natgillin/translations-raw huggingface dataset:
With regards to the claim that virtually no Gd becomes liberated from gadodiamide in the body, PRAC noted that at 37°C in human serum Gd rapidly dissociates from its chelator in vitro (Frenzel et al. 2008).
Odbor PRAC je v zvezi s trditvijo, da se iz gadodiamida v telo ne sprosti skoraj nič gadolinija, opozoril, da se in vitro pri 37 °C gadolinij hitro odcepi od svojega kelatorja v človeški serum (Frenzel idr., 2008).
For the linear agents evaluated in non-clinical studies the T1 signal intensity in the DCN has been shown to persist for at least 1 year without any reduction in intensity.
Za linearna sredstva, ovrednotena v nekliničnih študijah, se je dokazalo, da se je v globokih možganskih jedrih intenzivnost signala T1 ohranila vsaj eno leto, brez zmanjšanja njegove intenzivnosti.
PRAC conclusions on grounds for re-examination
Zaključki odbora PRAC v zvezi z razlogi za ponovno proučitev
However, PRAC considered the clinical utility outweighing the risks related to accumulation of gadolinium is limited to the delayed phase liver imaging and thus PRAC recommended that the indication of gadobenic acid is restricted to this use only.
Vendar je menil, da je klinična koristnost, ki prevlada nad tveganji, povezanimi s kopičenjem gadolinija, omejena na zapoznelo fazo slikanja jeter, zato je priporočil, naj se indikacija gadobenske kisline omeji samo na to uporabo.
This relationship further strengthens the interpretation of the MRI studies as evidence that accumulation of gadolinium in the brain is causally related to exposure to GdCAs.
Ta povezava še dodatno podpira razlago iz študij MRI v dokaz, da je kopičenje gadolinija v možganih vzročno povezano z izpostavljenostjo sredstvom GdCA.
GdCAs can be differentiated by their structure: linear (gadodiamide, gadopentetic acid, gadobenic acid, gadoxetic acid, gadoversetamide) or macrocyclic (gadoteridol, gadobutrol, gadoteric acid), and by the overall charge on the complex formed (ionic or non-ionic).
Sredstva GdCA je mogoče razlikovati po njihovi strukturi: linearna (gadodiamid, gadopentetska kislina, gadobenska kislina, gadoksetna kislina, gadoversetamid) ali makrociklična (gadoteridol, gadobutrol, gadoterska kislina) in po skupnem naboju tvorjenega kompleksa (ionski ali neionski).
The precise molecular forms of the soluble macromolecular bound Gd are not known but it is plausible that the macromolecules are bound to a dechelated Gd3+ ion.
Natančna molekulska oblika gadolinija, vezanega na topne makromolekule, ni znana, verjetno pa so makromolekule vezane na dekelatiran ion Gd3+.
It is reasonable to suppose that gadolinium can de-chelate from linear GdCAs and bind to macromolecules in human brains similarly as what is observed in rodent brains.
Upravičena je domneva, da gadolinij lahko dekelatira iz linearnih sredstev GdCA in se veže na makromolekule v človeških možganih podobno, kot je bilo ugotovljeno pri možganih glodavcev.
• Data on stability, as well as in vitro and non-clinical studies, show that linear gadolinium-containing contrast agents (GdCAs) release gadolinium from the ligand molecules to a greater extent than macrocyclic agents.
• Podatki o stabilnosti ter študije in vitro in neklinične študije dokazujejo, da linearna kontrastna sredstva, ki vsebujejo gadolinij, (GdCA) sproščajo gadolinij iz molekul ligandov v večji meri kot makrociklična sredstva;
• In addition to NSF, there is also evidence that other harmful outcomes are associated with exposure to linear GdCAs, in particular gadolinium-associated skin plaques.
• poleg dokazov za NSF obstajajo tudi dokazi, da so z izpostavitvijo linearnim sredstvom GdCA povezani tudi drugi škodljivi izidi, zlasti kožni plaki, povezani z gadolinijem;
The benefit of GdCAs has been demonstrated based on their ability to improve the quality of imaging for MRIs compared to unenhanced MRI scans by supporting the diagnostic performance of such scans in the detection of disease, prognosis and patient management in order to achieve a particular clinical outcome.
Koristnost sredstev GdCA je bila dokazana na podlagi njihove zmožnosti za izboljšanje kakovosti slik pri magnetnoresonančnem slikanju v primerjavi s slikami MRI, pri katerih kontrast ni bil izboljšan, saj povečajo diagnostično zmogljivost takih slik pri ugotavljanju bolezni, napovedi in obravnavanju bolnika za dosego določenega kliničnega izida.
The CHMP concluded that the risk of NSF is different for the different gadolinium-containing contrast agents, which lead to the categorisation of GdCAs into three risk groups for NSF (high risk, medium risk and low risk).
Zaključil je, da različna kontrastna sredstva, ki vsebujejo gadolinij, pomenijo različno tveganje NSF, zato so bila sredstva GdCA razvrščena v tri skupine tveganj NSF (veliko tveganje, srednje tveganje in majhno tveganje).
In view of the above, and the claim on the lack of clinical evidence of neurotoxicity due to deposited gadolinium, PRAC considered that while the clinical consequences of gadolinium retention in the brain are currently unknown or remain unclear, absent or limited information from case reports cannot be taken as evidence that such toxicity does not occur.
Odbor PRAC je glede na navedeno in ob upoštevanju trditve o pomanjkanju kliničnih dokazov za nevrotoksičnost zaradi odloženega gadolinija menil, da kljub temu da klinične posledice zadrževanja gadolinija v možganih trenutno niso znane ali so še vedno nejasne, neobstoječih ali omejenih informacij v poročilih o primerih ni mogoče šteti za dokaz, da taka toksičnost ne obstaja.
• CHMP considered options for risk minimisation measures.
• obor CHMP je proučil mogoče ukrepe za zmanjšanje tveganja.
Intra-articular products containing gadopentetic acid and gadoteric acid are administered at very low doses and present a low risk of tissue accumulation.
Izdelki za intraartikularno uporabo, ki vsebujejo gadopentetsko kislino in gadotersko kislino, se uporabljajo v zelo majhnih odmerkih in pomenijo majhno tveganje kopičenja v tkivu.
PRAC considered that it is highly unlikely that the release of Gd from gadodiamide is slower in vivo than in vitro.
Menil je, da je zelo malo verjetno, da bi bilo sproščanje gadolinija iz gadodiamida in vivo počasnejše kot in vitro.
The major route of excretion for GdCAs is renal, and prolonged elimination time due to severely impaired renal function could theoretically increase the potential for accumulation in brain tissue.
Sredstva GdCA se v glavnem izločijo prek ledvic, zaradi podaljšanega časa izločanja pri hudih motnjah v delovanju ledvic pa bi se teoretično lahko povečala možnost kopičenja v možganskem tkivu.
They are administered at low concentrations, approximately 200-fold lower than the intravenous use GdCA products, and the potential for patients to receive large numbers of repeated exposures is less for the MR arthrography indication than for the indications for the intravenous product.
Uporabljata se v nizkih koncentracijah, približno 200-krat nižjih kot pri intravenski uporabi izdelkov GdCA, možnost, da bi bolniki prejeli veliko ponovljenih izpostavljenosti, pa je pri indikaciji magnetnoresonančne artrografije manjša kot pri indikacijah izdelka za intravensko uporabo.
Repeat toxicity studies for gadodiamide showed that the absolute low levels of gadolinium in the brain were observed at 1 week post-dosing.
Ponovljene študije toksičnosti gadodiamida so dokazale, da so bile en teden po uporabi odmerkov v možganih ugotovljene absolutno nizke ravni gadolinija.
Such studies are considered unlikely to be feasible in view of the heterogeneity of the patient population that undergoes MRI.
Take študije zaradi heterogenosti populacije bolnikov, ki opravijo MRI, verjetno ne bi bile izvedljive.
There was also an intermediate position within the expert group that expressed a view that the linear agents should not be suspended but that macrocyclic agents should be used as the first line contrast agent (excepting for the liver), unless the MAHs produced relevant trial data clearly indicating superior patient management outcomes with use of their linear agent compared to macrocyclics.
Obstajalo je tudi vmesno stališče, in sicer v skupini strokovnjakov, ki je izrazila stališče, da se za linearna sredstva ne bi smelo začasno umakniti dovoljenja za promet, makrociklična sredstva pa bi se morala uporabljati kot kontrastno sredstvo prve izbire (razen pri jetrih), razen če je imetnik dovoljenja za promet z zdravilom predložil ustrezne podatke o preskušanju, ki jasno kažejo boljše izide pri obravnavanju bolnikov z uporabo linearnega sredstva kot z makrocikličnimi sredstvi.
The regions of the brain with the greatest potential for brain accumulation are the dentate nucleus and globus pallidus.
Predela možganov, kjer je kopičenje najbolj verjetno, sta nucleus dentatus in globus pallidus.
PRAC considered potential clinical studies to be conducted in order to fully address the serious concerns of plausible neurological effects.
Odbor PRAC je proučil morebitne klinične študije, ki bi se lahko izvedle za celovito obravnavanje resnih pomislekov glede verjetnih nevroloških učinkov.
In view of the above, the PRAC considered that the benefits of macrocyclic agents outweigh their risks.
Odbor PRAC je glede na navedeno menil, da koristi makrocikličnih sredstev prevladajo nad njihovimi tveganji.
• or that the product (potentially modified or not) does not undergo significant dechelation and does not lead to retention of gadolinium in tissues, including the brain in humans.
• ali da izdelek (lahko spremenjen ali ne) bistveno ne dekelatira ali ne povzroči zadrževanja gadolinija v tkivih, vključno z možgani pri ljudeh.
With regards to the claim that gadodiamide (Omniscan) has a unique indication in myocardial perfusion imaging PRAC considered that the whole body MRI indication encompasses imaging of the heart, including myocardial perfusion imaging.
Odbor PRAC je v zvezi s trditvijo, da ima gadodiamid (Omniscan) edinstveno indikacijo pri perfuzijskem slikanju miokardija kot takem, menil, da indikacija MRI celotnega telesa vključuje slikanje srca, vključno s perfuzijskim slikanjem miokardija.
Furthermore, CHMP agreed that a communication to healthcare professionals through a joint DHPC should be sent by the MAHs, to which the MAHs agreed.
Odbor CHMP se nadalje strinja, da bi morali imetniki dovoljenj za promet z zdravili zdravstvene delavce obvestiti v skupnem pismu za zdravstvene delavce, s čimer so se imetniki dovoljenja za promet strinjali.
In addition, two GdCA products, gadopentetic acid and gadoteric acid, are authorised as formulations for intra-articular administration for magnetic resonance arthrography and they are able to enhance specific lesions.
Poleg tega sta dva izdelka GdCA, in sicer gadopentetska kislina in gadoterska kislina, odobrena kot pripravka za intraartikularno uporabo pri magnetnoresonančni artrografiji; z njima je mogoče povečati določene lezije.
Toxicity of GdCAs has primarily been attributed to the dissociation of Gd from the chelated complexes.
Toksičnost sredstev GdCA je bila najprej pripisana disociaciji gadolinija iz kelatiranih kompleksov.
The CHMP further considered the statement addressing the potential harm associated with the gadolinium accumulation in the brain: “although no adverse neurological effects, such as cognitive or movement disorders, have been demonstrated to be caused by gadolinium accumulation in the brain, long-term safety data are limited.
Odbor CHMP je nadalje proučil navedbo, ki obravnava morebitne škodljive učinke, povezane s kopičenjem gadolinija v možganih: „čeprav še niso bili dokazani škodljivi nevrološki učinki, kot so kognitivne motnje ali motnje gibanja, ki naj bi jih povzročilo kopičenje gadolinija v možganih, so podatki o dolgoročni varnosti omejeni.
In view of the very low potential for retention of gadolinium in tissues, their stability and low risk of dechelation, PRAC maintained its recommendation that the benefits of macrocyclic agents outweigh their risks.
Odbor PRAC je glede na zelo majhno možnost zadrževanja gadolinija v tkivih, njihovo stabilnost in majhno tveganje dekelacije ohranil stališče, da koristi makrocikličnih sredstev prevladajo nad njihovimi tveganji.
Therefore the benefit of gadoxetic acid outweighs its risk.
Zato korist gadoksetne kisline prevlada nad njenimi tveganji.
Nevertheless, further analysis did not reveal Gd in them so that a low tissue Gd level was assumed, and it was not questioned what otherwise these dense structures could be.
Vendar nadaljnja analiza v njih ni razkrila gadolinija, zato se je domnevalo, da je raven gadolinija v tkivu nizka, ni pa se raziskalo, kaj bi sicer te goste strukture lahko bile.
• The restriction of the use of linear GdCAs will still leave patients in the remaining population exposed to the risk of harm, without knowing safe threshold level for retention in the brain and other tissues of the body to dechelated gadolinium.
• Po omejitvi uporabe linearnih sredstev GdCA bi bili bolniki v preostali populaciji še vedno izpostavljeni tveganju škodljivih učinkov, pri čemer ne bi bila znana varna mejna vrednost za zadrževanje dekelatiranega gadolinija v možganih in drugih tkivih telesa.
A rat study also confirmed the finding that dose-dependent level of Gd in the brain for linear agents was likely to be related to cumulative dose rather than a single large or repeat small dose regimens.
Študija na podganah je tudi potrdila ugotovitev, da je pri linearnih sredstvih raven gadolinija v možganih, ki je odvisna od odmerka, verjetno povezana s skupnim odmerkom in ne z režimoma enega velikega odmerka ali več majhnih odmerkov.
Indeed, PRAC considered the results of two intra-individual, crossover comparisons of 0.1 mmol/kg body weight with Multihance vs 0.1 mmol/kg body weight of two active comparators (gadopentetate dimeglumine and gadodiamide), in patients with known or suspected brain or spine disease undergoing MRI of the central nervous system (CNS) (MH-109, MH-130) and concluded that the studies were using a blinded comparison of MRI images obtained with two GdCAs side by side and have produced results favouring Multihance on the basis of brighter appearance of the images, but not reflecting any difference in the diagnostic information available or the impact on diagnostic thinking, patient management or clinical outcome.
Odbor PRAC je dejansko proučil rezultate dveh povezanih intraindividualnih primerjav uporabe sredstva Multihance v odmerku 0,1 mmol/kg telesne mase in dveh primerjalnih sredstev (gadopentetat dimeglumin in gadodiamid) v odmerku 0,1 mmol/kg telesne mase pri bolnikih z znano boleznijo možganov ali hrbtenice ali sumom na tako bolezen, ki so opravili MRI centralnega živčnega sistema (CNS) (MH-109, MH-130), ter zaključil, da so v študijah uporabili slepo primerjavo slik MRI, pridobljenih z vzporedno uporabo obeh sredstev GdCA, pridobljeni rezultati pa so zaradi svetlejših slik dali prednost sredstvu Multihance, niso pa izrazili razlik glede razpoložljivih diagnostičnih informacij ali vpliva na diagnostično razmišljanje, obravnavanje bolnika ali klinični izid.
Smith et al. 2017 described that stored Gd still decreases after one week so that obviously a transiently stored pool exists which is different from the material that persists long-term.
so leta 2017 opisali, da se količina shranjenega gadolinija po enem tednu še vedno zmanjšuje, tako da očitno obstaja skupina, ki se shrani kratkotrajno in se razlikuje od snovi, ki se ohrani dolgotrajno;
With regards to the condition for lifting the suspension the MAH shall submit evidence “that the product (potentially modified or not) does not undergo significant dechelation and does not lead to retention of gadolinium in tissues, including the brain in humans”, CHMP agreed in general with the proposal, however considered it necessary clarifying the meaning of this condition to avoid misunderstandings.
odbor CHMP se je v zvezi s pogojem, da mora imetnik dovoljenja za preklic začasnega umika dovoljenja predložiti dokaz, „da izdelek (lahko spremenjen ali ne) bistveno ne dekelatira ali ne povzroči zadrževanja gadolinija v tkivih, vključno z možgani pri ljudeh“, na splošno strinjal s predlogom, vendar je menil, da je treba pojasniti pomen tega pogoja za preprečitev nesporazumov.
Macrocyclic GdCAs
Makrociklična sredstva GdCA
There have been more recent MRI studies that have documented signal intensity increases in the brain in association with macrocyclic GdCAs, suggesting that these agents may also deposit gadolinium in the brain.
Na voljo so novejše MRI študije, s katerimi je bilo dokumentirano povečanje intenzivnosti signala v možganih v povezavi z makrocikličnimi sredstvi GdCA, kar kaže, da morda tudi ta sredstva odlagajo gadolinij v možganih.
Data in post mortem tissue samples have shown that the highest concentration of gadolinium in the brain was observed in patients that had several exposures to gadodiamide, suggesting that number of doses received had an impact on the deposition of gadolinium.
Podatki o vzorcih tkiv, vzetih po smrti, so pokazali, da je bila najvišja koncentracija gadolinija v možganih ugotovljena pri bolnikih, ki so bili večkrat izpostavljeni gadoliniju, kar kaže, da je število prejetih odmerkov vplivalo na odlaganje gadolinija.
With regards to the consideration of the risk of NSF, whilst PRAC relied on the previous assessment and classification of the risk of NSF across the GdCAs products, PRAC considered that the NSF risk contributes to the safety profile of GdCAs and is taken into account to conclude on the whole safety profile of these products and the subsequent impact on their benefit-risk balance.
V zvezi s pomislekom glede tveganja NSF je odbor PRAC na podlagi predhodne ocene in razvrstitve tveganja NSF pri izdelkih GdCA menil, da tveganje NSF prispeva k varnostnemu profilu sredstev GdCA ter se upošteva pri zaključku o celotnem varnostnem profilu teh izdelkov in naknadnem vplivu na njihovo razmerje med koristmi in tveganji.
The CHMP, in addition, considers that the benefit-risk balance of intravenous medicinal products containing gadodiamide, gadopentetic acid, and gadoversetamide is no longer favourable.
Poleg tega meni, da razmerje med koristmi in tveganji zdravil za intravensko uporabo, ki vsebujejo gadodiamid, gadopentetsko kislino in gadoversetamid ni več ugodno.
Based on the data available, no specific patient group that would not experience Gd retention in the brain could be identified, as both children and adults are expected to show accumulation of Gd in the brain.
Na podlagi razpoložljivih podatkov ne bi bilo mogoče opredeliti specifične skupine bolnikov, pri kateri se gadolinij ne bi zadržal v možganih, saj se pričakuje, da se bo pokazalo, da se gadolinij odlaga v možganih otrok in odraslih.
In view of a potential difference in the frequency of hypersensitivity reactions, PRAC pointed out that these are known infrequent reactions for all GdCAs.
Odbor PRAC je v zvezi z morebitno različno pogostnostjo preobčutljivostnih reakcij poudaril, da je znano, da te pri vseh sredstvih GdCA niso pogoste.
PRAC also maintained its conclusions that benefits of the intra-articular presentation of the linear GdCA Magnevist outweigh their risks (subject to changes to the product information) as they are administered at very low doses and present a low risk of tissue accumulation.
Odbor PRAC je tudi vztrajal pri zaključkih, da intraartikularna uporaba linearnega sredstva GdCA Magnevist prevlada nad njegovimi tveganji (vendar je treba spremeniti informacije o izdelku), saj se uporablja v zelo majhnih odmerkih in pomeni majhno tveganje kopičenja v tkivu.
Macrocyclic GdCAs have a very low potential for retention of gadolinium in tissues, are very stable and have a low risk of dechelation.
Pri makrocikličnih sredstvih GdCA je možnost zadrževanja gadolinija v tkivih zelo majhna, zelo so stabilna in pomenijo majhno tveganje dekelacije.
The implemented risk minimisation measures appear to be effective based on annual reviews of spontaneous case reports.
Na podlagi letnih pregledov spontanih poročil o primerih se zdi, da so bili izvedeni ukrepi za zmanjšanje tveganja učinkoviti.
However, they described the TEM finding of electrondense lumps in the tissues of ProHance-treated animals which at first were assumed to be Gd deposits, obviously because they looked like them.
Opisali pa so zatrdline s povečano gostoto elektronov, ki so jih s transmisijsko elektronsko mikroskopijo (TEM) ugotovili v tkivih živalih, obravnavanih s sredstvom ProHance, za katere se je najprej domnevalo, da so depoziti gadolinija, očitno zato, ker so jim bili podobni.
Since the finalisation of the referral, several studies in animals and in humans have been published showing accumulation of gadolinium following administration of GdCAs in tissues such as liver, kidney, muscle, skin and bone.
Po zaključku napotitve je bilo objavljenih več študij na živalih in ljudeh, ki so po uporabi sredstev GdCA pokazale kopičenje gadolinija v tkivih, npr. v jetrih, ledvicah, mišicah, koži in kosteh.
Final benefit-risk balance
Končno razmerje med koristmi in tveganji
This is a clinically relevant benefit as they allow enhancement of dynamic phase liver imaging for highly vascularised hepatic lesions and also detection of lesions that are visible only in the delayed phase.
To je klinično pomembna korist, saj omogočata izboljšanje kontrasta v dinamični fazi slikanja jeter pri zelo vaskulariziranih jetrnih lezijah in tudi za odkrivanje lezij, ki jih je mogoče videti samo v zapozneli fazi.
• PRAC considered options for risk minimisation measures.
• odbor PRAC je proučil mogoče ukrepe za zmanjšanje tveganja.
Firstly, PRAC noted that accumulation in the brain is an intrinsic property of intravenous linear GdCAs and therefore, information on brain accumulation in the SmPC will not lead to a reduction of potential risks associated with this accumulation.
Prvič, odbor PRAC je poudaril, da je kopičenje v možganih intrinzična lastnost linearnih sredstev GdCA za intravensko uporabo, zato se zaradi informacij o kopičenju v možganih v povzetku glavnih značilnosti zdravila ne bodo zmanjšala morebitna tveganja, povezana s tem kopičenjem.
• variation to the terms of the marketing authorisation for the intraarticular linear agent gadopentetic acid (Magnevist), and the intravenous linear agents gadoxetic acid (Primovist) and gadobenic acid (Multihance) with changes to SmPC sections 4.1, 4.2, 4.4 and 5.2, including removal of indications,
• spremembo pogojev dovoljenja za promet z linearnim sredstvom gadopentetska kislina za intraartikularno uporabo (Magnevist) ter linearnimi sredstvi gadoksetno kislino (Primovist) in gadobensko kislino (Multihance) za intravensko uporabo s spremembami oddelkov 4.1, 4.2, 4.4 in 5.2 v povzetkih glavnih značilnosti zdravila, vključno z izbrisom indikacij,
With regards to the claim of a lower risk of cardiovascular adverse events for Multihance, PRAC considered that nonclinical data as well as available clinical data do not indicate a difference in cardiovascular risk (inducing QT prolongation) within the delayed phase liver imaging agents.
Odbor PRAC je v zvezi s trditvijo, da pomeni sredstvo Multihance manjše tveganje neželenih kardiovaskularnih dogodkov, menil, da neklinični podatki in razpoložljivi klinični podatki ne kažejo različnega kardiovaskularnega tveganja (vključno s podaljšanjem QT) pri sredstvih za slikanje jeter v zapozneli fazi.
For lifting the suspension, the PRAC recommended that MAHs should provide evidence:
Za preklic začasnega umika dovoljenja je odbor PRAC priporočil, naj imetniki dovoljenja za promet z zdravilom zagotovijo dokaze:
The benefit-risk balance of medicinal products containing intravenous gadobenic acid (in all other indications than liver imaging), gadodiamide, gadopentetic acid (IV presentation), and gadoversetamide is no longer favourable and these marketing authorisations should be suspended.
Razmerje med koristmi in tveganji pri zdravilih, ki vsebujejo gadobensko kislino za intravensko uporabo (pri vseh drugih indikacijah, razen slikanja jeter), gadodiamid, gadopentetsko kislino (predstavitev IV ) in gadoversetamid ni več ugodno ter bi bilo treba ta dovoljenja za promet začasno umakniti.