendronate increases compressive strength of vertebra, but also increases microdamage accumulation, in monkey bone. The aim of this study is to examine the effects of these bisphosphonates on collagen crosslinks and intrinsic material properties, in addition to microdamage accumulation, in vertebral cancellous bone in ovariectomized cynomolgus monkeys. Sixty female monkeys aged 9-17years were divided into five groups: sham and ovariectomized groups were treated daily for 17months with lactose vehicle, and the other three groups were given minodronic acid daily at 0.015 or 0.15mg/kg or alendronate daily at 0.5mg/kg orally. After sacrifice, lumbar vertebrae were subjected to histomorphometry, microdamage measurement, analysis of collagen crosslinking and compressive mechanical tests. Minodronic acid caused dose-dependent suppression of increased bone remodeling due to ovariectomy, and low-dose minodronic acid suppressed remodeling same level as alendronate. However, low-dose minodronic acid did not change microdamage accumulation, collagen maturity and the pentosidine level, whereas high-dose minodronic acid and alendronate increased these parameters. Compressive ultimate load was increased following high-dose minodronic acid and alendronate, but no treatment altered the reduction in intrinsic material properties caused by ovariectomy. These findings suggest that deterioration of bone material and formation of pentosidine and microdamage induced by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate, but this was not reflected in any significant change of mechanical properties.
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Affiliation(s)
- Tasuku Mashiba
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan.
| | - Mitsuru Saito
- Department of Orthopedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Yoshiki Yamagami
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Makoto Tanaka
- Research Promotion, Ono Pharmaceutical Co., Ltd., Osaka, Japan
| | - Ken Iwata
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Tetsuji Yamamoto
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan
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Erfani M, Rahmani N, Doroudi A, Shafiei M. Preparation and evaluation of rhenium-188-pamidronate as a palliative treatment in bone metastasis. Nucl Med Biol 2017; 49:1-7. [PMID: 28279906 DOI: 10.1016/j.nucmedbio.2017.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 02/13/2017] [Accepted: 02/22/2017] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Rhenium-188-hydroxyethylidene diphosphonate (188Re-HEDP) as a first generation bisphosphonate has been widely used for bone seeking radiopharmaceutical in cases of metastatic bone disease. No study has been yet reported on preparing a complex of 188Re with pamidronate (3-aminohydroxypropylidene-1,1-bisphosphonic acid) (PMA) as a second generation bisphosphonate. Based on this fact, it was hypothesized that a bone-seeking 188Re-PMA radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. METHODS Pamidronate was labeled with 188ReO4- eluted from the alumina based 188W/188Re generator. Labeling was optimized, and radiochemical analysis was performed by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). Biodistribution of this radioconjugate was evaluated and verified further in mice. RESULTS 188Re-PMA was prepared successfully in a high labeling yield (˃95%) corresponding to a specific activity of 124MBq/μmol and good in vitro stability, but it is likely to consist of multiple species. In biodistribution studies selective uptake and retention of activity in the skeletal system (0.81±0.25% ID/g and 0.57±0.16 at 4 and 48h in bone post injection respectively) followed by clearance in the soft tissues were observed. CONCLUSION These results show that due to its biological capabilities it would be advantageous to use 188Re-PMA for bone pain palliation therapy.
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Affiliation(s)
- Mostafa Erfani
- Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), P.O.Box: 14395-836, Tehran, Iran.
| | - Nasim Rahmani
- School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, P.O.Box: 61357-33184, Ahvaz, Iran
| | - Alireza Doroudi
- School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, P.O.Box: 61357-33184, Ahvaz, Iran
| | - Mohammad Shafiei
- Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), P.O.Box: 14395-836, Tehran, Iran
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Guven MN, Seckin Altuncu M, Demir Duman F, Eren TN, Yagci Acar H, Avci D. Bisphosphonate-functionalized poly(β-amino ester) network polymers. J Biomed Mater Res A 2017; 105:1412-1421. [PMID: 28165665 DOI: 10.1002/jbm.a.36026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/26/2017] [Accepted: 01/31/2017] [Indexed: 01/20/2023]
Abstract
Three novel bisphosphonate-functionalized secondary diamines are synthesized and incorporated into poly(β-amino ester)s (PBAEs) to investigate the effects of bisphosphonates on biodegradation and toxicity of PBAE polymer networks. These three novel amines, BPA1, BPA2, and BPA3, were prepared from the reactions of 1,4-butanediamine, 1,6-hexanediamine, or 4,9-dioxa-1,12-dodecanediamine with tetraethyl vinylidene bisphosphonate, respectively. The PBAE macromers were obtained from the aza-Michael addition reaction of these amines to 1,6-hexane diol diacrylate (HDDA) and poly(ethylene glycol) diacrylate (PEGDA, Mn = 575) and photopolymerized to produce biodegradable gels. These gels with different chemistries exhibited similar degradation behavior with mass loss of 53-73% within 24 h, indicating that degradation is mostly governed by the bisphosphonate group. Based on the in vitro cytotoxicity evaluation against NIH 3T3 mouse embryonic fibroblast cells, the degradation products do not exhibit significant toxicity in most cases. It was also shown that PBAE macromers can be used as cross-linkers for the synthesis of 2-hydroxyethyl methacrylate hydrogels, conferring small and customizable degradation rates upon them. The materials reported have potential to be used as nontoxic degradable biomaterials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1412-1421, 2017.
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Affiliation(s)
- Melek Naz Guven
- Department of Chemistry, Bogazici University, 34342 Bebek, Istanbul, Turkey
| | | | - Fatma Demir Duman
- Graduate School of Materials Science and Engineering, Koc University, Sariyer, Istanbul, 34450, Turkey
| | - Tugce Nur Eren
- Department of Chemistry, Bogazici University, 34342 Bebek, Istanbul, Turkey
| | - Havva Yagci Acar
- Graduate School of Materials Science and Engineering, Koc University, Sariyer, Istanbul, 34450, Turkey.,Department of Chemistry, Koc University, Sariyer, Istanbul, 34450, Turkey
| | - Duygu Avci
- Department of Chemistry, Bogazici University, 34342 Bebek, Istanbul, Turkey
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Kimmel D. Mechanism of Action, Pharmacokinetic and Pharmacodynamic Profile, and Clinical Applications of Nitrogen-containing Bisphosphonates. J Dent Res 2016; 86:1022-33. [DOI: 10.1177/154405910708601102] [Citation(s) in RCA: 183] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Nitrogen-containing bisphosphonates (nBPs) are bone-specific agents that inhibit farnesyl diphosphate synthase. nBPs’ strong affinity for bone, and not for other tissues, makes them potent inhibitors of bone resorption and bone remodeling activity, with limited potential for side-effects in non-skeletal tissues. Five nBPs are currently approved in the United States. The primary indications are for treatment of osteoporosis (alendronate, ibandronate, and risedronate) and treatment/prevention of skeletal-related events (SREs) in multiple myeloma and breast and prostate cancer patients (ibandronate, pamidronate, and zoledronic acid). nBPs are the most efficacious drugs available for these diseases, reducing osteoporotic fracture risk by 50–60% in persons with low bone mass or prior osteoporotic fracture, and SREs by one-third in cancer patients. The absorbed nBP dose for cancer patients is from seven to ten times that in osteoporosis patients. nBPs are unique in that they first exert profound pharmacodynamic effects long after their blood levels reach zero. Current pharmacokinetic studies indicate that approximately half of any nBP dose reaches the skeleton, with an early half-life of ten days, and a terminal half-life of about ten years. Practical study design limitations and theoretical considerations suggest that both the half-life and the amount of nBP retained in the skeletons of patients on long-term nBP therapy are substantially overestimated by extrapolation directly from current pharmacokinetic data. In fact, the amount of nBP being released from skeletal tissues of long-term-treated patients, particularly in osteoporosis patients, becomes insufficient to maintain full pharmacodynamic efficacy relatively soon after dosing is interrupted.
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Affiliation(s)
- D.B. Kimmel
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
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25
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Kanoriya D, Pradeep AR, Garg V, Singhal S. Mandibular Degree II Furcation Defects Treatment With Platelet-Rich Fibrin and 1% Alendronate Gel Combination: A Randomized Controlled Clinical Trial. J Periodontol 2016; 88:250-258. [PMID: 27712462 DOI: 10.1902/jop.2016.160269] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Different materials have been investigated for renewal of lost supporting periodontal structures and tested for furcation defect treatment. Platelet-rich fibrin (PRF) is a pool of growth-promoting factors and cytokines that promote bone regeneration and maturation of soft tissue. Alendronate (ALN), an influential member of the bisphosphonate group, is known to enhance osteoblastogenesis and inhibit osteoclastic bone resorption, thus promoting tissue regeneration. This randomized trial was done to assess effectiveness of PRF and 1% ALN gel combination in mandibular degree II furcation defect treatment in comparison with PRF and access therapy alone. METHODS Seventy-two mandibular molar furcation defects were treated with either access therapy alone (group 1), access therapy with PRF (group 2), or access therapy with PRF and 1% ALN (group 3). Plaque index, modified sulcus bleeding index, probing depth (PD), relative vertical attachment level (RVAL) and relative horizontal attachment level (RHAL), and intrabony defect depth were recorded at baseline and 9 months postoperatively. Radiographically, defect fill, assessed in percentage, was evaluated at baseline, before surgery, and 9 months post-therapy. RESULTS Group 3 showed greater PD reduction and RVAL and RHAL gain when compared with groups 1 and 2 postoperatively. Moreover, group 3 sites showed a significantly greater percentage of radiographic defect fill (56.01% ± 2.64%) when compared with group 2 (49.43% ± 3.70%) and group 1 (10.25% ± 3.66%) at 9 months. CONCLUSIONS Furcation defect treatment with autologous PRF combined with 1% ALN gel results in significant therapeutic outcomes when compared with PRF and access therapy alone. Combining ALN with PRF has potential for regeneration of furcation defects without any adverse effect on healing process.
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Affiliation(s)
- Dharmendra Kanoriya
- Department of Periodontology, Government Dental College and Research Institute (GDCRI), Bangalore, Karnataka, India
| | - A R Pradeep
- Department of Periodontology, Government Dental College and Research Institute (GDCRI), Bangalore, Karnataka, India
| | - Vibhuti Garg
- Department of Periodontology, Government Dental College and Research Institute (GDCRI), Bangalore, Karnataka, India
| | - Sandeep Singhal
- Department of Periodontology, Government Dental College and Research Institute (GDCRI), Bangalore, Karnataka, India
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Abstract
OBJECTIVE Due to accumulation in the bone matrix and a half-life of at least 10 years, it is important to understand the cellular impact of bisphosphonates (BPs). This study assessed the effects of alendronate (ALN) on human primary osteoblasts. MATERIAL AND METHODS Osteoblasts were incubated with ALN (5, 20 and 100 μM), and both cells and cell culture media were harvested after d 1, 3, 7 or 14. Proliferation was evaluated by 3H-thymidine incorporation and tetrazolium dye (MTT) colorimetric assay, and viability by the lactate dehydrogenase (LDH) activity in the medium. Differentiation was evaluated using protein Luminex multiplex assays and RT-PCR. RESULTS ALN had no significant effects on cell viability. The lower concentrations enhanced the proliferation, whereas 100 μM diminished the proliferation. mRNA expression of osteocalcin (OC), alkaline phosphatase (ALP) and α-1 type 1 collagen were reduced, whereas ALN enhanced the expression of leptin mRNA and the secretion of interleukin-8 (IL-8) and regulated on activation normal T cell expressed and secreted (RANTES). CONCLUSIONS ALN enhanced the secretion of immune factors from human osteoblasts. Combined with a lower rate of proliferation and a decline in differentiation, this indicates that higher dosages or accumulation may cause undesirable local changes in bone.
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Kanoriya D, Pradeep AR, Singhal S, Garg V, Guruprasad CN. Synergistic Approach Using Platelet-Rich Fibrin and 1% Alendronate for Intrabony Defect Treatment in Chronic Periodontitis: A Randomized Clinical Trial. J Periodontol 2016; 87:1427-1435. [PMID: 27562221 DOI: 10.1902/jop.2016.150698] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Platelet-rich fibrin (PRF) is a reservoir of concentrated platelets that provides a pool of biologic growth-promoting factors and cytokines, which help in mediating regeneration of lost bone and soft tissue maturation. Alendronate (ALN), a member of the amino-bisphosphonate group, is known to enhance periodontal tissue regeneration by inhibiting osteoclast-mediated bone resorption and promoting osteoblast-mediated osteogenesis. The current intervention aims to assess combined effectiveness of PRF and 1% ALN with access therapy in intrabony defect (IBD) treatment in patients with chronic periodontitis (CP). METHODS Single IBDs in 90 patients were categorized into three groups: 1) group 1 had access therapy alone; 2) group 2 had access therapy with PRF; and 3) group 3 had access therapy with PRF + 1% ALN. Site-specific plaque index, modified sulcus bleeding index, probing depth (PD), clinical attachment level (CAL), and gingival marginal level, included as parameters for clinical assessment, were evaluated before surgery at baseline and 9 months postoperatively. Percentage IBD depth reduction, assessed using radiographs, was evaluated at baseline and postoperatively. RESULTS Compared with groups 1 and 2, group 3 exhibited significantly greater reduction in PD and gain in CAL postoperatively. Significantly greater IBD depth reduction was shown in group 3 (54.05% ± 2.88%) compared with group 2 (46% ± 1.89%) and group 1 (7.33% ± 4.86%) postoperatively. CONCLUSION Combined approach therapy of PRF + 1% ALN for IBD treatment in patients with CP showed better clinical parameter outcomes with greater IBD depth reduction compared with PRF and access therapy alone.
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Affiliation(s)
- Dharmendra Kanoriya
- Department of Periodontology, Government Dental College and Research Institute, Bengaluru, Karnataka, India
| | - A R Pradeep
- Department of Periodontology, Government Dental College and Research Institute, Bengaluru, Karnataka, India
| | - Sandeep Singhal
- Department of Periodontology, Government Dental College and Research Institute, Bengaluru, Karnataka, India
| | - Vibhuti Garg
- Department of Periodontology, Government Dental College and Research Institute, Bengaluru, Karnataka, India
| | - C N Guruprasad
- Department of Periodontology, Government Dental College and Research Institute, Bengaluru, Karnataka, India
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Abstract
Hypercalcemia is a common complication of cancer and occurs in 10—20% of patients. Although treatment of the underlying cancer is the optimal therapy, this may not be prac tical or available for many patients. This re port details our approach to the management of hypercalcemia at the British Columbia Can cer Agency, Vancouver Cancer Centre. The recommended approach to therapy is hydra tion followed by pamidronate and if needed, calcitonin. If no response is noted, plicamy cin may be used as a second line agent. In patients with multiple myeloma and lym phoma, prednisone is also suggested.
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Affiliation(s)
- Lynne Nakashima
- B.C. Cancer Agency, Vancouver Cancer Centre, Pharmacy Department, Vancouver, British Columbia, Canada
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Menzdorf L, Weuster M, Klüter T, Brüggemann S, Behrendt P, Fitchen-Oestern S, Varoga D, Seekamp A, Purcz N, Glueer CC, Pufe T, Lippross S. Local pamidronate influences fracture healing in a rodent femur fracture model: an experimental study. BMC Musculoskelet Disord 2016; 17:255. [PMID: 27283180 PMCID: PMC4899908 DOI: 10.1186/s12891-016-1113-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 06/02/2016] [Indexed: 11/17/2022] Open
Abstract
Background Bisphosphonates are a main component in the therapy of osteoporosis and other bone resorptive diseases. Previous studies have shown a positive effect of systemically applied bisphosphonates on fracture healing. Nevertheless high doses are related to side effects like osteonecrosis of the jaw, nephrotoxis and gastrointestinal symptoms. In this study we investigated the effect of locally applied pamidronate on fracture healing. Methods In a rodent model a simple femur fracture was set in female Wistar rats. We performed intramedullary fixation of the fracture and placed a collagen matrix around the fracture area. One group was treated with pamidronate, the other group with placebo via the matrix. To investigate the volume and quality of the callus we used micro-CT (μCT) and histology after 14 and 28 days. Results Our results show a positive influence of local applied pamidronate on callus volume. After 14 days an insignificant increase of callus volume in the treated animals was seen. 28 days after trauma the increase of callus volume in the treatment group was significantly higher in comparison to the control group. Osteonecrosis was not seen. Conclusions Locally applied bisphosphonates increase the callus volume in fracture healing.
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Affiliation(s)
- Leif Menzdorf
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
| | - Matthias Weuster
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Tim Klüter
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Stefan Brüggemann
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Peter Behrendt
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Stefanie Fitchen-Oestern
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Deike Varoga
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Andreas Seekamp
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Nicolai Purcz
- Department of Oral and Maxillofacial Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Claus C Glueer
- Section of Biomedical Imaging, Department of Radiology and Neuroradiology, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Thomas Pufe
- Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany
| | - Sebastian Lippross
- Department of Trauma Surgery, University Medical Center of Schleswig-Holstein, Campus Kiel, Kiel, Germany
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Conry RM, Rodriguez MG, Pressey JG. Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients. Clin Sarcoma Res 2016; 6:6. [PMID: 27127605 PMCID: PMC4848872 DOI: 10.1186/s13569-016-0046-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 03/29/2016] [Indexed: 12/29/2022] Open
Abstract
Background Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. Methods The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression. Results In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18–20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA. Conclusions Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.
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Affiliation(s)
- Robert M Conry
- Division of Hematology Oncology, University of Alabama at Birmingham, 2145 Bonner Way, Birmingham, AL 35243 USA
| | - Michael G Rodriguez
- Department of Radiology, University of Alabama at Birmingham, 619 19th St South, Birmingham, AL 35249 USA
| | - Joseph G Pressey
- Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, Birmingham, AL 35233 USA ; Cancer & Blood Disorders Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH USA
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Coleman R. Bone targeted treatments in cancer - The story so far. J Bone Oncol 2016; 5:90-92. [PMID: 27761363 PMCID: PMC5063216 DOI: 10.1016/j.jbo.2016.03.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 03/24/2016] [Indexed: 02/04/2023] Open
Affiliation(s)
- Robert Coleman
- University of Sheffield Weston Park Hospital, Sheffield S10 2SJ, United Kingdom
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32
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Storrer CLM, Deliberador TM, Giovanini AF, Crivellaro V, Zielak JC, Romito GA. Effect of alendronate on the progression of periodontitis induced by Porphyromonas gingivalis and Fusobacterium nucleatum: a study in rats. Clin Oral Investig 2016; 20:2565-2573. [DOI: 10.1007/s00784-016-1769-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 02/29/2016] [Indexed: 01/03/2023]
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Could drugs inhibiting the mevalonate pathway also target cancer stem cells? Drug Resist Updat 2016; 25:13-25. [PMID: 27155373 DOI: 10.1016/j.drup.2016.02.001] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 12/12/2015] [Accepted: 01/28/2016] [Indexed: 02/07/2023]
Abstract
Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.
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Kemnitz M, Tabatabai M, Utterodt A, Ritter H. New materials from dimethacrylates bearing phosphonic acid and thioether groups. POLYM INT 2015. [DOI: 10.1002/pi.5048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Melanie Kemnitz
- Institute of Organic Chemistry and Macromolecular Chemistry; Heinrich-Heine-University; Universitätsstraße 1 40225 Düsseldorf Germany
| | - Monir Tabatabai
- Institute of Organic Chemistry and Macromolecular Chemistry; Heinrich-Heine-University; Universitätsstraße 1 40225 Düsseldorf Germany
| | - Andreas Utterodt
- Heraeus Kulzer GmbH; Philipp-Reis-Straße 8 61273 Wehrheim Germany
| | - Helmut Ritter
- Institute of Organic Chemistry and Macromolecular Chemistry; Heinrich-Heine-University; Universitätsstraße 1 40225 Düsseldorf Germany
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Schott S, Vallet S, Tower RJ, Noor S, Tiwari S, Schem C, Busch C. In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis. Invest New Drugs 2015; 33:816-26. [PMID: 25986684 DOI: 10.1007/s10637-015-0253-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 05/12/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2'-desoxyuridine (5-FdU) results in N(4)-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2'-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. METHODS In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. RESULTS A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. CONCLUSION The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation.
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Affiliation(s)
- Sarah Schott
- Department of Gynecology and Obstetrics, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany,
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Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages. Nat Commun 2015; 6:6332. [PMID: 25757189 DOI: 10.1038/ncomms7332] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 01/20/2015] [Indexed: 12/28/2022] Open
Abstract
Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.
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Bhansali RS. Non-surgical periodontal therapy: An update on current evidence. World J Stomatol 2014; 3:38-51. [DOI: 10.5321/wjs.v3.i4.38] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 11/06/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Periodontal disease is an inflammatory condition that involves a complex interaction between pathogenic bacteria, environmental and acquired factors and host related factors. Till recently periodontal treatment was directed primarily towards reduction of bacterial load by subgingival debridement of root surfaces and modification of environmental risk factors. The current paradigm of periodontal disease stresses greater role of host-mediated inflammatory response in tissue destruction characteristic of periodontal disease. Various therapeutic modalities have been developed adjuvant to mechanical periodontal therapy. The use of laser and photodynamic therapy show great promise but their effectiveness has still not been conclusively proven. Chemotherapeutic agents, either systemic and local antimicrobials or host modulating drugs, played pivotal role in better and more predictable management of periodontal disease. The present review focuses on the best available evidence, for the current management of the chronic periodontal patients, gathered from systematic reviews and meta-analysis of mechanical non surgical periodontal therapy (NSPT) (subgingival debridement, laser therapy and photodynamic therapy) and the adjunctive chemotherapeutic approaches such as systematic and local antibiotics and antiseptics, subgingival pocket irrigation and host modulation therapies. The review also attempts to briefly introduce future developments in some of these modalities. At the end, the review summarizes the analysis of the current evidence that suggests that thorough subgingival debridement remains the mainstay of NSPT and that adjunct use of chemotherapeutic agents may offer better management of clinical parameters in periodontitis patients.
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38
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Kemnitz M, Tabatabai M, Utterodt A, Ritter H. Phosphonate-Containing Polymeric Networks: Swelling in Water Controlled by Metal Ions. MACROMOL CHEM PHYS 2014. [DOI: 10.1002/macp.201400458] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Melanie Kemnitz
- Institute of Organic Chemistry and Macromolecular Chemistry; Heinrich-Heine University; Universitätsstraße 1 40225 Düsseldorf Germany
| | - Monir Tabatabai
- Institute of Organic Chemistry and Macromolecular Chemistry; Heinrich-Heine University; Universitätsstraße 1 40225 Düsseldorf Germany
| | - Andreas Utterodt
- Heraeus Kulzer GmbH; Philipp-Reis-Straße 8 61273 Wehrheim Germany
| | - Helmut Ritter
- Institute of Organic Chemistry and Macromolecular Chemistry; Heinrich-Heine University; Universitätsstraße 1 40225 Düsseldorf Germany
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Furlaneto FA, Nunes NL, Oliveira Filho IL, Frota NP, Yamamoto KO, Lisboa MR, Ervolino E, Taba M, Rêgo RO, Messora MR. Effects of Locally Administered Tiludronic Acid on Experimental Periodontitis in Rats. J Periodontol 2014; 85:1291-301. [DOI: 10.1902/jop.2014.130581] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Gonnelli S, Caffarelli C, Tanzilli L, Pondrelli C, Lucani B, Franci BM, Nuti R. Effects of intravenous zoledronate and ibandronate on carotid intima-media thickness, lipids and FGF-23 in postmenopausal osteoporotic women. Bone 2014; 61:27-32. [PMID: 24389416 DOI: 10.1016/j.bone.2013.12.017] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 12/09/2013] [Accepted: 12/15/2013] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Osteoporosis and atherosclerosis are interconnected entities and share also some pathophysiological mechanisms. Moreover, recent literature data have supported the hypothesis that bisphosphonates (BPs) may have some antiatherogenic actions. This study aimed to evaluate the effects of one year with zoledronate or ibandronate given intravenously on lipid profile and on carotid artery intima-media thickness (CA-IMT). METHODS Sixty postmenopausal osteoporotic women (mean age: 66.6±7.8years) were randomly assigned to 1-year treatment with zoledronate 5mg i.v. annually or ibandronate 3mg i.v. every 3 months. In all patients at baseline and after 12months we measured CA-IMT, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), 25-hydroxyvitamin D (25OHD), bone alkaline phosphatase (B-ALP), type I collagen β carboxy telopeptide (βCTX), osteocalcin (OC), fibroblast growth factor 23 (FGF-23) and sclerostin. RESULTS The osteoporotic women treated with zoledronate showed a greater reduction in CA-IMT than those treated with ibandronate. HDL-C and HDL-C/LDL-C ratio showed a significant (p<0.01) increase in the 2 groups, whereas, LDL-C showed a reduction in the two groups which, however, reached statistical significance (p<0.05) only in the zoledronate group. FGF-23 serum levels showed a similar and significant decrease in both the women treated with zoledronate and in those treated with ibandronate. At the end of the study period sclerostin serum levels showed a higher increase in the patients treated with zoledronate than in those treated with ibandronate. CONCLUSION In osteoporotic women both zoledronate and ibandronate given intravenously resulted in an increase in HDL-C/LDL-C ratio and a reduction of CA-IMT which was significant only for zoledronate. Further prospective studies are needed to clarify whether the change in FGF-23 and sclerostin levels is a marker or a potential mechanism of the action of BPs at a vascular level.
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Affiliation(s)
- S Gonnelli
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy.
| | - C Caffarelli
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
| | - L Tanzilli
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
| | - C Pondrelli
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
| | - B Lucani
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
| | - B M Franci
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
| | - R Nuti
- Department of Medicine, Surgery and Neuroscience, University of Siena, Italy
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The effect of alendronate on proteome of hepatocellular carcinoma cell lines. INTERNATIONAL JOURNAL OF PROTEOMICS 2014; 2014:532953. [PMID: 24653834 PMCID: PMC3932719 DOI: 10.1155/2014/532953] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 12/13/2013] [Accepted: 12/14/2013] [Indexed: 12/12/2022]
Abstract
Cancer is a life threatening disorder effecting 11 million people worldwide annually. Among various types of cancers, Hepatocellular carcinoma (HCC) has a higher rate of mortality and is the fifth leading cause of cancer related deaths around the world. Many chemotherapeutic drugs have been used for the treatment of HCC with many side effects. These drugs are inhibitors of different cell regulatory pathways. Mevalonate (MVA) pathway is an important cellular cascade vital for cell growth. A variety of inhibitors of MVA pathway have been reported for their anticancerous activity. Bisphosphonates (BPs) are members of a family involved in the treatment of skeletal complications. In recent years, their anticancer potential has been highlighted. Current study focuses on exploring the effects of alendronate (ALN), a nitrogen containing BP, on hepatocellular carcinoma cell line using genomic and proteomics approach. Our results identified ten differentially expressed proteins, of which five were up regulated and five were down regulated in ALN treated cells. Furthermore, we also performed gene expression analysis in treated and control cell lines. The study may help in understanding the molecular mechanism involved in antitumor activity of ALN, identification of possible novel drug targets, and designing new therapeutic strategies for HCC.
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Yavropoulou MP, Pikilidou M, Yovos JG. Anti-osteoporotic drugs and vascular calcification: the bidirectional calcium traffic. J Vasc Res 2013; 51:37-49. [PMID: 24280985 DOI: 10.1159/000355204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 08/19/2013] [Indexed: 11/19/2022] Open
Abstract
During the last years, numerous epidemiological studies have demonstrated a direct relationship between vascular calcification and low bone mineral density. This observation is in line with experimental data demonstrating the osteogenic characteristics of calcified arteries. Various common risk factors have been suggested to link vascular calcification and bone loss, including aging, estrogen deficiency, vitamin D and K deficiency, diabetes mellitus, renal failure, smoking, chronic inflammation and oxidative stress. Although the underlying pathogenetic mechanisms are not yet clear, current research is focusing on anti-osteoporotic agents that could potentially affect the deposition of calcium in the arterial wall and thus provide an additional therapeutic strategy in elderly osteoporotic women prone to calcific cardiovascular disease.
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Affiliation(s)
- Maria P Yavropoulou
- Division of Endocrinology and Metabolism, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Zhao Y, Tian L, Sheng W, Miao J, Yang J. Hypalgesia effect of IL-24, a quite new mechanism for IL-24 application in cancer treatment. J Interferon Cytokine Res 2013; 33:606-11. [PMID: 23869901 DOI: 10.1089/jir.2012.0146] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Tumor suppressor melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) has been extensively regarded as an anti-oncogene; however, that whether IL-24, as a member of IL-10 family, is involved in cancer pain was seldom reported before. In this study, we found that IL-24 mediated by adenovirus could significantly increase the plantar mechanical pain threshold in both operation side and contralateral side of the animal models, which were established by injecting 5×103 Walker 256 rat breast cancer ascitic tumor cells into rats' tibia bone medullary canals; IL-24 could also suppress in vitro Walker 256 cells growth by inducing cell apoptosis. Pathologically, IL-24 could protect bone trabecula and substantia corticalis ossium from being completely destructed. Enzyme-linked immunosorbent assay (ELISA) showed that IL-24 treatment could increase the β-endorphin levels and decrease the IL-6 concentration in plasma of animals. Our study indicated that IL-24 has a potential treatment effect on cancers not only by inhibiting tumor proliferation, but also by the promotion of β-endorphin synthesis, inhibition of IL-6 secretion to relieve cancer pain.
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Affiliation(s)
- Yaodong Zhao
- 1 Shanghai 10th People's Hospital, School of Medicine, Tongji University , Shanghai, China
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Yamagami Y, Mashiba T, Iwata K, Tanaka M, Nozaki K, Yamamoto T. Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys. Bone 2013; 54:1-7. [PMID: 23356990 DOI: 10.1016/j.bone.2013.01.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 01/09/2013] [Accepted: 01/11/2013] [Indexed: 01/22/2023]
Abstract
Suppression of bone remodeling by bisphosphonates leads to accumulation of microdamage in bone. If this microdamage develops due to suppressed repair of remodeling only, more potent bisphosphonates should cause more damage. In this study, we evaluated the effects of reduced bone turnover produced by a potent bisphosphonate, minodronic acid, on microdamage accumulation, the degree of mineralization and mechanical properties of bone in ovariectomized cynomolgus monkeys, and compared these effects with those of alendronate. Sixty female monkeys aged 9-17 years old were divided into five groups. The sham group and the ovariectomized group were treated daily for 17 months with lactose vehicle. The other three groups were treated daily with minodronic acid at a dose of 0.015 mg/kg or 0.15 mg/kg, or alendronate at 0.5mg/kg orally. After sacrifice, lumbar vertebrae and left femurs were subjected to histomorphometry, microdamage, mineralization analyses, and mechanical testing. Minodronic acid suppressed bone remodeling of cancellous and cortical bone in a dose-dependent manner and the higher dose of minodronic acid suppressed bone remodeling more strongly than alendronate. The lower dose of minodronic acid did not increase microdamage accumulation and compressive strength, but the higher dose of minodronic acid and alendronate resulted in similar increases in cancellous microdamage accumulation and ultimate load in lumbar vertebra. There were no significant differences among the groups in microdamage, degree of mineralization and mechanical properties in cortical bone of the femoral shaft; however, only alendronate showed a tendency to increase highly mineralized osteons and microdamage. These findings suggest that microdamage caused by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate although this was not reflected in any significant change of mechanical properties.
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Affiliation(s)
- Yoshiki Yamagami
- Department of Orthopedic Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Bilgici ZS, Buyukgumus O, Altin A, Avci D. Synthesis and polymerizations of novel bisphosphonate-containing methacrylates derived from alkyl α
-hydroxymethacrylates. POLYM INT 2013. [DOI: 10.1002/pi.4517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
| | - Ozlem Buyukgumus
- Department of Chemistry; Bogazici University; 34342 Bebek Istanbul Turkey
| | - Ayse Altin
- Department of Chemistry; Bogazici University; 34342 Bebek Istanbul Turkey
| | - Duygu Avci
- Department of Chemistry; Bogazici University; 34342 Bebek Istanbul Turkey
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Pradeep A, Kumari M, Rao NS, Naik SB. 1% Alendronate Gel as Local Drug Delivery in the Treatment of Class II Furcation Defects: A Randomized Controlled Clinical Trial. J Periodontol 2013; 84:307-15. [DOI: 10.1902/jop.2012.110729] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Farnesyl pyrophosphate synthase: a key enzyme in isoprenoid biosynthetic pathway and potential molecular target for drug development. N Biotechnol 2013; 30:114-23. [DOI: 10.1016/j.nbt.2012.07.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Revised: 07/05/2012] [Accepted: 07/05/2012] [Indexed: 11/19/2022]
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Weber J, Grossmann G, Demadis KD, Daskalakis N, Brendler E, Mangstl M, Schmedt auf der Günne J. Linking 31P Magnetic Shielding Tensors to Crystal Structures: Experimental and Theoretical Studies on Metal(II) Aminotris(methylenephosphonates). Inorg Chem 2012; 51:11466-77. [DOI: 10.1021/ic301192y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Johannes Weber
- Department of Chemistry, Ludwig-Maximilians-Universität, D-81377 Munich, Germany
| | - Gisbert Grossmann
- Department of Chemistry, Technische Universität Dresden, D-01062 Dresden, Germany
| | - Konstantinos D. Demadis
- Crystal Engineering, Growth and
Design Laboratory, Department of Chemistry, University of Crete, P.O. Box 2208,
Voutes Campus, Heraklion GR-71003, Crete, Greece
| | - Nikos Daskalakis
- Crystal Engineering, Growth and
Design Laboratory, Department of Chemistry, University of Crete, P.O. Box 2208,
Voutes Campus, Heraklion GR-71003, Crete, Greece
| | - Erica Brendler
- Fakultät für Chemie
und Physik, TU Bergakademie Freiberg, Leipziger
Strasse 29, D-09599 Freiberg, Germany
| | - Martin Mangstl
- Department of Chemistry, Ludwig-Maximilians-Universität, D-81377 Munich, Germany
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Abstract
OBJECTIVES To provide an up-to-date review of current literature on the pathophysiology, diagnosis, and management of five key malignancy-related complications: superior vena cava syndrome, malignant pericardial effusion, malignant spinal cord compression, hypercalcemia, and acute tumor lysis syndrome. DATA SOURCES Database searches and review of relevant medical literature. DATA SYNTHESIS Malignancy-related complications demand increased attention from intensivists due to their frequency and increasing cancer prevalence. Although such complications portend a poor prognosis, proper acute management can improve short-term outcomes by facilitating either definitive care of the underlying malignancy or the institution of appropriate palliative measures. CONCLUSIONS Knowledge of malignancy-induced complications in critically ill patients expedites the ability of the intensivist to properly manage them. Five complications commonly requiring emergency management are addressed in this review. Specifically, superior vena cava syndrome may warrant radiation, chemotherapy, vascular stenting, or surgical resection. Malignant pericardial effusion may require emergency pericardiocentesis if cardiac tamponade develops. Malignant spinal cord compression demands immediate spinal imaging, glucocorticoids, and either surgery or radiation. Hypercalcemia requires aggressive intravenous hydration and a bisphosphonate. Acute tumor lysis syndrome necessitates intravenous hydration, rasburicase, and management of associated electrolyte abnormalities.
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Hochdörffer K, Abu Ajaj K, Schäfer-Obodozie C, Kratz F. Development of novel bisphosphonate prodrugs of doxorubicin for targeting bone metastases that are cleaved pH dependently or by cathepsin B: synthesis, cleavage properties, and binding properties to hydroxyapatite as well as bone matrix. J Med Chem 2012; 55:7502-15. [PMID: 22882004 DOI: 10.1021/jm300493m] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Bone metastases are a frequent cause of morbidity in cancer patients. The present palliative therapeutic options are chemotherapy, hormone therapy, and the administration of bisphosphonates. The affinity between bisphosphonates and the apatite structure of bone metastases is strong. Thus, we designed two low-molecular-weight and water-soluble prodrugs which incorporate a bisphosphonate group as a bone targeting ligand, doxorubicin as the anticancer agent, and either an acid-sensitive bond (1) or a cathepsin B cleavable bond (3) for ensuring an effective release of doxorubicin at the site of action. Cleavage studies of both prodrugs showed a fast release of doxorubicin but sufficient stability over several hours in human plasma. Effective binding of prodrug 1 and 3 was demonstrated with hydroxyapatite and with native bone. In orientating toxicity studies in nude mice, the MTD of 1 was 3-fold higher compared to conventional doxorubicin, whereas 3 showed essentially the same MTD as doxorubicin.
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Affiliation(s)
- Katrin Hochdörffer
- Division of Macromolecular Prodrugs, Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany
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