natgillin/translations-raw huggingface dataset:
Additionally, the urinary pH value and the relative weight of kidneys were increased at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Poleg tega sta se vrednost pH urina in relativna masa ledvic zvečali pri izpostavljenostih, za katere menimo, da dovolj presegajo največjo izpostavljenost pri človeku, kar kaže na majhen pomen za klinično uporabo.
These antibodies may induce clinical allergic reactions, inactivate the enzymatic activity or accelerate the elimination of asparaginase.
Ta protitelesa lahko sprožijo klinične alergijske reakcije, inaktivirajo encimsko aktivnost ali pospešijo izločanje asparaginaze.
Spectrila is prepared and given by healthcare personnel.
Zdravilo Spectrila pripravljajo in dajejo zdravstveni delavci.
Asparaginase is distributed mainly within the intravascular space.
Asparaginaza se porazdeli v glavnem znotraj intravaskularnega prostora.
5 vials
1 viala 5 vial
Other medicines and Spectrila
Druga zdravila in zdravilo Spectrila
Since Spectrila is usually used in combination therapy with other antineoplastic agents, the demarcation from undesirable effects of other medicinal products is often difficult.
Ker se zdravilo Spectrila navadno uporablja v kombinirani terapiji z drugimi zdravili z delovanjem na novotvorbe, je razmejitev od neželenih učinkov drugih zdravil pogosto težavna.
The majority of anti-asparaginase antibodies developed in the time gap between the last asparaginase infusion on day 33 and start of post-induction treatment at day 79.
Večina antiasparaginaznih protiteles se je razvila v časovnem intervalu med zadnjo infuzijo asparaginaze 33. dne in začetkom postindukcijskega zdravljenja 79. dne.
*Produced in Escherichia coli cells by recombinant DNA technology.
*Izdelane v celicah Escherichia coli s tehnologijo rekombinantne DNA.
• mild to moderate reduction in all blood cell counts
• blago do zmerno zmanjšanje števila vseh vrst krvničk,
Most hypersensitivity reactions to asparaginase are observed during subsequent treatment phases (reinduction treatment, delayed intensification).
Največ preobčutljivostnih reakcij na asparaginazo ugotavljajo med poznejšimi fazami zdravljenja (reindukcijsko zdravljenje, odložena intenzifikacija).
• diabetic ketoacidosis (complication due to uncontrolled blood sugar)
• diabetična ketoacidoza (zaplet zaradi nenadzorovanega krvnega sladkorja),
Therefore, vincristine should be given 3 to 24 hours before administration of asparaginase in order to minimise toxicity.
Zato je treba vinkristin dati 3 do 24 ur pred dajanjem asparaginaze, da se toksičnost čim bolj zmanjša.
To aid traceability of rASNase batches and distinction between different ASNase and rASNase products, the product information should include in section 4.4 of the SmPC and relevant section of the PL a prominent statement that the name and batch number of the administered product should be clearly recorded in the patient records.
Za namenom ohranjanja sledljivosti serij rASNaze in za razlikovanje med zdravili z različnimi ASNazami in rASNazami mora biti v informacijah o zdravilu v poglavju 4.4 SmPC-ja in ustreznem poglavju navodila za uporabo vključena navedba, da morata biti ime in številka serije uporabljenega zdravila jasno zabeležena v kartoteki bolnika.
No reproduction studies in animals with asparaginase were performed but studies with asparaginase preparations in mice, rats, chicken and rabbits have shown embryotoxic and teratogenic effects (see section 5.3).
Opravili niso nobenih študij razmnoževanja pri živalih z asparaginazo, so pa študije z drugimi zdravili z asparaginazo pri miših, podganah, piščancih in kuncih pokazale embriotoksične in teratogene učinke (glejte poglavje 5.3).
The mean (Standard Deviation, SD) of the volume of distribution at steady state (Vdss) was 2.47 l (0.45 l).
Povprečje (standardna deviacija, SD) porazdelitvenega volumna v stanju dinamičnega ravnovesja (Vdss) je bilo 2,47 l (0,45 l).
The objective of the study was to demonstrate the non-inferiority of Spectrila to the reference E. coli-asparaginase with regard to the primary endpoint.
Cilj študije je bil dokazati neinferiornost zdravila Spectrila v primerjavi z referenčno asparaginazo E. coli glede primarnega končnega opazovanega dogodka.
Spectrila is used to treat adults and children with acute lymphoblastic leukaemia (ALL) which is a form of blood cancer.
Zdravilo Spectrila se uporablja za zdravljenje odraslih in otrok z akutno limfoblastno levkemijo (ALL), ki je oblika krvnega raka.
Concomitant treatment with corticosteroids contributes to this effect.
Sočasno zdravljenje s kortikosteroidi prispeva k temu učinku.
Based on results from animal studies and its mechanism of action, Spectrila should not be used during pregnancy unless the clinical condition of the woman requires treatment with asparaginase.
Na podlagi rezultatov študij na živalih in njenega mehanizma delovanja zdravila Spectrila ne smete uporabljati pri nosečnicah, razen če klinično stanje ženske zahteva zdravljenje z asparaginazo.
6 22880 Wedel Germany
22880 Wedel Nemčija
Peak (Cmax) of asparaginase activity in serum was reached with a delay of approximately 2 hours after the end of the infusion.
Največja (Cmax) aktivnost asparaginaze v serumu je bila dosežena z zakasnitvijo približno 2 ur po koncu infuzije.
Immediately after the end of infusion of asparaginase, serum levels of glutamine declined by a maximum of 50 % from pre-dose levels of about 400 µM but rapidly returned to normal values within a few hours.
Takoj po koncu infuzije asparaginaze se je serumska raven glutamina zmanjšala za največ 50 % od ravni pred odmerkom, ki je bila okrog 400 µM, a se je hitro, v nekaj urah, vrnila na normalne vrednosti.
Children 0 - 12 months old
Otroci, stari od 0 do 12 mesecev
Spectrila can induce antibodies of different immunoglobulin classes (IgG, IgM, IgE).
Zdravilo Spectrila lahko sproži nastajanje protiteles, ki spadajo v različne skupine imunoglobulinov (IgG, IgM, IgE).
In addition, treatment with asparaginase can result in disturbances in organ systems which exhibit a high level of protein synthesis.
Poleg tega lahko zdravljenje z asparaginazo povzroči motnje v organskih sistemih, v katerih je visoka raven sinteze beljakovin.
If allergic symptoms occur, administration of asparaginase must be discontinued immediately and appropriate treatment given, which may include antihistamines and corticosteroids.
Če nastopijo alergijski simptomi, je treba takoj prekiniti dajanje asparaginaze in zagotoviti ustrezno zdravljenje, ki lahko vključuje antihistaminike in kortikosteroide.
After induction treatment, patients continued treatment with chemotherapy regimens which included further treatment with asparaginases.
Po indukcijskem zdravljenju so bolniki nadaljevali zdravljenje s kemoterapevtskimi shemami, v katere je bilo vključeno nadaljnje zdravljenje z asparaginazami.
RPLS is treated symptomatically, including measures to treat any seizures.
RPLS zdravimo simptomatsko, vključno z ukrepi za zdravljenje kakršnih koli epileptičnih napadov.
There are no data on the use of asparaginase in pregnant women.
Podatkov o uporabi asparaginaze pri nosečnicah ni.
Low asparaginase activity levels are often accompanied by the appearance of anti-asparaginase antibodies.
Nizko raven aktivnosti asparaginaze pogosto spremlja pojav antiasparaginaznih protiteles.
This regimen has been shown to reduce the gastrointestinal and haematological effects of methotrexate.
Pokazali so, da ta shema zdravljenja zmanjša gastrointestinalne in hematološke učinke metotreksata.
Normal cells can make asparagine for themselves, while some cancer cells cannot.
Normalne celice lahko asparagin izdelujejo same, nekatere rakaste celice pa tega ne morejo.
• abnormal laboratory tests including changes in protein levels in the blood, changes in blood fat or in liver enzyme values or high level of urea in the blood
• abnormalni laboratorijski testi, vključno s spremembami ravni beljakovin v krvi, spremembami krvnih maščob ali vrednosti jetrnih encimov ali visoka raven sečnine v krvi.
Serum amylase and lipase are usually elevated, although in some patients they can be normal due to impaired protein synthesis.
Serumska amilaza in lipaza sta navadno zvišani, čeprav sta lahko pri nekaterih bolnikih normalni zaradi okvarjene sinteze beljakovin.
Concomitant vaccination with live vaccines increases the risk of serious infection.
Sočasna vakcinacija z živimi vakcinami zveča tveganje resne okužbe.
The mean ± SD terminal half-life (elimination half-life) of asparaginase activity in serum was 25.8 ± 9.9 h, with a range between 14.2 and 44.2 h.
Povprečni ± SD končni razpolovni čas (razpolovni čas izločanja) aktivnosti asparaginaze v serumu je bil 25,8 ± 9,9 ure, z razponom med 14,2 in 44,2 ure.
The mean asparagine concentrations in serum remained below 0.5 µM from immediately after the end of first infusion of asparaginase until at least three days after the last infusion.
Srednja serumska koncentracija asparagina je ostala pod 0,5 µM od takoj po koncu prve infuzije asparaginaze do vsaj tri dni po zadnji infuziji.
• coagulation disorders including symptomatic thrombosis related to the use of central venous catheters,
• motnje koagulacije, vključno s simptomatsko trombozo, povezano z uporabo centralnih venskih katetrov,
Duration of administration
Trajanje uporabe
If you are sexually mature you must use contraceptives or remain abstinent during chemotherapy and for up to 3 months after the end of treatment.
Če ste spolno zreli, morate med kemoterapijo in do 3 mesece po končanem zdravljenju uporabljati kontracepcijo ali se vzdržati spolnih odnosov.
Serum and urine glucose levels should be regularly monitored and managed as clinically indicated.
Redno moramo spremljati raven glukoze v serumu in urinu in jo obravnavati, kot je klinično indicirano.
Non-clinical repeat-dose toxicity and safety pharmacology studies in rats revealed no special hazard for humans, except a slight but significant saluretic effect at doses below the recommended dose for ALL/LBL patients.
Predklinične študije toksičnosti in varnostne farmakologije ponavljajočih se odmerkov pri podganah ne kažejo posebnega tveganja za človeka, razen majhnega, a značilnega saluretičnega učinka pri odmerkih, manjših od priporočenega odmerka za bolnike z ALL/LBL.
Concomitant administration of glucocorticoids may be a contributing factor.
Sočasno dajanje glukokortikoidov utegne biti dejavnik, ki k temu prispeva.
However, in rare cases it can result in diabetic ketoacidosis.
V redkih primerih pa lahko povzroči diabetično ketoacidozo.
Median (range) maximum serum concentrations of asparaginase activity were 2,324 U/l (1,6254,819 U/l).
Mediana (razpon) največje serumske koncentracije aktivnosti asparaginaze je bila 2.324 E/l (1.625-4.819 E/l).
In contrast to normal cells, lymphoblastic tumour cells have a very limited capacity for synthesising asparagine because of a significantly reduced expression of asparagine synthetase.
Za razliko od normalnih celic imajo limfoblastne tumorske celice zelo omejeno sposobnost sintetiziranja asparagina zaradi značilno zmanjšane ekspresije asparaginske sintetaze.
However, in rare cases severe hypertriglyceridaemia (triglycerides > 1,000 mg/dl) has been reported which increases the risk of development of acute pancreatitis.
Vendar so v redkih primerih poročali o hudi hipertrigliceridemiji (trigliceridi >1.000 mg/dl), ki zvečuje nevarnost razvoja akutnega pankreatitisa.
Recommended control examinations for patients of all age groups
Priporočeni kontrolni pregledi za bolnike vseh starostnih skupin Aktivnost asparaginaze
• depression, hallucination or confusion
• depresija, halucinacije ali zmedenost,
• mild tremor (shaking) of the fingers
• blag tremor (tresenje) prstov rok,
Qualitatively, the same asparaginase-induced adverse drug reactions are observed in adults and children; however, some of these undesirable effects (e.g. thromboembolic events) are known to occur with a higher frequency in adult patients compared to the paediatric population.
Pri odraslih in otrocih ugotavljajo kvalitativno enake neželene učinke zdravila, ki jih povzroča asparaginaza; vendar je znano, da se nekateri od teh neželenih učinkov (npr. trombembolični dogodki) pogosteje pojavljajo pri odraslih bolnikih kot v pediatrični populaciji.
• loss of appetite or weight loss
• izguba apetita ali hujšanje,
• a serious allergic reaction which causes difficulty in breathing or dizziness,
• resna alergijska reakcija, ki povzroči oteženo dihanje ali omedlevico,
In such cases, a switch to a different asparaginase preparation should be considered.
V takih primerih je treba razmisliti o prehodu na drugačno zdravilo z asparaginazo.
Preferably, levels should be measured three days after the last asparaginase administration, i.e. usually directly before the next dose of asparaginase is given.
Raven je treba po možnosti izmeriti tri dni po zadnjem dajanju asparaginaze, navadno torej neposredno pred dajanjem naslednjega odmerka asparaginaze.
In addition to asparagine, asparaginase is also able to cleave the amino acid glutamine to glutamic acid and ammonia, however with much less efficiency.
Poleg asparagina lahko asparaginaza cepi tudi aminokislino glutamin v glutaminsko kislino in amoniak, vendar mnogo manj učinkovito.
Median (range)
Mediana (razpon)
EXP: In-use stability has been demonstrated for 2 days at 2 °C - 8 °C.
EXP: Stabilnost med uporabo so dokazali za 2 dni pri 2 °C - 8 °C.
Common Depression, hallucination, confusion
Pogosti depresija, halucinacije, zmedenost
Concomitant use of glucocorticoids and/ or anticoagulants with asparaginase may increase the risk of a change in coagulation parameters (see section 4.4).
Sočasna uporaba glukokortikoidov in/ali antikoagulantov z asparaginazo lahko zveča tveganje sprememb koagulacijskih parametrov (glejte poglavje 4.4).
0 (0 - 2) h
0 (0-2) h razpolovni čas
Asparaginase lowers asparagine level in blood cancer cells and stops the cancer growing.
Asparaginaza znižuje raven asparagina v celicah krvnega raka in zaustavi njegovo rast.
In very rare cases, severe hyperammonaemia has been reported which may induce neurologic disorders such as seizures and coma.
V zelo redkih primerih so poročali o hudi hiperamonemiji, ki lahko povzroča nevrološke težave, na primer epileptične napade in komo.
Due to the asparagine concentration gradient between the extra- and intravascular space, asparagine levels are subsequently also reduced in the extravascular spaces, e.g. the cerebrospinal fluid.
Zaradi koncentracijskega gradienta asparagina med ekstravaskularnim in intravaskularnim prostorom se nato koncentracija asparagina zniža tudi v ekstravaskularnih prostorih, npr. cerebrospinalni tekočini.
All cells need an amino acid called asparagine to stay alive.
Vse celice potrebujejo za življenje aminokislino, ki se imenuje asparagin.
This syndrome is characterised in magnetic resonance imaging (MRI) by reversible (from a few days to months) lesions/oedema, primarily in the posterior region of the brain.
Za ta sindrom so na magnetno-resonančnih slikah značilne reverzibilne (od nekaj dni do nekaj mesecev trajajoče) lezije/edemi, predvsem v zadajšnjih predelih možganov.
This can promote tendency to bleeding (anticoagulants) or thrombosis (glucocorticoids).
To lahko zveča nagnjenost h krvavitvi (antikoagulanti) ali trombozi (glukokortikoidi).
Spectrila is used as part of a combination therapy.
Zdravilo Spectrila se uporablja kot del kombiniranega zdravljenja.
Discontinuation or dose reduction of concomitantly administered immunosuppressive medicinal products may be necessary.
Mogoče bo potrebna ukinitev ali zmanjšanje odmerka sočasno uporabljenih imunosupresivnih zdravil.
Patients received asparaginase at a dose of 10,000 U/m², adjusted to the current age of the patient at the time of administration (< 6 months: 6,700 U/m²; 6 - 12 months: 7,500 U/m²; > 12 months: 10,000 U/m²) on days 15, 18, 22, 25, 29, and 33 of induction treatment.
Bolniki so prejeli asparaginazo v odmerku 10.000 E/m², prilagojenem glede na trenutno starost bolnika v času dajanja (<6 mesecev: 6.700 E/m²; 6 - 12 mesecev: 7.500 E/m²; >12 mesecev: 10.000 E/m²) na 15., 18., 22., 25., 29. in 33. dan indukcijskega zdravljenja.
These patients should no longer be treated with any asparaginase preparation.
Ti bolniki se ne smejo več zdraviti z nobenim zdravilom z asparaginazo.
Pharmacokinetic parameters of Spectrila were determined in 7 adult patients after intravenous infusion of 5,000 U/m².
Farmakokinetične parametre zdravila Spectrila so določili pri 7 odraslih bolnikih po intravenski infuziji 5.000 E/m².
Philadelphia chromosome-positive patients
Bolniki, pozitivni na kromosom Philadelphia
Changes in endocrine pancreatic function are observed very commonly during treatment with asparaginase and manifest predominantly as hyperglycaemia.
Spremembe endokrine funkcije pankreasa zelo pogosto ugotavljajo med zdravljenjem z asparaginazo, kažejo pa se pretežno kot hiperglikemija.
Aggressive alkalinisation of the urine and use of allopurinol can prevent urate nephropathy.
Agresivna alkalizacija urina in uporaba alopurinola lahko preprečita uratno nefropatijo.
• Hypersensitivity to the active substance, any native (non-pegylated) E. coli-asparaginase preparation or to any of the excipients listed in section 6.1.
• Preobčutljivost na zdravilno učinkovino, kateri koli nativen (nepegiliran) pripravek asparaginaze E. coli ali katero koli pomožno snov, navedeno v poglavju 6.1.
The primary toxicity of asparaginase results from immunologic reactions caused by exposure to the bacterial protein.
Primarna toksičnost asparaginaze je posledica imunoloških reakcij, ki jih povzroča izpostavljanje bakterijski beljakovini.
Vaccination
Vakcinacija
OTHER Store in a refrigerator.
DRUGI PODATKI Shranjujte v hladilniku.
To dissolve the powder, 3.7 ml of water for injections are carefully squirted against the inner wall of the vial with an injection syringe (do not squirt directly on or into the powder).
Prašek raztopite tako, da z injekcijsko brizgo previdno izbrizgate 3,7 ml vode za injekcije proti notranji steni viale (ne brizgajte vode neposredno na prašek ali vanj).
Spectrila should not be used during pregnancy unless the clinical condition of the woman requires treatment with asparaginase.
Zdravila Spectrila ne smete uporabljati pri nosečnicah, razen če klinično stanje nosečnice zahteva zdravljenje z asparaginazo.
In the majority of cases, your treatment can be continued by switching to other medicines containing different forms of asparaginase.
Večinoma je zdravljenje mogoče nadaljevati tako, da zdravilo zamenjamo z drugimi zdravili, ki vsebujejo drugačne oblike asparaginaze.
A comparable proportion of patients in both groups developed anti-asparaginase antibodies before the start of the post-induction treatment phase (Spectrila 54.6 % vs. reference E. coli-asparaginase 52.5 %).
V obeh skupinah so se pri primerljivem deležu bolnikov razvila antiasparaginazna protitelesa pred začetkom faze postindukcijskega zdravljenja (zdravilo Spectrila 54,6 % proti referenčni asparaginazi E. coli 52,5 %).
Treatment with asparaginase should be discontinued in patients developing acute pancreatitis.
Zdravljenje z asparaginazo je treba prekiniti pri bolnikih, pri katerih se razvije akutni pankreatitis.
Paediatric population Data on safety of Spectrila in infants < 1 year of age is limited.
Pediatrična populacija Podatkov o varnosti zdravila Spectrila pri dojenčkih, mlajših od 1 leta, je malo.
Table 2: Frequency of patients with allergic reactions (MC-ASP.5/ALL; Safety analysis set) Treatment group
Preglednica 2: Pogostnost bolnikov z alergijskimi reakcijami (MC-ASP.5/ALL; skupina za varnostno analizo)
On the basis of the scientific conclusions for asparaginase (centrally authorised product) the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing asparaginase (centrally authorised product) is unchanged subject to the proposed changes to the product information.
Na podlagi znanstvenih zaključkov za asparaginazo (zdravilo, ki je pridobilo dovoljenje za promet po centraliziranem postopku) odbor CHMP meni, da je razmerje med koristjo in tveganjem zdravil(-a), ki vsebuje(-jo) asparaginazo (zdravilo, ki je pridobilo dovoljenje za promet po centraliziranem postopku) nespremenjeno ob upoštevanju predlaganih sprememb v informacijah o zdravilu.
Data on efficacy and safety of Spectrila in the post-induction treatment phases are very limited.
Podatkov o učinkovitosti in varnosti zdravila Spectrila v postindukcijskih fazah zdravljenja je zelo malo.
Therefore, Spectrila must not be used during breast-feeding.
Zato se zdravilo Spectrila med dojenjem ne sme uporabljati.
EU/1/15/1072/002 (5 vials)
EU/1/15/1072/002 (5 vial)
Complete asparagine depletion in CSF Yesc
Popolno izčrpanje asparagina v CSF
In the study in children/adolescents aged 1 - 18 years with de novo ALL (study MC-ASP.5/ALL), by day 33 of induction treatment 10 patients in the Spectrila group (10.3 %) and 9 in the reference group (8.9 %) were measured positive for anti-asparaginase antibodies at least at one time point.
V študiji pri otrocih in mladostnikih, starih 1-18 let, z de novo ALL (študija MC-ASP.5/ALL) je bilo do 33. dne indukcijskega zdravljenja 10 bolnikov v skupini z zdravilom Spectrila (10,3 %) in 9 v referenčni skupini (8,9 %) pozitivnih za antiasparaginazna protitelesa vsaj v eni časovni točki.
During treatment with asparaginase-containing regimens, myelosuppression, potentially affecting all three cell lines, and infections can occur.
Med zdravljenjem s terapevtskimi shemami, ki vsebujejo asparaginazo, se lahko pojavijo mielosupresija, ki lahko prizadene vse tri celične linije, in okužbe.
Patients with severe hypertriglyceridaemia are at increased risk of developing acute pancreatitis.
Pri bolnikih s hudo hipertrigliceridemijo je večje tveganje nastanka akutnega pankreatitisa.
If allergic symptoms occur, intravenous infusion of Spectrila must be discontinued immediately.
Če se pojavijo alergijski simptomi, je treba nemudoma prekiniti intravensko infuzijo zdravila Spectrila.
Conversely, the antitumour effects of methotrexate are enhanced when asparaginase is administered 24 hours following methotrexate treatment.
Nasprotno se protitumorsko delovanje metotreksata zveča, če damo asparaginazo 24 ur po zdravljenju z metotreksatom.
There is no known case of an overdose with asparaginase where patients showed any signs of an overdose.
Ne poznamo nobenega primera prevelikega odmerjanja asparaginaze, kjer bi bolniki kazali kakršne koli znake prevelikega odmerjanja.
To avoid this, vincristine is usually given 3 - 24 hours before asparaginase.
Temu se navadno izognemo tako, da vinkristin damo 3-24 ur pred asparaginazo.
Treatment may be monitored based on the trough serum asparaginase activity measured three days after administration of Spectrila.
Spremljanje zdravljenja lahko temelji na najmanjši aktivnosti serumske asparaginaze, izmerjene tri dni po dajanju zdravila Spectrila.
Patients received 5,000 U/m² asparaginase (Spectrila versus a reference E.coli- asparaginase) at days 12, 15, 18, 21, 24, 27, 30, and 33 of induction treatment.
Bolniki so prejeli po 5.000 E/m² asparaginaze (zdravila Spectrila oziroma referenčne asparaginaze E. coli) na 12., 15., 18., 21., 24., 27., 30. in 33. dan indukcijskega zdravljenja.
Median trough serum asparaginase activities were measured in 81 children/adolescents with de novo ALL three days after infusion of asparaginase (just before the next dose had to be given) during induction treatment and ranged from 168 to 184 U/l (study MC-ASP.5/ALL).
Mediano najnižjo aktivnost asparaginaze v serumu so izmerili pri 81 otrocih/mladostnikih z de novo ALL tri dni po infuziji asparaginaze (tik preden je bilo treba dati naslednji odmerek) med indukcijskim zdravljenjem in je bila v mejah med 168 in 184 E/l (študija MC-ASP.5/ALL).
Symptomatic thromboses related to the use of central venous catheters have been described, too.
Opisali so tudi simptomatske tromboze, povezane z uporabo centralnih venskih katetrov.
However, when asparaginase was given after cytarabine a synergistic effect was observed.
Če pa damo asparaginazo po citarabinu, so ugotovili sinergističen učinek.