Molekularny mechanizm dzialania bisfosfonianow i ich zastosowanie w praktyce klinicznej

• Autorzy: Mytnik E , Kuryszko J. , Chmielewska E. , Kafarski P.

Warianty tytułu

EN

Molecular mechanism of the action of bisphosphonates and its role in clinical practice

• Języki publikacji: PL

Abstrakty

EN

Bisphosphonates are a unique class of drugs. As a family they are characterized pharmacologically by their ability to inhibit bone resorption, whereas, pharmacokinetically, they are classified by their similarity in absorption, distribution and elimination. Bisphosphonates have become the most important class of antiresorptive drugs, not only for the treatment of Paget’s disease, but also for other diseases that involve excessive osteoclast-mediated bone resorption, such as tumor-induced osteolysis and hypercalcemia as well as osteoporosis. Although all bisphosphonates have similar psychochemical properties, their antiresorbing activities differ substantially. The structure of the R2 side chain is the major determinant of antiresorptive potency, both phosphonate groups are also required for the drugs to be active. Activity is dramatically increased when the amino group is contained in the aliphatic carbon chain. They act by inhibiting the enzyme farnesyl diphosphate synthase. Despite this, the molecular mode of their action is still not clear. There is substantial evidence that BPs can have a direct effect on osteoclasts by mechanisms that may lead to osteoclast cell death by apoptosis. BPs can also inhibit proliferation and cause cell death in macrophages in vitro. It has been shown that the toxic effect of BPs on macrophages is also due to the induction of apoptotic, rather than necrotic, cell death. Bisphosphonates may inhibit osteoclast-mediated bone resorption by several routes, although a direct effect on mature osteoclasts is the most likely. Bisphosphonates perturb cellular metabolism and induce osteoclast apoptosis. The molecular mechanisms by which these effects are brought about are only now becoming clear. The simple bisphosphonates that closely resemble pyrophosphonates (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in the induction of osteoclast apoptosis. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signaling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is primarily due to the loss of geranylgeranylated small GTPases.

Słowa kluczowe

PL

bisfosfoniany; mechanizm dzialania; mechanizmy molekularne; zastosowanie; osteoporoza; leczenie

• Wydawca: -
• Czasopismo: Medycyna Weterynaryjna
• Rocznik: 2010
• Tom: 66
• Numer: 05
• Opis fizyczny: s.307-310,bibliogr.

Twórcy

autor

Mytnik E

• Uniwersytet Przyrodniczy we Wroclawiu, ul.Kozuchowska 5, 51-631 Wroclaw

autor

Kuryszko J.

autor

Chmielewska E.

autor

Kafarski P.

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