Slovenian Veterinary Research 2024 | Vol 61 No 2 | 97 The Effect of Ascending Doses of Ketoprofen on Biochemical and Coagulation Parameters in Lambs Key words drug safety; haemostatic function; hepatotoxicity; ketoprofen; lambs; nephrotoxicity; non-steroidal anti-inflammatory drug Mehmet Nihat Ural1*, Kamil Üney2 1Istanbul Directorate of Provincial Agriculture and Forestry, Istambul, Turkey, 2Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, 42031 Konya, Turkey *Corresponding author: nihatural@yahoo.com Abstract: Ketoprofen (KTP) is a non-steroidal anti-inflammatory drug (NSAID) used as an analgesic, antipyretic and anti-inflammatory agent in human and veterinary medi- cine. Although KTP is used in the treatment of diseases such as musculoskeletal in- flammation, endotoxemia, pneumonia, enteritis in sheep and minor surgical procedures such as dehorning and castration there is no information about its safety. The aim of this study is to determine the effect of KTP on biochemical and coagulation parameters following intramuscular (IM) administration of different doses of KTP to lambs. In the study, 18 clinically healthy lambs were randomly divided into three groups of 6 animals each. KTP was administered IM to lambs at doses of 1.5, 3 and 6 mg/kg. Biochemical and coagulation parameters were evaluated by taking blood samples before drug ad- ministration (0 hour) and at 24 hours and 48 hours after administration. No local or systemic side effects were observed in lambs after the administration of KTP at dif- ferent doses. The aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) values at 24 hours significantly increased compared to 0 hours in all dosage groups (p<0.05). KTP did not cause a significant change in albumin (ALB), al- anine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine (CRE), CK and LDH values in different dose groups. The AST value was only significantly higher in the 6 mg/ kg dose group compared to the 1.5 mg/kg dose group at 24 hours (p<0.05). Although there was no statistically significant difference in intragroup prothrombin time (PT), fi- brinogen and D-dimer levels in all dose groups, a significant increase was observed in the activated partial thromboplastin time (aPTT) value of 6 mg/kg dose group at the 24 hours compared to the 0 hour (p< 0.05). As a result, after IM administration of 1.5, 3 and 6 mg/kg, increased CK and LDH values, which may be associated with muscle damage, may limit use of KTP via IM injection in lambs. Received: 19 March 2023 Accepted: 6 July 2023 Slov Vet Res DOI 10.26873/SVR-1725-2023 UDC 577:591.111.1:591.182:611.018.5:615.212:616-001:636.32/.38 Pages: 97–103 Original Research Article Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs), which are widely used in painful and inflammatory conditions such as lameness, foot rot, castration, vasectomy, mastitis and laparoscopy in sheep, act by inhibiting the effect of the cy- clooxygenase enzyme, which is responsible for the synthe- sis of prostaglandins (1-3). Ketoprofen (KTP), is a NSAID belonging to the arylpropionic acid group and exists as a chiral compound with R(-) and S(-) isomers present in the racemic formulation. In animals, the S(-) form is more ac- tive and there is interconversion between the forms (4). In sheep, the suppression of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) production has been reported for up to 12 hours following a single intravenous injection of 1.5 or 3 mg/kg of KTP (5). In addition, a study in sheep reported that the 4 mg/kg subcutaneous administration of KTP at 90 minutes before the procedure failed to alleviate the post- surgical pain response (6). It is known that NSAID therapy has serious side effects such as gastrointestinal ulceration or bleeding, liver and 98 | Slovenian Veterinary Research 2024 | Vol 61 No 2 kidney damage, allergic reactions, myocardial infarction and cardiac sudden death. Coagulation, hematological and biochemical parameters are used to evaluate the effects of drugs on physiological and pathological conditions (7,8). Coagulation parameters (aPTT, PT, fibrinojen, D-dimer) reflect coagulation disorders, while hematological param- eters (WBC, RBC, hemogram, hematocrit, platelet) reflect bone marrow functions and fluid electrolyte balance, bio- chemical parameters (albumin, ALP, ALT, AST, BUN, choles- terol, CK, creatinine, GGT, TP and triglyceride) reflect liver, kidney, muscle and lipid metabolism functions (9,10). In studies conducted in calves, horses, dogs, pig and chil- dren, it has been shown that the administration of KTP at recommended doses does not cause any side effects (11- 15). On the other hand, some studies in laboratory animals have reported that KTP administered at recommended therapeutic doses causes side effects such as gastroin- testinal irritation, impaired kidney function, hepatopathies, prolonged bleeding and clotting times (13,16). In some cas- es, NSAIDs may need to be used in high doses. However, high doses of this group of drugs may cause undesirable effects. In the literature review, no reference was found re- garding the effect of increasing doses of KTP on biochemi- cal and coagulation parameters in lambs. The aim of this study was to determine the effects of KTP on biochemical and coagulation parameters after single doses of 1.5, 3 and 6 mg/kg in lambs. Material and Methods Animals The study was performed on a commercial farm located in the district of Kadınhanı, Konya Province, Türkiye. The study was performed on 18 female Akkaraman lambs (3-6 months old, 23-36 kg) who were determined to be healthy in the general clinical examination and had not received any medication treatment in the one months prior to the study. The animals were divided into different groups 7 days before the start of the study and numbered with oily paint. The lambs were fed with commercial feed (CP-5621, Ankara, Türkiye) twice a day and alfalfa hay, grass hay and water were given ad libitum. All procedures on animals were approved of the Local Ethics Committee for Animal Experiments at Selcuk University on December 27, 2022 with the approval number 2022/140. Experimental design A total of 18 lambs were randomly divided into three groups of 6 animals each. KTP (100 mg/ml, Ba-Keto, Injection Solution, Bavet, Turkey) was administered as a single dose via intramuscular injection into the neck region of the lambs in the first, second and third groups at doses of 1.5 mg/kg, 3 mg/kg and 6 mg/kg, respectively, following the dosage references from previous studies (5,6). In the study, blood samples were collected from the jugular vein at 0, 24 and 48 hours using a venipuncture technique. Blood samples were collected into gel tubes (2 ml) for biochemical anal- ysis and into sodium citrate tubes (2 ml) for coagulation tests. After centrifuging the blood samples at 3,500g for 10 minutes, the resulting serum and plasma samples were carefully transferred into 2 ml Eppendorf tubes. The serum samples were stored in a deep freezer at -80°C until the day of analysis, while the plasma samples were analyzed within 3 hours for coagulation tests. Throughout the experimental protocol, the injection site was monitored for swelling, red- ness and pain and the animals were closely observed for any clinical changes. Analysis of biochemical parameters Biochemical parameters including serum albumin (ALB), aspartate aminotransferase (AST), alanine aminotransfer- ase (ALT), blood urea nitrogen (BUN), creatine kinase (CK), creatinine (CRE) and lactate dehydrogenase (LDH) levels were determined using an automated analyzer device (Lab- 300plus, Instrumentation Laboratory, Milano, Italy) from serum samples stored at -80°C. Analysis of coagulation parameters In plasma samples, the measurement of clotting factors including prothrombin time (PT), activated partial throm- boplastin time (aPTT), fibrinogen (FIB) and D-Dimer was performed using a coagulation analysis device (Siemens, A-7799, Sysmex CA 1500, Germany). Statistical analysis The research data was presented as mean ± standard de- viation (SD). Statistical analysis was conducted using the SPSS software (version 26.0, IBM). Biochemical and co- agulation parameters were analyzed for homogeneity of variances. Values that showed normal distribution with p-values > 0.05 were considered for parametric statistical analysis. In both intragroup and intergroup comparisons of data, one-way analysis of variance (ANOVA) and post-hoc Tukey test were used (SPSS 26.0). P < 0.05 value was con- sidered statistically significant. Results No adverse reactions, general (in their feeding, drinking, defecation and behavior) or local (pain, swelling, redness), were observed during clinical observation of lambs follow- ing intramuscular administration of KTP at doses of 1.5, 3 and 6 mg/kg. The effect of KTP on the biochemical parameters of lambs after intramuscular administration at doses of 1.5, 3 and 6 mg/kg is presented in Table 1. In the evaluation within the group, there was no statistically significant difference in Slovenian Veterinary Research 2024 | Vol 61 No 2 | 99 ALB, ALT, CRE and BUN values in all dose groups (p>0.05). However, the AST, CK and LDH values at 1.5, 3 and 6 mg/kg doses increased at 24 hours compared to 0 hour (P<0.05). The AST and CK values at 1.5, 3 and 6 mg/kg doses de- creased at 48 hours compared to 24 hours (P<0.05). There was no statistically significant difference in ALB, ALT, BUN, CRE, CK and LDH values between the groups (P>0.05). However, AST value in the 6 mg/kg dose group at 24 hours was significantly higher than that in the 1.5 mg/kg dose group (P<0.05). The effect of KTP on coagulation parameters in lambs at doses of 1.5, 3 and 6 mg/kg after intramuscular administra- tion is presented in Table 2. In the within-group evaluation, there was no statistically significant difference in PT and D-Dimer values in all dose groups (P>0.05). However, the aPTT value increased significantly at 6 mg/kg at 48 hours compared to 0 hours (P<0.05). In the evaluation between groups, there was no statistically significant difference in PT and D-Dimer values (P>0.05). However, the aPTT value in the 3 mg/kg dose group was significantly lower at 48 hours compared to the value in the 1.5 mg/kg dose group Table 1: The effects on biochemical parameters of intramuscular administration of ketoprofen at doses of 1.5, 3 and 6 mg/kg to lambs (n=6, mean ± SD) Parameters Sampling Time (Hour) 1.5 mg/kg 3 mg/kg 6 mg/kg ALB (g/L) 0 29.83±5.91 33.25±3.03 32.58±4.34 24 34.25±1.72 35.33±3.33 34.42±2.73 48 33.66±1.63 35.08±6.74 33.33±3.63 ALT (U/L) 0 16.08±3.64 19.17±3.60 17.92±4.76 24 19.67±6.22 22.75±7.44 24.08±6.59 48 18.33±4.89 15.50±5.00 19.33±1.08 AST (U/L) 0 97.25±16.67y 104.00±12.15y 97.17±6.35z 24 147.17±10.44b,x 164.08±12.71ab,x 180.33±13.85a,x 48 115.42±13.25y 121.33±29.44y 124.58±20.31y BUN (mg/dL) 0 72.08±6.71 73.33±9.01 73.75±6.05 24 75.58±7.79 70.25±7.11 70.92±8.79 48 70.58±6.33 71.58±5.39 70.25±7.24 CRE (mg/dL) 0 0.65±0.04 0.64±0.06 0.68±0.04 24 0.79±0.18 0.76±0.16 0.71±0.13 48 0.72±0.14 0.61±0.14 0.72±0.15 CK (U/L) 0 223.75±22.94y 243.58±11.00y 231.33±41.68y 24 399.25±73.72x 384.42±38.51x 426.33±145.25x 48 252.67±35.07y 268.25±16.58y 285.92±55.26y LDH (U/L) 0 620.00±47.18y 640.92±35.72y 629.92±47.10y 24 891.50±128.45x 880.25±152.23x 877.58±153.09x 48 827.00±81.93x 830.50±113.06x 818.08±140.62x a,b Superscripts with different letter in the same raw show statistically significant differences (P < 0.05). x,y,z Superscripts with different letter in the same column show statistically significant differences (P < 0.05). ALB; Albümin, AST; aspartate aminotransferase, ALT; alanine aminotransferase, BUN; blood urea nitrogen, CRE; Creatinine, CK; creatine kinase and LDH; lactate dehydrogenase. 100 | Slovenian Veterinary Research 2024 | Vol 61 No 2 and the fibrinogen value in the 3 mg/kg dose group was significantly higher at 24 hours compared to the value in the 1.5 mg/kg dose group (P<0.05). Discussion KTP, a widely used NSAID in humans and animals, is a po- tent cyclooxygenase inhibitor. Unlike other NSAIDs, it also inhibits lipoxygenase and creates a double blockade in ara- chidonic acid metabolism. The recommended dose of KTP is 2 mg/kg for cats and dogs, 2.2 mg/kg for horses and 3 mg/kg for cattle and small ruminants (4,16). Since the ef- fect of KTP varies depending on the dose, it can be applied in increasing doses (17,18), but undesirable effects may oc- cur when used in increasing doses. The doses (1.5, 3 and 6 mg/kg) selected in this study and sample collection times were determined by considering previous studies in pigs, sheep and cattle (5,19,20). Common side effects of KTP are observed when it is used at higher doses than recommend- ed or for a prolonged period of time. However, side effects are rarely reported after a single administration at the rec- ommended dose (21). KTP administered intravenously at a dose of 3 mg/kg for 5 days was well tolerated in calves (11). It has been found that gastrointestinal side effects tend to occur when dogs are given KTP for 30 days, but the le- sions healed after administration have been discontinued (13). Horses did not show any clinical adverse effects dur- ing administration of 2.2 mg/kg three times daily KTP (12). Oral administration of KTP in children has been reported to be well tolerated for up to three weeks (15). In pigs, there was no change in serum biochemical values at the single intramuscular dose of 3, 6 and 9 mg/kg and 3 mg/kg for 3 days (14). In this study, no side effects were observed af- ter IM administration of 1.5, 3 and 6 mg/kg KTP to lambs, but statistically significant intra and intergroup differences were observed in some biochemical and coagulation pa- rameters. Most of the reports on the side effects of KTP administered at recommended treatment doses are ob- tained from humans and laboratory animals. These effects include gastrointestinal irritation, impaired kidney function, hepatopathies, prolonged bleeding and clotting times and photosensitivity (10,14). Gastrointestinal ulceration occurs due to inhibition of PGE2 synthesis and decreased pro- duction of mucosal protective agents (22). Nephrotoxicity is related to the inhibition of prostaglandins in the kidneys that are essential for salt and water balance, vascular tone, blood flow and renin secretion (23). Coagulation disorders are the result of thromboxane A2 deficiency in platelets after administration of COX1 inhibitors (24). Phototoxicity results from damage to cell membranes by radical interme- diates (25). In this study, AST, CK and LDH values increased at 24 hours compared to 0 hours in all dose groups (P<0.05). It was ob- served that AST and CK values decreased (P<0.05) in 48 hours compared to 24 hours, but LDH value did not change. The increase in serum CK and LDH levels may occur due to muscle damage caused by IM drug administration (26,27). Table 2: The effects on coagulation parameters of intramuscular administration of ketoprofen at doses of 1.5, 3 and 6 mg/kg to lambs (mean ± SD) Parameters Sampling Time (Hour) 1.5 mg/kg 3 mg/kg 6 mg/kg PT (sn) 0 12.80±0.47 13.42±1.13 13.22±1.28 24 14.65±2.32 13.55±1.15 12.87±1.03 48 12.75±0.66 12.70±0.74 13.42±1.01 aPTT (sn) 0 38.17±0.83 36.47±2.46 37.28±2.04y 24 39.30±1.87 35.85±1.20 40.53±7.21xy 48 40.75±3.03a 35.62±3.15b 44.40±1.75a,x Fibrinogen (g/L) 0 2.21±0.17 1.88±0.25 1.96±0.28 24 1.53±0.56b 2.35±0.50a 1.60±0.55ab 48 1.98±1.05 2.41±0.56 2.41±0.75 D-DIMER (ng/L) 0 457.67±64.97 501.83±85.35 535.83±51.57 24 551.00±57.84 487.33±104.93 501.33±114.63 48 524.67±82.46 518.50±62.91 512.00±63.22 a,b Superscripts with different letter in the same raw show statistically significant differences (P < 0.05). x,y Superscripts with different letter in the same column show statistically significant differences (P < 0.05). PT; prothrombin time, aPTT; activated partial thromboplastin time Slovenian Veterinary Research 2024 | Vol 61 No 2 | 101 The halflife of CK is approximately 2 hours (28), thus indi- cating that the transient increase in serum CK level seen in this study is due to IM drug administration. In our study, it was concluded that mild and transient increases in enzyme levels, particularly within the same dosage groups, are re- lated to the metabolism and elimination processes of KPT. In the current study, it was determined that KTP did not cause a significant change in ALB, ALT, BUN, CRE, CK and LDH values in different dose groups. Only the AST value in the 6 mg/kg dose group was significantly higher at the 24 hours compared to the 1.5 mg/kg dose group (p<0.05). It was determined that the elevated AST level returned to its normal levels in the 48 hours. AST also known as serum glutamate-oxaloacetate transaminase (SGOT), is found mainly in the heart, liver, kidneys and muscle tissue and high blood concentrations indicate liver damage or disease (29). Serum AST and ALT levels can be used as an indicator of liver damage. ALT is more liver specific than AST. AST in- stead of ALT can only be used when ALT is not present and there is no known muscle pathology causing an increase in AST (30). In previous studies, it was reported that KTP ad- ministration increased the AST enzyme in mice (31), dogs (32) and donkeys (33). These results are consistent with the results of our study. Low elevations in serum enzyme levels have been reported during KTP therapy and this has rarely been associated with significant acute liver injury (31). KTP blocks the formation of thromboxane A2 by inhibiting thromboxane cyclooxygenase. It creates a systemic bleed- ing tendency by disrupting platelet aggregation and thus prolonging bleeding time (34, 35). In this study, although no statistically significant difference was found in intragroup PT, fibrinogen and D-dimer levels in all dose groups, a sig- nificant increase was observed in aPTT value at 6 mg/kg in 24 hours compared to 0 hour (p<0.05). PT and aPTT are commonly used coagulation measurement parameters in the evaluation of secondary hemostasis in humans and an- imals (36). aPTT level in healthy sheep has been reported to be between 29.2 ± 3.2 and 41.1 ± 8.7 seconds (37). It was reported that the administration of flunixin meglumine and meloxicam in sheep prolonged aPTT, but these changes were not statistically significant (38). It has been deter- mined that carprofen increased the aPTT value in dogs on the 5, 7 and 12 days after administration (36). It has been reported that the administration of meloxicam and KTP in ponies did not cause any difference in fibrinogen, PLT, PT and aPTT values and did not affect the coagulation param- eters (39). In this study, it was concluded that the fact that the fibrinogen value in the 3 mg/kg dose group was higher at 24 hours compared to the value in the 1.5 mg/kg dose group was not significant. Conclusion In conclusion, after IM administration of 1.5, 3 and 6 mg/ kg of KTP, it was observed that CK and LDH values, which may be associated with muscle damage, were increased. This may limit use of KTP via IM route in lambs. In all dose groups, AST values, which may be associated with metabo- lism processes of KTP, were increased. The aPTT value in- creased at the dose of 6 mg/kg. For the effective and safe use of KTP in lambs, its hematological, biochemical, mo- lecular and pathological safety must be demonstrated after repeated administrations and other administration routes. Acknowledgements The authors would like to express their gratitude to the peo- ple working on the farm where the experimental procedure on the lambs took place. 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Meloxicam and ketoprofen did not alter coagulation and haematological parameters of healthy ponies.In: Proceedings of the 11th International Congress of World Equine Veterinary Association, Guarujá: WEVA, 2009. https://www. ivis.org/library/weva/weva-internal-congress-brazil-2009/meloxi- cam-and-ketoprofen-did-not-alter-coagulation (20. 1. 2023) Slovenian Veterinary Research 2024 | Vol 61 No 2 | 103 Vpliv naraščajočih odmerkov ketoprofena na biokemične in koagulacijske parametre pri jagnjetih M. N. Ural, K. Üney Izvleček: Ketoprofen (KTP) je nesteroidno protivnetno zdravilo (NSAID), ki se v humani in veterinarski medicini uporablja kot sredstvo proti bolečinam, povišani temperaturi in vnetju. Čeprav se KTP pri ovcah uporablja za zdravljenje mišično- skeletnih vnetij, endotoksemije, pljučnice, enteritisa in pri manjših kirurških posegih, kot sta odstranjevanje rogov in kas- tracija, ni podatkov o varnosti zdravila. Namen te študije je bil ugotoviti vpliv biokemijskih in koagulacijskih parametrov po intramuskularni (IM) aplikaciji različnih odmerkov KTP pri jagnjetih. Vrednosti aspartataminotransferaze (AST), kreatin kinaze (CK) in laktat dehidrogenaze (LDH) so se po 24 urah v primerjavi z 0 urami v vseh skupinah znatno povečale (p < 0,05). KTP ni povzročil značilnih sprememb vrednosti albumina (ALB), alanin aminotransferaze (ALT), dušika sečnine v krvi (BUN), kreatinina (CRE), CK in LDH v različnih skupinah odmerkov. Vrednost AST je bila po 24 urah pomembno višja le v skupini z odmerkom 6 mg/kg v primerjavi s skupino z odmerkom 1,5 mg/kg (p < 0,05). Čeprav znotraj posameznih skupin ni bilo statistično pomembnih razlik v vrednostih protrombinskega časa (PT), fibrinogena in D-dimerov, smo v skupini z odmerkom 6 mg/kg v 24 urah v primerjavi z uro 0 opazili znatno povečanje vrednosti aktiviranega delnega tromboplastinskega časa (aPTT) (p < 0,05). Posledično bi lahko povečane vrednosti CK in LDH (ki so lahko povezane s poškodbami mišic) omejile uporabo IM aplikacije KTP pri jagnjetih. Ključne besede: varnost zdravil; hemostatska funkcija; hepatotoksičnost; ketoprofen; jagnjeta; nefrotoksičnost; nester- oidno protivnetno zdravilo