natgillin/translations-raw huggingface dataset:
Taking into account the extensive exposure and the absence of clinical or non-clinical adverse outcomes of gadolinium accumulation in the brain, CHMP considered that such harmful effects and potential interaction with disease processes are “possible” rather than “plausible”, as the latter would imply a stronger potential for harm; in this sense, “yet” was also removed.
Uzimajući u obzir široki razmjer izlaganja i manjak kliničkih i nekliničkih podataka o štetnim nuspojavama uzrokovanih taloženjem gadolinija u mozgu, CHMP smatra da su takvi štetni učinci i moguća interakcija s bolestima „mogući”, a ne „vjerojatni” jer potonji izraz ukazuje na veću mogućnost štetnih nuspojava; u tom smislu uklonjena je i riječ „još”.
Furthermore, recent publications have shown that gadolinium also accumulates in the brain.
Štoviše, nedavne objave ukazuju na to da se gadolinij taloži i u mozgu.
Whereas
Na taj način
Thus, rather weak binding of linear chelators to Gd becomes obvious in various experiments (including Port et al 2009, Sieber et al 2008), and this makes it unlikely that the complex is fully stable in vivo.
Stoga slabo vezanje linearnih kelatora za gadolinij postaje očito u raznim eksperimentima (uključujući Port i dr., 2009.; Sieber i dr., 2008.).
Adverse effects might be delayed and might be subtle, including effect on fine motor skills or cognitive impairment, particularly in those with ongoing neurological disease.
Štetni učinci mogu biti odgođeni i suptilni, uključujući učinak na fine motoričke vještine ili kognitivno oštećenje, posebno u bolesnika s trajnom neurološkom bolesti.
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.
U pogledu tvrdnje da Multihance ima manji rizik od štetnih kardiovaskularnih događaja, PRAC smatra da neklinički podaci te dostupni klinički podaci ne dokazuju razliku u pogledu kardiovaskularnih rizika (uključujući produljenje QT intervala) pri primjeni sredstava za snimanje jetre u odgođenoj fazi.
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).
GdCA-ovi razlikuju se prema svojoj strukturi: linearna (gadodiamid, gadopentetična kiselina, gadobenska kiselina, gadoksetična kiselina, gadoversetamid) ili makrociklička (gadoteridol, gadobutrol, gadoterična kiselina) te prema ukupnom naponu formiranog kompleksa (ionskog ili neionskog).
There are practical difficulties in clinical daily life for implementing an effective restriction of the number of doses administered during the lifetime of a patient.
Postoje praktične poteškoće u svakodnevnom kliničkom životu koje sprječavaju primjenu djelotvornog ograničenja broja doza koje se primjenjuju tijekom cijelog života bolesnika.
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.
Postoje i nedavna MRI ispitivanja koja bilježe povećanje intenziteta signala u mozgu povezano s makrocikličkim GdCA-ovima, što ukazuje na to da i ta sredstva mogu taložiti gadolinij u mozgu.
With regards to non-clinical studies, unchelated gadolinium in the form of gadolinium chloride has been shown to be toxic with effects including cellular necrosis, fibrosis, and lesions related to mineral deposition (Spencer et al. 1997; Rees et al. 1997), and an in vitro study in rat neurons reported gadolinium-induced cytotoxicity via oxidative injury (Xia et al. 2011).
Neklinička ispitivanja pokazala su da je nekelirani gadolinij u obliku gadolinijeva klorida toksičan te ima učinke kao što su stanična nekroza, fibroza i lezije povezane s taloženjem minerala (Spencer i dr. 1997.; Rees i dr. 1997.), a in vitro ispitivanje na štakorima pokazalo je citotoksičnost uzrokovanu gadolinijem putem oksidacijske ozljede (Xia i dr. 2011.).
Another study showed that administration of the linear GdCAs gadodiamide and gadobenic acid directly into the cerebrospinal fluid (CSF) resulted in increased signal intensity in the DCN in rats up to 5 weeks after administration.
Drugo ispitivanje pokazalo je da primjena linearnih GdCA-ova, gadodiamida i gadobenske kiseline, izravno u cerebrospinalnu tekućinu (CSF) dovodi do povećanja intenziteta signala u DCN-u u štakora 5
1 ICP-MS: Inductively coupled plasma mass spectrometry
1 ICP-MS: masena spektrometrija s induktivno spregnutom plazmom tjedana nakon primjene.
The increased potential to release gadolinium in the brain would be expected with the linear agents, which have a lower kinetic and thermodynamic stability and are thus more prone to release gadolinium in the tissue environment.
Pri primjeni linearnih sredstava očekuje se veća mogućnost otpuštanja gadolinija u mozak jer imaju manju kinetičku i termodinamičku stabilnost te stoga postoji veća vjerojatnost da će otpustiti gadolinij u okolno tkivo.
In view of a potential difference in the frequency of hypersensitivity reactions, PRAC pointed out that these are known infrequent reactions for all GdCAs.
Uzimajući u obzir moguću razliku u učestalosti reakcija preosjetljivosti, PRAC je istaknuo da su poznate neučestale reakcije za sva GdCA sredstva.
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.
CHMP je razmotrio i izjavu koja se odnosi na moguće štetne učinke povezane s taloženje gadolinija u mozgu: „Iako još nije dokazano da taloženje gadolinija u mozgu ima štetne neurološke učinke, na primjer kognitivne poremećaje ili poremećaje kretanja, podaci o dugoročnoj sigurnosti ograničeni su.
In view of (a) the evidence suggesting that linear GdCAs release Gd from their chelating ligand molecules due to the low kinetic and thermodynamic stability; (b) the known toxicity of unchelated gadolinium; (c) the data supporting the ability of linear GdCAs to distribute and accumulate in the brain; (d) the fact that linear agents are retained and persist for up to one year or longer in the brain; and (e) the deposition in other tissues with related harm; PRAC considered that there are reasonable and serious concerns raised as to the potential of neurological harm associated with the accumulation of gadolinium in the brain.
Uzimajući u obzir (a) dokaz koji govori da linearni GdCA-ovi otpuštaju gadolinij iz kelacijskih molekula liganda zbog niske kinetičke i termodinamičke stabilnosti; (b) poznatu toksičnost nekelacijskog gadolinija; (c) podatke koji pokazuju sposobnost linearnih GdCA-ova da se distribuiraju i talože u mozgu; (d) činjenicu da se linearna sredstva zadržavaju u mozgu jednu godinu ili duže; i (e) taloženje u drugim tkivima uz povezanu štetu; PRAC smatra da postoje razumne i ozbiljne zabrinutosti u pogledu neurološkog oštećenja uzrokovanog taloženjem gadolinija u mozgu.
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.
Ispitivanje na štakorima potvrdilo je i da je razina gadolinija u mozgu ovisno o dozi linearnih sredstava vjerojatno povezana s ukupnom dozom, a ne jednom velikom ili više malih doza.
Therefore, PRAC considered that restriction of the use of linear GdCAs to certain indications or to certain groups of patients would not be justified and would still leave patients exposed to the risk of gadolinium brain accumulation and that risk minimisation measures such as warnings in the SmPC or other contraindications would not limit the exposure to linear GdCAs as no safe level of gadolinium brain accumulation has been established.
Stoga PRAC smatra da ograničenje uporabe linearnih GdCA-ova na određene indikacije ili na određene skupine bolesnika ne bi bilo opravdano i da bi bolesnici i dalje bili izloženi riziku od taloženja gadolinija u mozgu te da mjere za smanjenje rizika kao što su upozorenja u sažetku opisa svojstava lijeka ili druge kontraindikacije ne bi ograničile izloženost linearnim GdCA-ovima jer nije utvrđena sigurna razina za taloženje gadolinija u mozgu.
Macrocyclic agents show only a transient increase in Gd in the brain and undergo early washout.
Makrociklička sredstva pokazuju samo prijelazno povećanje gadolinija u mozgu i rano se ispiru.
In rat studies, residual Gd found in the rat brain after repeated administration of linear GdCAs was present in at least 3 distinctive forms - soluble small molecules, presumably intact GdCA, soluble macromolecules and to the largest extent an insoluble form.
U ispitivanjima na štakorima, ostaci gadolinija u mozgu štakora nakon ponovljene primjene linearnih GdCA-ova pronađeni su u najmanje 3 različita oblika - topive male molekule, vjerojatno netaknuti GdCA, topive makromolekule i u najvećoj mjeri oblik koji nije topiv.
For the linear agent gadoxetic acid that has shown clinical utility in liver imaging, in view of its substantial liver uptake, its administration at a low dose (0.025 mmol/kg of body weight) and the short time to the delayed phase scanning (20 mins), the PRAC considered that it provides an additional benefit to patient management with an exposure to gadolinium that is minimised by the low dose administered and the short time to the delayed phase.
U pogledu linearnog sredstva gadoksetične kiseline koja je pokazala kliničku korist pri snimanju jetre, uzimajući u obzir značajan unos u jetru, primjenu u niskoj dozi (0,025 mmol/kg tjelesne mase) i kratko vrijeme do odgođene faze snimanja (20 minuta), PRAC smatra da pruža dodatnu korist za upravljanje bolesnikom koji se izlaže gadoliniju jer se to izlaganje smanjuje primjenom niske doze i kratkim vremenom do odgođene faze.
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.
GdCA sredstava su bubrezi, a produljeno vrijeme izlučivanja zbog teškog oštećenja bubrežne funkcije moglo bi teoretski povećati mogućnost taloženja u moždanom tkivu.
Non-clinical evidence also shows potential for release of gadolinium from the chelating ligand in the brain with linear GdCAs, but not with macrocyclic GdCAs (Frenzel et al. 2017).
Neklinički dokazi također pokazuju potencijal otpuštanja gadolinija iz kelirajućeg liganda u mozgu nakon primjene linearnih GdCA-ova, ali ne nakon primjene makrocikličkih GdCA-ova (Frenzel i dr. 2017.).
In addition, with regards to the SmPCs of macrocyclic GdCAs (Dotarem, Prohance, and Gadovist) recommending higher dose in CNS imaging to improve visualisation and angiography but not in whole body imaging, PRAC considered that clinically relevant differences in diagnostic performance between Multihance and macrocyclic agents need to be supported by robust evidence from comparative clinical studies rather than a comparison of the approved SmPCs, which may have limitations.
Nadalje, u pogledu sažetaka opisa svojstava lijeka za makrocikličke GdCA-ove (Dotarem, Prohance i Gadovist) u kojima se preporučuje veća doza za CNS snimanje kako bi se poboljšala vidljivost i angiografija, ali ne i za snimanje cijelog tijela, PRAC smatra da klinički relevantne razlike u dijagnostičkoj izvedbi Multihancea i makrocikličkih sredstava trebaju biti potkrijepljene snažnim dokazima iz komparativnih kliničkih ispitivanja, a ne usporedbom odobrenih sažetaka opisa svojstava lijeka koji imaju ograničenja.
Two linear GdCAs, gadoxetic acid and gadobenic acid, have been shown to have an uptake by hepatocytes and are the only liver-specific agents that can provide both the dynamic and the delayed phase imaging.
Dokazano je da dva linearna GdCA-a, gadoksetičnu kiselinu i gadobensku kiselinu, unose hepatociti te su jedina sredstva specifična za jetru koja omogućuju snimanje jetre i u dinamičnoj i odgođenoj fazi.
PRAC recommended restriction of use, in the lowest dose that provides sufficient enhancement for diagnostic purposes and through appropriate warning in the product information in order to minimise the potential for accumulation of gadolinium in the brain and other organs and tissues.
PRAC je preporučio ograničenje uporabe, primjenom najmanje doze koja pruža dovoljno poboljšanje u dijagnostičke svrhe i odgovarajućih upozorenja u informacijama o lijeku kako bi se smanjila mogućnost taloženja gadolinija u mozgu, drugim organima i tkivima.
However, in view of the extent of the hepatic uptake, the high dose (0.05 mmol/kg body weight) required and the long time to the onset of delayed phase imaging (40 mins), the PRAC considered that the benefit of gadobenic acid containing products in all the authorised indication including the liver imaging does not outweigh the potential and identified risks associated to the use of this product.
Međutim, uzimajući u obzir razmjer unosa u jetru, potrebnu visoku dozu (0,05 mmol/kg tjelesne mase) i vrijeme potrebno za nastupanje odgođene faze snimanja (40 minuta), PRAC smatra da korist lijekova koji sadržavaju gadobensku kiselinu za sve odobrene indikacije, uključujući snimanje jetre, ne nadmašuje moguće i utvrđene rizike povezane s uporabom tog lijeka.
The T1 signal enhancement was documented in several non-clinical as well as clinical studies, demonstrating that the data is consistent across mouse, rat and human, which confirms the robustness of the findings of signal intensity increases.
Poboljšanje T1 signala dokumentirano je u nekoliko nekliničkih, kao i kliničkih ispitivanja, što dokazuje da su podaci dosljedni kod miševa, štakora i ljudi.
PRAC maintained its view that conducting clinical studies to fully address the potential risk associated with Gd accumulation in the brain would not be feasible within a reasonable period of time.
PRAC je ostao pri svojem mišljenju da provedba kliničkih ispitivanja radi potpunog rješavanja rizika povezanih s taloženjem gadolinija u mozgu nije provediva u razumnom vremenskom roku.
Intravenous linear Gadolinium-containing contrast agents (GdCAs)
Intravenska linearna kontrastna sredstva koja sadržavaju gadolinij
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.
Nadalje, dva GdCA proizvoda, gadopentetična kiselina i gadoterična kiselina ovlaštena su kao formulacije za intraartikularnu primjenu za MR artrografiju te mogu poboljšati vidljivost određenih lezija.
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.
PRAC je ostao i pri svojim zaključcima o tome da koristi intraartikularne primjene lijeka Magnevist s linearnim GdCA sredstvima nadmašuju s njim povezane rizike (podliježe izmjenama informacija o lijeku) jer se lijek primjenjuje u vrlo niskim dozama i predstavlja nizak rizik od taloženja u tkivu.
While accumulation in terms of T1w signal intensity increases and gadolinium measured in the brain (likely in the form of intact GdCA molecule) has been seen in the short term with these agents, long-term persistence in the brain was not be observed.
Iako je primijećeno kratkoročno taloženje u pogledu povećanja intenziteta T1w signala i izmjerenog gandolinija u mozgu (vjerojatno u obliku netaknute GdCA molekule) nakon primjene tih sredstava, nije primijećeno dugotrajno zadržavanje u mozgu.
A higher in vivo than in vitro stability would require the occurrence of stabilising agents in vivo, but no conclusive evidence confirming increases of the stability of the Gd complex in the body has been provided by the MAH.
Da bi stabilnost bila veća in vivo nego in vitro potrebna je pojava sredstava za stabilizaciju in vivo, ali nositelj odobrenja nije podnio uvjerljive dokaze koji potvrđuju povećanje stabilnosti gadolinijskog kompleksa u tijelu.
Therefore, it is considered that gadoxetic acid brings an additional benefit to patient management with an exposure to gadolinium that is minimised by the low dose administered, the very significant hepatic uptake and the short time to the delayed phase scanning.
Stoga se smatra da gadoksetična kiselina donosi dodatnu korist za upravljanje bolesnikom jer se izlaganje gadoliniju smanjuje primjenom male doze, značajnim unosom u jetru i kratkim vremenom snimanja u odgođenoj fazi.
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.
Ova veza dodatno podupire tumačenja ispitivanja magnetske rezonancije (MRI) koja smatraju da je taloženje gadolinija u mozgu uzročno povezano s izlaganjem GdCA-ovima.
Impact of renal impairment
Utjecaj oštećenja bubrega
No such enhancement was observed with gadoterate meglumine (Dotarem).
Takvo poboljšanje nije primijećeno pri primjeni gadoterata meglumina (Dotarem).
• Clinical studies, both observational and interventional, to fully address the serious concerns of potential neurological effects are not considered feasible within a reasonable period of time.
• Smatra se da provedivost kliničkih ispitivanja, i promatračkih i intervencijskih radi rješavanja ozbiljnih zabrinutosti u vezi s mogućim neurološkim učincima nije moguća u razumnom vremenskom roku.
With regards to the MAH's claim that linear GdCAs do not cause more marked Gd retention and do not have a slower release from brain tissues compared to macrocyclic GdCAs, PRAC considered that the study of McDonald et al. (2017), confirming T1 hyperintensity in the rat lateral dentate nucleus 1 week after administration of macrocyclic agents (Gadovist and Prohance), has several shortcomings:
U pogledu tvrdnji nositelja odobrenja za stavljanje u promet da linearni GdCA-ovi ne uzrokuju istaknutije zadržavanje gadolinija i ne otpuštaju se sporije iz moždanog tkiva u usporedbi s makrocikličkim GdCa-ovima, PRAC smatra da ispitivanje McDonalda i dr. (2017.) koje potvrđuje preosjetljivost T1 signala u bočnom dentatnom nukleusu štakora 1 tjedan nakon primjene makrocikličkih sredstava (Gadovist i Prohance) ima nekoliko nedostataka:
Data from non-clinical electron microscopy (EM) studies of brain tissue have also provided evidence of filamentous electron-dense Gd deposits in the regions where T1 hyper intensity has been observed following dosing with gadodiamide.
Podaci iz nekliničkih ispitivanja elektronske mikroskopije (EM) moždanog tkiva dokazali su vlaknaste guste naslage gadolinija u područjima na kojima je primijećen T1 hiperintezitet nakon primjene doze gadodiamida.
physiology and functionality of many different areas of the body and internal organs as part of a diagnostic workup investigating a wide range of diseases including cancer, inflammatory diseases and degenerative conditions.
To poboljšanje kontrasta pokazalo važnim za vizualizaciju anatomije, fiziologije i funkcionalnosti različitih dijelova tijela i unutarnjih organa u okviru dijagnostike u kojoj se istražuje cijeli niz bolesti, uključujući rak, upalne bolesti i degenerativna stanja.
The highest amount of gadolinium recovered from the rat brain tissue was found to be with gadodiamide, followed by gadobenate and gadopentetate.
Najveća količina gadolinija pronađena u moždanom tkivu štakora bila je nakon primjene gadodiamida, zatim gadobenata te na kraju gadopentetata.
• To update the SmPC to make the physician aware of the accumulation in the brain and to reduce exposure and communicate about such update;
• ažuriranje sažetaka opisa svojstava lijeka kako bi liječnici bili upoznati s taloženjem u mozgu, smanjenje izlaganja i obavješćivanje o takvim promjenama;
Therefore, the PRAC considered that the benefits of these products outweigh their risks.
Stoga PRAC smatra da koristi tih lijekova nadmašuju s njima povezane rizike.
The PRAC also noted that high GdCAs doses were tested (20x2.5 mmol) by McDonald et al., and the study duration is comparably short (e.g. the total doses tested in Frenzel et al 2017 was half that of McDonald et al (10x2.5mmol), while the time period to the last tissue sampling in Frenzel et al 2017 was 24 days instead of 7 days in McDonald 2017.)
PRAC je napomenuo i da su McDonald i dr. ispitali velike doze GdCA-ova (20 x 2,5 mmol) te da je trajanje ispitivanja usporedivo kratko (npr. ukupan broj ispitanih doza u ispitivanju Frenzela i dr. iz 2017. bio je upola manji od onoga u ispitivanju McDonalda i dr. (10 x 2,5 mmol).
Lanthanide ions such as gadolinium can bind to Ca2+ binding enzymes and interfere with calcium channels, due to competition with Ca2+ in cellular and biochemical processes, which can lead to adverse biological effects (Sherry et al. 2009).
Ioni lantanida kao što je gadolinij mogu se vezati na enzime koji se vežu na Ca2+ i miješaju s kanalima kalcija zbog nadmetanja s Ca2+ u staničnim i biokemijskim procesima.
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.
Omjer koristi i rizika lijekova koji sadržavaju intravensku gadobensku kiselinu (za sve indikacije osim snimanja jetre), gadodiamid, gadopentetičnu kiselinu (IV. prezentacija) i gadoversetamid više nije povoljan i ta se odobrenja za stavljanje u promet trebaju obustaviti.
In relation to the statement about the macrocyclic early washout “macrocyclic agents show only a transient increase in Gd in the brain and undergo early washout”, the CHMP considered it sufficient to reflect the observation that measurements of gadolinium in the brain over longer periods showed differences between linear and macrocyclic agents in terms of accumulation over time.
U pogledu izjave o ranom ispiranju makrocikličkih sredstava „makrociklička sredstva pokazuju samo prijelazno povećanje gadolinija u mozgu te se rano ispiru”, CHMP smatra da je ta izjava dovoljna kako bi se objasnilo da su mjerenja gadolinija u mozgu tijekom duljeg vremenskog razdoblja pokazala drugačije rezultate u pogledu taloženja tijekom vremena kod linearnih i makrocikličkih sredstava.
For lifting the suspension, the PRAC recommended that MAHs should provide evidence:
Kako bi se obustava ukinula, PRAC je nositeljima odobrenja za stavljanje u promet preporučio da dostave sljedeće dokaze:
• 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.
• Da se uporaba linearnih GdCA sredstava i ograniči, bolesnici u preostalim skupinama i dalje će biti izloženi riziku jer se ne zna koja je sigurna razina za zadržavanje dekeliranog gadolinija u mozgu i drugim tjelesnim tkivima.
In view of the claimed differences of hypersensitivity reactions with Omniscan versus other GdCAs based on meta-analyses of available epidemiological data, PRAC considered these differences are too subtle to influence the benefit-risk balance, and that extremely large clinical trials would be necessary to confirm a statistical difference in frequency of hypersensitivity reactions.
Uzimajući u obzir tvrdnje o razlikama u reakcijama preosjetljivosti nakon primjene Omniscana u usporedbi s drugim GdCA sredstvima koje se temelje na analizi dostupnih epidemioloških podataka, PRAC smatra da su te razlike toliko neznatne da ne mogu utjecati na omjer koristi i rizika te da je potrebno provesti iznimno velika klinička ispitivanja radi potvrđivanja statističke razlike u učestalosti reakcija preosjetljivosti.