Halogenated salicylanilides - flukicide drugs

Klozantel, rafoksanid i oksiklozanid su antiparazitski lijekovi iz skupine salicilanilida sa specifičnim djelovanjem protiv metilja u preživača. Zbog velike sposobnosti vezanja ovih spojeva za albumine u krvnoj plazmi distribucija u tkiva je slaba, što rezultira i znatno manjom koncentracijom u bubrezima, jetri, masti i mišićima. Njihovo je djelovanje je stoga učinkovitije protiv odraslih metilja koji se uglavnom hrane krvlju dok je protiv mlađih stadija parazita, koji se više hrane stanicama jetre, njihova djelotvornost znatno manja. Prema mehanizmu djelovanja klozantel, rafoksanid i oksiklozanid spadaju u vodikove (protonske) ionofore. Narušavanjem gradijenta protona preko unutarnje mitohondrijske membrane selektivno sprečavaju sintezu ATP-a i djeluju kao blokatori procesa oksidativne fosforilacije u metiljima. Zbog nepravilne upotrabe antiparazitskih lijekova (nepoštivanje preporučenih doza ili karencije) dolazi do pojave njihovih rezidua u hrani životinjskog podrijetla i samim time s obzirom na dokazana toksična svojstva koja posjeduju rizika po ljudsko zdravlje. Budzći da klozantel, rafoksanid i oksiklozanid mogu biti dostupni u kombinaciji s drugim antiparaziticima, njihovo određivanje u tkivima uglavnom uključuje razvoj multikomponentnih metoda koje se temelje na selektivnim tehnikama pročišćavanja uzoraka (SPE, QuEChERS) uz osjetljivu detekciju spektrometrijom masa (MS/MS, TOF/MS). U sklopu nacionalnih monitoring programa zemalja Europske unije na rezidue antiparazitskih lijekova u životinjama i proizvodima životinjskog podrijetla, u razdoblju od 2009. do 2019. godine, ovi su spojevi prema Uredbi Komisije (EZ) br. 37/2010 detektirani u koncentracijama višim od dopuštenih. Najviše pozitivnih uzoraka sadržavalo je klozantel, a gledajući samo posljednjih pet godina klozantel, rafoksanid i oksiklozanid zajedno čine gotovo 50 % svih nesukladnih rezultata u uzorcima pretraženim na B2a podgrupu spojeva.Closantel, rafoxanide and oxyclozanide are anthelmintic agents, classified as salicylanilides, with fasciolicidal activity in ruminants. Due to their extensive plasma protein binding, they are poorly distributed to tissues, resulting in several-fold lower concentrations detected in kidney, liver, fat and muscle. They are much more effective against adult liver flukes, which are known to feed mainly on blood, than against immature stages of flukes, which are thought to feed on liver cells rather than blood. In terms of their mode of action, closantel, rafoxanide and oxyclozanide can be considered proton ionofores. They prevent the production of the proton gradient across the inner mitochondrial membrane, selectively inhibiting ATP synthesis and therefore acting as an uncoupler of oxidative phosphorylation in flukes. If anthelmintic drugs are not administered properly (in the recommended doses or not adhering to withdrawal periods), their residues can be detected in foods of animal original, which poses a human health threat due to their toxicological properties. Since closantel, rafoxanide and oxyclozanide are mostly available in combination with other anthelmintics, their determination requires the development of multiresidue methods that unite selective sample preparation techniques (SPE, QuEChERS) with sensitive mass spectrometry detection (MS/MS, TOF/MS). These substances were reported in concentrations above the MRL values stipulated in Commission Regulation (EU) No 37/2010, in the EFSA reports for the period 2009–2019 for monitoring veterinary medicinal product residues and other substances in live animals and animal products in EU Member States. In non-compliant samples, closantel was the most commonly detected substance, while in the last five years alone, closantel, rafoxanide, and oxyclozanide together account for nearly 50% of all non-compliant results in samples screened for the B2a subgroup of compounds