Faculty of Veterinary Medicine University of Zagreb
Abstract
The pathogenesis and pathology of the rodenticidal action of indomethacin, a non-steroidal antiinflammatory drug, were investigated. Sixteen Norway rats and 16 albino mice, aged 10-12 weeks with mean mass of 99.6 g and 28.4 g, respectively were divided into eight groups of 4 rats (R1, R2, R3 and R4) and 4 mice (M1, M2, M3 and M4). Rodents in R1 and M1 were controls (0 mg/kg indomethacin), while those in R2, R3, R4, and M2, M3, M4 were each given 83 mg/kg, 166 mg/kg and 250 mg/kg body mass of indomethacin orally, respectively. Clinical signs, symptoms and mortalities were monitored, while detailed postmortem examination was carried out. Indomethacin caused anorexia, dehydration and weakness, which became progressively worse with time; and there was 100% mortality within 36 and 82 hours in mice and rats, respectively. Seven rats (43.8%) were diarrheic, and had bilateral medial canthi haemorrhages. Gross lesions in all the rodents include congested and haemorrhagic stomach and intestinal mucosae, with focal areas of ulcerations, and focal pale areas on the liver. Histopathological changes in various organs were similar, irrespective of the animal species and dose of indomethacin, and include widespread congestion and haemorrhage, thrombi in arterioles and capillaries of the kidney, heart, lungs, brain, testes and splenic fat. There was widespread glandular degeneration and necrosis, erosions, ulcerations in the stomach and small intestines, renal glomerular and tubular degeneration, hepatocellular necrosis, myocardiac necrosis, testicular and neuronal degeneration. Indomethacin appears to cause widespread endothelial and mucosal damage, haemorrhage and vascular thrombosis, leading to ischaemic necrosis, with subsequent multiple organ failure and death. The mechanisms of action and implications of the
use of indomethacin as a rodenticide to domestic pets are discussed.Istražena je patogeneza i patologija rodenticidnoga učinka nesteroidnoga protuupalnoga lijeka
indometacina. Istraživanje je provedeno na 16 smeđih štakora prosječne tjelesne mase od 99,6 g i 16 albino miševa prosječne tjelesne mase od 28,4 g u dobi od 10 do 12 tjedana. Životinje su bile podijeljene u osam skupina. U svaku skupinu uvrštena su četiri štakora (R1, R2, R3, R4) odnosno četiri miša (M1, M2, M3, M4). Životinje pod oznakom R1 i M1 bile su kontrolne i nisu dobivale indometacin. Štakorima skupina R2, R3, R4 te miševima skupina M2, M3, M4 oralnim je putem apliciran indometacin u dozama od 83 mg/kg, 166 mg/kg i 250 mg/kg. Promatrani su klinički znakovi i uginuća. Uginule životinje bile su razuđene. Indometacin je uzrokovao anoreksiju, dehidraciju i slabost te100%-tnu smrtnost tijekom 36 sati nakon primjene u miševa i 82 sata nakon primjene u štakora. U sedam štakora (43,8%) zabilježen je proljev te krvarenje po sluznici medijalnih očnih kutova. U svih je glodavaca dokazana punokrvnost, krvarenja po sluzici želuca i crijeva sa žarišnim ulceracijama te mjestimično bljedilo jetre. Patohistološke promjene u različitim organima bile su slične bez obzira na vrstu životinje i dozu. Najčešće je ustanovljena kongestija organa i krvarenja te trombi u arteriolama i kapilarama bubrega, srca, pluća, mozga, sjemenika i slezene. Zabilježena je i žljezdana degeneracija kao i nekroze, erozije, ulceracija želuca i tankog crijeva, glomerulotubularna degeneracija bubrega, hepatocelularna nekroza, nekroza miokarda te degeneracija sjemenika i živčanih stanica. Čini se da indometacin uzrokuje značajno oštećenje endotela i sluznice, krvarenje i vaskularnu trombozu koja prelazi u ishemičnu nekrozu s posljedičnim zatajenjem mnogih organa i uginućem. Detaljno su obrazloženi mehanizmi djelovanja indometacina kao rodenticida
