| Abstract | Cilj istraživanja
Cilj ovog rada je dati detaljan uvid u najnovija saznanja o farmakološkim svojstvima
botulinum toksina tipa A (BoNT-A) te dati kratak povijesni pregled od otkrića molekule
toksina do prve primjene lijeka u kliničkoj praksi. Posebno će se opisati trenutno registrirani
pripravci BoNT-A na globalnom tržištu, njihove sličnosti i razlike s obzirom na formulaciju,
indikacije i ostale karakteristike bitne za kliničku primjenu.
Materijali i metode
Za potrebe ovog specijalističkog rada pretraživana je relevantna znanstvena i stručna
literatura, znanstvene publikacije, baza lijekova Agencije za lijekove i medicinske proizvode
Republike Hrvatske, mrežne stranice Europske agencije za lijekove, te Američke agencije za
hranu i lijekove.
Bibliografske baze podataka pretraživane su prema ključnim riječima: botulinum toxin type A,
Botox, Dysport, Xeomin, indications, mechanism of action, side-effects, dosing, clinical effect,
clinical trials, disease.
Rezultati
Clostridium botulinum je gram pozitivna anaerobna sporogena bakterija s jedinstvenim
svojstvom proizvodnje botulinum neurotoksina, od kojih je danas opisano 7 podtipova (A-G).
Biološki aktivni dio molekule BoNT tipa A čini polipeptidni lanac od ~150 kDa koji se sastoji
od lakog lanca (L lanac; 50 kDa) i teškog lanca (H lanac; 100 kDa). L i H lanac se drže
zajedno dugačkim peptidnim pojasom i jednom disulfidnom vezom. Dvije poddomene H
lanca omogućuju specifično vezanje za živčane završetke te endocitozu neurotoksina, pri
čemu uslijed kiselog pH u endosomu dolazi do pucanja disulfidne veze i translokacije kratkog
lanca toksina u citosol. L lanac je o Zn2+ ovisna proteaza koja specifično cijepa SNAP-25,
jedan od proteina ključih za proces lučenja neurotransmitora iz živčanih okončina. Visoka
selektivnost za kolinergične neurone dovodi do inhibicije lučenja acetilkolina i mišićne
paralize te disfunkcije autonomnih sinapsi, simptoma karakterističnih za botulizam. Međutim,
pikogramske količine BoNT-A injicirane izravno u mišić ili u dermis terapijski se koriste kod
različitih stanja karakteriziranih hiperkontraktilnošću mišića te autonomnih poremećaja. Do
sada postoje tri registrirana pripravka BoNT-A na tržištu Europske unije: Botox®, Dysport® i
Xeomin®. U ovom radu su uspoređene njihove sličnosti i razlike, od procesa proizvodnje,
doziranja, do odobrenih indikacija.
Zaključak
Temelj farmakološkog djelovanja BoNT-A je inhibicija lučenja neurotransmitora iz perifernih
kolinergičnih, ali i senzornih okončina. BoNT-A je potentan i neurospecifičan, ima ograničen
stupanj difuzije nakon lokalne primjene te je njegovo djelovanje reverzibilno. Usprkos
određenim nedostacima u razumijevanju mehanizma djelovanja i farmakokinetike toksina
nakon lokalne primjene, pripravci BoNT-A se široko koriste u različitim indikacijama, a
primjenu karakterizira dugo djelovanje nakon jednokratne primjene te dobra podnošljivost.
Primjena BoNT-A do sada je odobrena kod 11 indikacija, dok se off-label primjenjuje u više
od 20 indikacija. |
| Abstract (english) | Objectives
The objective of this paper is to give insights into the latest knowledge about pharmacological
characteristics of botulinum toxin type A (BoNT-A) and give a brief historical overview of
the discovery the toxin molecule until the first application of the drug in clinical practice. The
currently registered BoNT-A preparations in the global market, their similarities and
differences in terms of formulation, indications and other characteristics relevant to clinical
application will be described in particular.
Material and methods
For the needs of this paper relevant scientific and professional literature, scientific
publications, medicine database of the Agency for Medicinal Products and Medical Products
of the Republic of Croatia, the web pages of the European Medicines Agency, and the
American Food and Drug Agency were searched.
Bibliographic databases are searched by keywords: botulinum toxin type A, Botox, Dysport,
Xeomin, indications, mechanism of action, side-effects, dosing, clinical effect, clinical trials,
disease.
Results
Clostridium botulinum is a genus of sporulating and anaerobic Gram-positive, rod-shaped
bacteria with unique properties of botulinum neurotoxin production of which 7 subtypes (AG)
are now described. The biologically active part of the BoNT type A molecule comprises a
polycompetent chain of ~ 150 kDa consisting of a light chain (L chain, 50 kDa) and a heavy
chain (H chain, 100 kDa). L and H chain are held together by a long peptide belt and one
disulfide bond . Two subdomains of the H chain provide specific binding to the nerve endings
and endocytosis of the neurotoxin, whereby due to the acidic pH in the endosome disulfide
linkage and the short chain toxin translocation into the cytosol occur. L chain is a Zn2+
dependent protease that specifically cleaves SNAP-25, one of the key proteins for the process
of secrete neurotransmitters from the nerve endings. High selectivity for cholinergic neurons
leads to inhibition of the secretion of acetylcholine and muscle paralysis, and dysfunction of
autonomic synapses, symptoms typical of botulism. However, the picogram amounts of
BoNT-A injected directly into the muscle or dermis are therapeutically used in various
conditions characterized by muscular hypercontractility and autonomic disorders. So far, there
are three registered BoNT-A preparations in the EU market: Botox®, Dysport® and Xeomin®.
In this paper, their differences are compared, from the production process, the difference in
doses, to the approved indications.
Conclusion
The basis of the pharmacological action of BoNT-A is the inhibition of neurotransmitter
secretion from the peripheral cholinergic, but also the sensory endings. BoNT-A is potent and
neurospecific, has a limited degree of diffusion after local application, and its action is
reversible. Despite certain deficiencies in understanding the mechanism of action and the
pharmacokinetic properties of the toxins in the body, BoNT-A preparations are widely used in
various indications, and the administration is characterized by long acting after single use and
good tolerance. The use of BoNT-A has so far been approved in 11 indications, while offlabel
is applied in more than 20 indications. |
