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chemical structure and the action mechanism bisfosfonatov

Timely diagnostics, treatment and aftertreatment of patients with malignant neoplasms (ZNO) various localisation is one of actual problems of modern medicine as annually the population case rate grows.

According to last published data of statistics in 2012 in Russia it has been taped 525 931 new cases of a malignant neoplasm [31]. Advance of malignant process, development of metastasises, essentially worsens quality of a life of patients and the basic disease forecast. So, metastasises in an osteal tissue cause a pain, pathological fractures, neurologic disturbances and progressing constraint of movements [52]. A special place among complications occupy a hypercalcemia and infections [40].

Hypercalcemia - rising of level of calcium (squirrels-skorrigirovannogo) above the normal value making 2,1-2,7 mmol/l. This most serious of menacing to a life of the patient of metabolic complications which are registered in 40 % of observations. The hypercalcemia can be bound to development of osteal osteolytic metastasises or result from action paratgormonpodobnogo a peptide cosecreted by cells of a tumour. A hypercalcemia principal cause at malignant tumours - rezorbtsija bones therefore calcium level increases in blood serum, kidneys do not cope with its egestion that can lead to their lesion [74].

Bisfosfonaty (BF) - steady synthetic analogues of a pyrophosphate, powerful inhibitors rezorbtsii bones osteoclasts [32, 59]. BF are a part
Therapies sick of a multiple myeloma, and also a prostate cancer, a cancer of a mammary gland and others ZNO for which development of osteal metastasises [12 is characteristic, 38, 39, 88, 90]. In Russia, according to the analysis of structure of case rate ZNO in 2012, among women the first place occupies a mammary gland cancer (20,7 %), among men - lung tumours (18,7 %), a prostate (12,1 %) [31]. BF, possessing powerful antirezorbtivnoj activity, are key preparations in complex treatment of patients set forth above ZNO, relieve a pain, reduce risk of pathological fractures and improve the general condition of patients, essentially raising quality of a life of patients [22, 23].

In 2003 cases of an atypical necrosis of a jaw at the patients receiving therapy bisfosfonatami [140, 146, 184] for the first time have been described. Subsequently in the USA, France, England, Italy, Germany and other countries the set of similar clinical cases of development of an osteonecrosis of a jaw has been described. Now in the world it is published more than 1300 articles and it is described more than 15000 cases bisfosfonatnogo an osteonecrosis of jaws (BONCH) [85, 89, 95, 111, 112, 121, 128, 133, 135, 142, 145, 146, 148, 153, 174, 181, 189].

The criteria recognised in the world for diagnosis statement «bisfosfonatnyj the jaw osteonecrosis» is presence of a site of the bared osteal tissue in the maxillofacial area, 8 weeks present more, at presence at the patient of therapy bisfosfonatami in the anamnesis or now, under condition of absence of radial therapy in the field of a jaw [169].

BF are chemical analogues of an inorganic pyrophosphate and are characterised the basic by a chain, consisting of atoms of phosphorus and Carboneum R-R - R and two lateral groups Ja1i R2 attached to the central atom of Carboneum [56, 164]. Chemical stability BF and their fastness to enzymatic and acid hydrolysis speaks presence of atom of Carboneum which provides stability of a molecule and its fastness to disintegration, and also R-S-R structure which provides ability to bind bivalent ions of metals, for example Ca2 + (the Drawing 1).

Hydroxylic or aminoradikaly R1
Strengthen ability to contact a mineral matrix of a bone whereas radicals R2 influence on antirezorbtivnuju ability [170].

In a human body the inorganic pyrophosphate is a product of many chemical reactions thanks to what can be found out in many tissues. The first researches spent in 1960th years have shown, that the inorganic pyrophosphate provided inhibition of a calcareous infiltration at the expense of linkage with crystals gidroksiappatita on the basis of what the hypothesis has been formulated, that adjustment of level of inorganic Natrii phosphas can be used for adjustment of a mineralization of a bone [97].

BF basically contact those sites in a bone where there are active processes remodelirovanija. They quickly leave system circulation and are besieged on a surface of a mineral matrix of a bone in sites with hyperactivity of osteoclasts.

Fig. 1. The scheme. A molecule structure bisfosfonatov (on De Ponte, 2012, with changes) [94].

It has been proved, that in a phase rezorbtsii osteoclasts are in an acidic microenvironment which promotes liberation BF from a surface of an osteal tissue, providing local their high concentration [165]. Further BF are absorbed by osteoclasts, that leads to direct inhibition of activity of osteoclasts owing to toxic action on a cell (reduction of osteoclasts in size, condensation, a cellular fragmentation), leading to an apoptosis. On the other hand, inhibition can occur owing to disturbance of intracellular vesicular transport [80] that leads to disorganisation of a cytoplasmatic skeleton and formation disturbance «the goffered edge» an osteoclast [165]. «The goffered edge» or «a brush border» is the zone formed on the party of an adhering of an osteoclast to the blasted surface where there is a secretion of hydrolytic enzymes. Osteal rezorbtsija occurs under «the goffered edge», in the closed space.

BF, according to Roelofs A.J. And co-workers. (2006), have an effect as on cells of an osteal tissue (osteoclasts, osteoblasts, osteocytes) [140, 161], and on macrophages [99, 163], endothelial cells [117, 189], monocytes, tumoral cells (for example, cells of a plural myeloma and a prostate cancer) [120, 185].

Influence on osteoclasts: reduction of quantity of osteoclasts, reduction of activity of osteoclasts, oppression of adhesion of osteoclasts to an osteal tissue, start of processes of an apoptosis of osteoclasts [115, 165, 173, 190].

Influence on osteoblasts: according to Shipman et al. (1997г.), bisfosfonaty stimulate formation by osteoblasts of the factor, which inhibits activation and formation of osteoclasts (an inhibitor osteoklasticheskoj rezorbtsii) [178]. The exact mechanism of this process definitively is not found out.

Being based on the spent researches of the molecular mechanism of action, bisfosfonaty can be parted on two groups (Table 1): anazotic bisfosfonaty (preparations of 1 generation), and also nitrogen-bearing (nitrogene-containing) bisfosfonaty (preparations of 2 and 3 generations) [101].

Bisfosfonaty the first generation (klodronat, etidronat) are metabolized intracellularly to cytotoxic analogues ATF which cannot undergo to hydrolysis in a cell and, accordingly, keep the energy necessary for synthesis of an Isopentylum-pyrophosphate. Accumulation of these metabolites in a cell inhibits cellular functions and starts apoptosis processes, owing to inhibition of ATF-DEPENDENT enzymes [161].

Bisfosfonaty the second generation (pamidronat and alendronat) and the third generation (rizedronat, ibandronat, zolendronat) influence on mevalonatnyj a way, at the expense of inhibition farnezilbifosfatsintetazy (according to researches Coxon F.P. And co-workers.) [100, 101]. Inhibition of the given enzyme interferes with processes preniljatsii small GtF-az (Ras, Rho, Rab) which are the important alarm fibers necessary for normal activity of osteoclasts [91, 124, 170]. Preniljatsija - protsessprisoedinenija hydrophobic molecules of some of products of a metabolism of cholesterol to fibers. Small proteins, such as GTF-ELEMENTS, are built in a cellular membrane with the help farnezil - and geranilgeranil - lateral chains and send specific signals to a cell which regulate set of cellular functions. However, as soon as fibers have no lateral lipide chains, they are not capable to transfer signals. Therefore cells are inactivated, lose the membrano-specific proteins, and apoptosis processes finally are started. Such blocking occurs in osteoclasts owing to absorption by them bisfosfonatov from a surface of an osteal tissue [131] (the Drawing 2).

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Table 1

General characteristic bisfosfonatov various groups

Generation Examples R1 R2 antirezorbtivnyj potential Indications to application
I Etidronat (Didronel) OH CH3 1 h Osteoporosis
Klodronat (Bonefos, Loron) Cl Cl 10 h The hypercalcemia caused by malignant tumours
II Pamidronat (Aredia, Novartis) IT (CH2) 2NH2 100 h Metastatic lesion of bones, plural myeloma
Alendronat (Fosamax, Merck) OH (CH2) sNH2 1000 h Osteoporosis, illness Pedzheta
III Rizedronat (Actonel, P &G) OH CI С-3-пиридин 5000 h Osteoporosis, illness Pedzheta
Ibandronat (Bonviva, Roche) OH Cl 3CI I.A'lCI ІД

(C5H11)

10000х Osteoporosis
Zolendronovaja acid (Zometa, Novartis) OH СИ2-имидазол 20000 h Metastatic lesion of bones, plural myeloma
Zolendronovaja acid (Aclasta, Novartis) OH СИ2-имидазол 20000 h Osteoporosis, illness Pedzheta

Fig. 2. The scheme. The action mechanism bisfosfonatov (on Bartl R. et al., with additions) [88].


1.2.

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Scientific source ZASLAVSKAYA NATALIA ALEKSANDROVNA. OPTIMIZATION of PREVENTIVE MAINTENANCE And TREATMENT BISFOSFONATNYH of OSTEONECROSES of JAWS At PATIENTS WITH MALIGNANT NEOPLASMS. The dissertation on competition of a scientific degree of the candidate of medical sciences. Moscow - 2014. 2014

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