Systemic absortion and adverse effects of topical ocular use of ketorolac tromethamine and sodium diclofenac in New Zealand rabbits for 90 days

Abstract

Absorção sistêmica e efeitos adversos do uso tópico ocularpor 90 dias de cetorolaco de trometamina e diclofenacode sódio em coelhos da raça Nova Zelândia] ABSTRACT  The effect of the systemic absorption of 0.1% diclofenac sodium (DS) eyedrop was compared to that of 0.5% ketorolac tromethamine (KT) in female New Zealand white rabbits treated on both eyes three times a day for 90 days. The rabbits were divided in three groups of six animals (n= 18): KT group, DS group, and control (Co) group, in which saline (0.9% NaCl) solution was instilled. Water and food consumption were measured daily, clinical examination was performed weekly, and blood samples were collected every 30 days for laboratory examination. The plasma was analyzed for the presence of KT and DS by solid-phase extraction (SPE) associated with mass spectrometry (MS). Systemic absorption of these drugs was confirmed by SPE-MS, allowing their separation and identification in the plasma. At the end of the treatment, the animals were euthanized and necropsied, and no macroscopic or microscopic changes were found. This observation confirmed the laboratory results, which were within normal reference standards for the species. According to the results obtained, it can be concluded that treatment with eyedrops containing KT and DS for 90 days in healthy rabbits does not cause adverse systemic effects. RESUMOComparou-se o efeito da absorção sistêmica do colírio de diclofenaco de sódio 0,1% (DS) em relação ao de cetorolaco de trometamina 0,5% (CT) em coelhas da raça Nova Zelândia, tratadas nos dois olhos, três vezes ao dia, por 90 dias. As coelhas foram separadas em três grupos de seis animais (n=18): grupo CT, grupo DS e grupo controle (Co), no qual foi instilada solução fisiológica (NaCl 0,9%). Os consumos de água e ração foram mensurados diariamente, os exames clínicos foram realizados semanalmente e o sangue foi coletado a cada 30 dias para realização de exames laboratoriais. O plasma foi analisado para detectar a presença de CT e DS por extração em fase sólida (SPE) associada à espectrometria de massas (MS). A absorção sistêmica desses fármacos foi confirmada por SPE-MS, permitindo sua separação e identificação no plasma. Ao final do tratamento, os animais foram eutanasiados e necropsiados, e não foram encontradas alterações macroscópicas ou microscópicas. Essa observação confirmou os resultados laboratoriais, que estavam dentro dos padrões de referência para a espécie. De acordo com os resultados obtidos, pode-se concluir que o tratamento com colírio contendo KT e DS, por 90 dias, em coelhos saudáveis, não causa efeitos adversos sistêmicos.

Effects of trometamol ketorolac eye drops on blood count, serum biochemistry, and urinalysis in healthy dogs

“…Although systemic absorption of TK was not examined in the present study, it might have occurred because prednisolone and dexamethasone were detected in the plasma of healthy dogs 1, 7, and 14 days after both drugs were administered as ophthalmic solutions (Segabb et al, 2020;Ewald et al, 2022). Additionally, systemic absorption following the instillation of ophthalmic NSAIDs has been confirmed in chickens (diclofenac), rabbits (diclofenac and TK), and cats (flurbiprofen and diclofenac) (Griggs et al, 2017;Pereira et al, 2019;Hsu et al, 2015;Lanuza et al, 2016). In the present study, the dogs were not kept in a controlled environment.…”

“…Coagulation disorders, such as inhibition of platelet cyclo-oxygenase, reduced formation of pro-aggregatory eicosanoid thromboxane A 2 , and prevention of platelet aggregation, are adverse effects that may occur after long-term systemic administration of NSAIDs (Gilmour, 2004). The platelet count, prothrombin time, and thromboplastin time did not change significantly in rabbits receiving TK or diclofenac as ophthalmic solutions for 90 consecutive days (Pereira et al, 2019). Nevertheless, no previous studies or reports have evaluated the possible adverse events related to the blood or platelet count of dogs that received Arq.…”

“…However, in a study on cats treated with topical ophthalmic diclofenac four times/day for seven consecutive days, no changes were detected in the serum ALT, AP, or γ-glutamyl transpeptidase levels (Hsu et al, 2015). Similarly, the histology of the liver was normal in rabbits treated with topical TK or diclofenac ophthalmic solution for 90 days (Pereira et al, 2019). Normal ALT and AP values have also been reported in dogs that received oral NSAIDs for 90 consecutive days (Luna et al, 2007).…”

“…Occurrence of adverse systemic events secondary to topical administration of NSAIDs, although rare, has been reported in human beings as an in vitro inhibition of platelet function and exacerbation of bronchial asthma (Falcinelli et al, 2019;Syed et al, 2021). Systemic absorption following the instillation of ophthalmic NSAIDs has been confirmed in chickens, rabbits, and cats (Hsu et al, 2015;Lanuza et al, 2016;Griggs et al, 2017;Pereira et al, 2019). In chickens, topical administration of diclofenac to one or both eyes decreased total protein levels, but it did not alter plasma uric acid levels (Griggs et al, 2017).…”

Systemic absorption and gastrointestinal adverse effects from topical ketorolac and diclofenac ophthalmic solutions in healthy dogs

“…17 This was due in part to the higher daily mg/ kg dose of diclofenac administered to the cats due to their smaller size compared to our dogs and potentially to species differences in pharmacokinetics between dogs and cats (ie, due to differences in drug bioavailability, systemic clearance, and/or volume of distribution). In another study 24 of rabbits, diclofenac and ketorolac were administered for 90 days at a daily mg/kg dose similar to that in our study; while systemic absorption was only determined qualitatively in that study, none of the rabbits developed GI lesions or adverse effects with either NSAID. As such, it is important for clinicians and scientists to examine potential systemic adverse effects of topical NSAIDs (or other ophthalmic drugs) in the species of interest, as direct extrapolation between species is biased by key species differences in ocular anatomy and physiology.…”