This study aimed to determine the pharmacokinetics and pharmacokinetic interaction between oxfend... more This study aimed to determine the pharmacokinetics and pharmacokinetic interaction between oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered either alone or co-administered to goats orally. The study was carried out to the cross-over design into three periods, with a washout period of 21 days among administrations, on six healthy Alpine goats 1 year of age. The plasma concentrations of oxfendazole, oxfendazole metabolites fenbendazole and fenbendazole sulfone, and oxyclozanide were determined using HPLC-UV, and data were analyzed by the non-compartmental method. The plasma concentrations of oxfendazole were similar in both oxfendazole and combined groups. When oxfendazole was administered alone or in combination with oxyclozanide, the compounds recovered in plasma were oxfendazole, fenbendazole sulfone, and fenbendazole. Oxyclozanide did not change the plasma disposition of oxfendazole. In the oxyclozanide group, t1/ 2λz, Cmax, Tmax, and AUC0-∞ were estimated at 15.3 h, 11.6 μg/mL, 24 h, and 554 h × μg/mL, respectively. In the oxyclozanide plus oxfendazole treatment group, AUC0-∞ (1111 h×μg/mL), and Cmax (23.9 μg/mL) values were increased. In goats, the anthelmintic efficacy of oxfendazole and oxyclozanide should be determined by taking into account their pharmacokinetic data.
Journal of Veterinary Pharmacology and Therapeutics, 2023
The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gas... more The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gastrointestinal nematodes. This study aimed to determine both the pharmacokinetics of oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered orally to sheep and whether there is a pharmacokinetic interaction between these two drugs. The study was conducted in a three-period, crossover pharmacokinetic design and on six healthy Awassi sheep 1-3 years of age.
This study aimed to determine the effects of dexamethasone and minocycline alone and combined tre... more This study aimed to determine the effects of dexamethasone and minocycline alone and combined treatment with N-acetylcysteine (NAC) and vitamin E on serum coenzyme Q10 (CoQ10) and matrix metalloproteinase-9 (MMP-9) levels in rats administered aflatoxin B1 (AFB1). The study was carried out on 66 male Wistar rats. Following the intraperitoneal (IP) administration of AFB1 at dose of 2 mg/kg, minocycline (45 and 90 mg/kg, IP) and dexamethasone (5 and 20 mg/kg, IP) were administered alone and combined with NAC (200 mg/kg, IP) and vitamin E (600 mg/kg, IP). CoQ10 and MMP-9 levels were analyzed using the HPLC-UV method and a commercial kit by ELISA, respectively. AFB1 increased MMP-9 level and decreased CoQ10 level compared to the control group. After dexamethasone and minocycline administration, there is no increase in CoQ10 level, which is caused by AFB1. However, dexamethasone and minocycline combined with NAC+vitamin E caused significant increases in CoQ10 levels. Dexamethasone and minocycline alone and combined with NAC+vitamin E decreased MMP-9 levels compared to the single AFB1 treated group. The use of MMPs inhibitors and oxidative stress-reducing agents is anticipated to be beneficial in the poisoning with AFB1.
Journal of Veterinary Pharmacology and Therapeutics, 2022
This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used... more This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2-20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC-UV. The pharmacokinetic parameters were analyzed using the non-compartmental method. In healthy calves, the t 1/2ʎz , C max , T max, and AUC 0-12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves.
Türkiye Klinikleri Veteriner Bilimleri Dergisi, 2021
Canlı vücudunda tamamı sentezlenemeyen vitaminler, fizyolojik fonksiyonlar için gerekli olup kend... more Canlı vücudunda tamamı sentezlenemeyen vitaminler, fizyolojik fonksiyonlar için gerekli olup kendilerine özgü spesifik görevleri olan maddelerdir. İlaç-ilaç ve ilaç-gıda etkileşimleri, ilaçların istenmeyen etkilerinin ortaya çıkmasında büyük rol oynar. Farmakokinetik temelli ilaç etkileşimleri daha çok enzim ve taşıyıcı transmembran proteinler düzeyinde gözlenir. Metabolik reaksiyonların çoğu sitokrom P450 ailesi tarafından gerçekleştirilir. Enzim aktivitesinin, inhibisyonu veya indüksiyonu substrat ilacın konsantrasyonunu değiştirir. ATP-bağlayıcı kaset taşıyıcılarından, Pglikoprotein ve meme kanser direnç proteini toksik maddelerin ve ksenobiyotiklerin hücrelerden dışarı atılmasında ve ilaç-ilaç, ilaç-gıda etkileşimlerinde rol oynarlar. Çoğu ilaç etkileşimlerinde, sitokrom P450 ve P-glikoprotein birlikte rol oynar. Hem farmakokinetik ve hem de farmakodinamik etkileşimler, ilaçların farmakolojik etkinliğinde artış ve azalışa neden olabilir. Etkide artış ölüme yol açabilecek düzeyde bir etkileşim oluşturabilirken, etkide azalış ise tedavide başarısızlığa neden olabilir. İlaçlar arasındaki etkileşimin klinik önem arz edip etmeyeceği, etkileşime giren ilaçların terapötik indeks ve vücuttaki farmakokinetik davranış özelliklerinin bilinmesiyle ön görülebilir. Vitaminler, hem beşeri hem de veteriner hekimlikte en fazla suistimal edilen bileşikler arasındadır. İnsan ve hayvanların, besinlerle aldıkları vitaminlere ilave olarak kullanılan vitaminler sağlık açısından risk oluşturmakta ve ilaç etkileşimlerinde çoğu kez vitaminlerin etkisi göz ardı edilmektedir. Vitaminlerle ilaçlar arasındaki etkileşimleri belirlemeye yönelik daha çok deneysel ve klinik çalışmalara ihtiyaç vardır. Bu derlemede, yoğun kullanılan vitaminlerin ilaç etkileşimlerindeki önemi irdelenecektir.
This study was conducted to investigate the effects of matrix metalloproteinase (MMP) inhibitors ... more This study was conducted to investigate the effects of matrix metalloproteinase (MMP) inhibitors dexamethasone and minocycline administrations-both single and in combination with N-acetylcysteine (NAC) and vitamin E-on the tissue distribution and lethal dose (LD) 50 of aflatoxin (AF)B 1 in rats. We performed this study on male Wistar rats (8-10 weeks) in two phases. In the first phase, rats were administered dexamethasone (5 and 20 mg/ kg) and minocycline (45 and 90 mg/kg), both as single treatments and in combination with NAC (200 mg/kg) and vitamin E (600 mg/kg); these treatments followed AFB 1 administration (2 mg/kg). In the second phase, the therapeutic effect value (TEV) was calculated to determine the treatment effect on the LD 50 level of AFB 1. The tissue affinity of AFB1 from high to low was liver, kidney, intestine, brain, heart, spleen, lung, testis, and vitreous humor, respectively. Dexamethasone at the 20 mg/kg dose significantly reduced AFB 1 concentrations in the plasma and the other tissues, except for the vitreous humor. The effects of minocycline on the plasma and tissue concentrations of AFB 1 varied by dose and tissue. The combinations of dexamethasone or minocycline with NAC and vitamin E increased the AFB 1 concentrations in the plasma and all tissues, except for vitreous humor and liver. In male rats, the LD 50 value of AFB 1 was 11.86 mg/kg. The TEV of dexamethasone (20 mg/kg) was calculated to be 1.5. Dexamethasone can be administered in repeated doses at ≥20 mg/kg to increase survival in AFB 1 poisoning.
Kronik obstrüktif akciğer hastalığında kolinerjik sistemin aktivitesi artar, bu da solunum yolu d... more Kronik obstrüktif akciğer hastalığında kolinerjik sistemin aktivitesi artar, bu da solunum yolu düz kaslarını kasarak soluk alışverişini sınırlandırır. Bu nedenle kolinerjik sinir sistemi aktivitesinin arttığı kronik obstrüktif akciğer hastalığı gibi olguların tedavisinde, antikolinerjik ilaçlar kullanılmaktadır. Antikolinerjik ilaçların bu endikasyonda kullanımı, asetilkolinin bronkokonstriksiyon ve mukus salgısını artırıcı etkisinin azaltılmasına dayanmaktadır. Son yapılan deneysel çalışmalar, asetilkolinin yangıda da önemli rol oynadığını ortaya koymuştur. Muskarinik M3 reseptör-noksan fareler ve M3 selektif antagonistler kullanılarak yapılan çalışmalar, parankimal hücrelerdeki M3 reseptörlerinin asetilkolinin proinflamatuar etkisine aracılık ettiğini ortaya koymuştur. Beta-2 (β2) adrenerjik agonist ile muskarinik antagonist kombinasyonlarının kronik obstrüktif akciğer hastalığı tedavisinde kullanılması önerilmektedir. Bu öneri, β2 adrenerjik reseptör uyarımının M3 reseptörlerini antagonize ederek farklı bir yolakla inflamatuar hücrelerde inhibisyona yol açacağına dayanmaktadır ancak bu antiinflamatuar etkiler, kronik obstrüktif akciğer hastalığında açıkça ortaya konulamamıştır. Muskarinik reseptörler aracılığıyla, asetilkolinin proinflamatuar etkilerinin aksine parasempatik sinir sistemini içeren kolinerjik antiinflamatuar yol, doku hasarı ve enfeksiyon durumunda organları korumak için aşırı inflamatuar yanıtları düzenler. Diğer yandan asetilkolinin, α7 nikotinik asetilkolin reseptör aracılığıyla makrofajlar ve Tip 2 doğal lenfoid hücreler dâhil olmak üzere lökositler üzerinde inhibitör etki oluşturduğu ortaya konmuştur. Kronik obstrüktif akciğer hastalığında, asetilkolinin antiinflamatuar hücreler üzerindeki bu inhibe edici etkisi tam olarak ortaya konmasa da kolinerjik antiinflamatuar yolağı içeren nöroimmün etkileşimlerin terapötik bir hedef olabileceği belirtilmektedir.
Tromboembolik hastalıklar, hayvanlarda ve özellikle kedi ve köpeklerde hayati risk oluşturan pato... more Tromboembolik hastalıklar, hayvanlarda ve özellikle kedi ve köpeklerde hayati risk oluşturan patolojik bozukluklardır. Antitrombotik ilaçlar, trombozun oluşumu ve genişlemesini önlemek için kullanılırken, trombolitik (fibrinolitik) ilaçlar oluşan pıhtıyı eritmek için kullanılır. Tromboz riskli kedi ve köpeklerde hangi grup antitrombotik ilacın ve uygulanacak dozaj rejiminin belirlenmesi klinik açıdan önem taşımaktadır. Antiplatelet ilaçlardan aspirin, klopidogrel, tiklopidin, antikoagülan ilaçlardan varfarin, heparin, düşük molekül ağırlıklı heparinler ve rivaroksaban ile fibrinolitik ilaçlardan streptokinaz kedi ve köpeklerde en sık kullanılan antitrombotik ilaçlardır. Arteriyel tromboembolizm tedavisinde antiplateletler önerilirken, venöz tromboembolizm vakalarında antikoagülanlar önerilmektedir. Bazı arteriyel tromboembolizm vakalarında ise antiplatelet ve antikoagülan ilaçlarla kombine tedavi tercih edilmektedir. Ayrıca, antitrombotik tedavinin izlenmesi, ilacın klinik etkinliğini ve istenmeyen etkilerini belirlemek için çok önemlidir. Terapötik ilaç takibi, özellikle antikoagülan ilaçlardan varfarin ve heparin gibi ilaçlar için kullanılmaktadır. Bu çalışmada, antitrombotik ilaçların kedi ve köpeklerde kullanımı, bu alandaki mevcut bilgi ve çalışmalar ışığında değerlendirilmiştir. Kedi ve köpeklerde çeşitli patofizyolojik olguların tetiklediği ve ciddi sağlık problemlerine yol açabilen trombozun önlenmesinde kullanılan antitrombotik ilaçların etkin ve güvenli kullanımı için ilave çalışmalara ihtiyaç olduğu anlaşılmaktadır.
Journal of Veterinary Pharmacology and Therapeutics, 2019
The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.... more The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co‐administered to dogs after oral treatment. Twelve healthy cross‐bred dogs (weighing 18–21 kg, aged 1–3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15‐day washout period, respectively. Second group received tablet form of ivermectin plus praziquantel. The plasma concentrations of ivermectin and praziquantel were determined by high‐performance liquid chromatography using a fluorescence and ultraviolet detector, respectively. The pharmacokinetic parameters of ivermectin following oral alone‐administration were as follows: elimination half‐life (t1/2λz) 110 ± 11.06 hr, area under the plasma concentration–time curve (AUC0–∞) 7,805 ± 1,768 hr.ng/ml, maximum concentration (Cmax) 137 ± 48.09 ng/ml, and time to reach Cmax (Tmax) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone‐administration were as follows: t1/2λz 7.39 ± 3.86 hr, AUC0–∞ 4,301 ± 1,253 hr. ng/ml, Cmax 897 ± 245 ng/ml, and Tmax 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except Tmax of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.
İstenmeyen ilaç reaksiyonları, ölüm dahil ciddi sağlık problemleri ve ekonomik kayıplara neden ol... more İstenmeyen ilaç reaksiyonları, ölüm dahil ciddi sağlık problemleri ve ekonomik kayıplara neden olmaktadır. İlaç kullanımı ve sonrasında gözlenebilen bu etkiler; ilaç, canlı, çevre, genetik polimorfizm ve bireysel duyarlılık gibi faktörlerle ilişkilidir. İlaç yan etkilerinden korunmak için ilaç istenmeyen etkileriyle ilişkili biyomarkerların belirlenmesi çok önemlidir. Biyomarker, biyolojik bir olgunun ölçülebilir bir göstergesi olarak tanımlanabilir. Biyomarkerlar, ilaç seçimi ve riskli ırk ve türlerin izlenmesi için de kullanılmaktadır. Hasarlı dokulardan dolaşım ve idrara geçen çeşitli proteinler ve nükleik asitler biyomarker olarak değerlendirilmektedir. Genetik ve moleküler biyoloji alanındaki gelişmeler konvansiyonel biyomarkerlardan daha duyarlı ve spesifik olan, genomik (farmakogenetik) markerlar olarak da tanımlanan biyomarkerların belirlenmesine neden olmuştur. İdeal bir biyomarker için bazı nitelikler belirlenmiş ve bunların bazıları; istenmeyen etkiyi mümkün olduğunca erken belirlemeli, etkinin derecesi ve dozla ilişkisini ortaya koymalı, tüm tür ve ırklar için aynı güvenirlikte olmalı, istenmeyen etkinin kaynağını belirtmelidir. Mevcut makalede ilaç istenmeyen etkilerinin belirlenmesinde kullanılan biyomarkerlar alanındaki son gelişmeler değerlendirilmiştir.
Journal of Veterinary Pharmacology and Therapeutics, 2019
This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmaco... more This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmacokinetics in milk and plasma after intramuscular administration. Five healthy dairy cows (Holstein, weighing 450–500 kg, aged 2–4 years) were used in this study. They received single intramuscular amoxicillin at a dose of 14 mg/kg body weight. Blood and milk samples were collected prior to drug administration (0); after 15, 30, 45, 60, and 90 min; and 2, 3, 4, 6, 8, 10, and 12 hr after administration. The plasma and milk concentrations of amoxicillin were determined using high performance liquid chromatography with ultraviolet detection. The passage ratio of amoxicillin into milk and plasma was determined using both AUC-based calculation and milk and plasma concentrations at sampling times; it was calculated 0.46 and 0.52, respectively. The terminal half-life and mean residence time of amoxicillin were 6.05 and 8.60 hr in plasma and 2.62 and 5.35 hr in milk, respectively. The Cmax2 levels of amoxicillin in plasma and milk were measured as 1,096 and 457 ng/ml, respectively. It was observed that amoxicillin exhibited a secondary peak in plasma and milk. This study was the first to report on the passage ratio of amoxicillin into milk in lactating cows.
This study determined the distribution of drugs to different milk fractions according to their ph... more This study determined the distribution of drugs to different milk fractions according to their physicochemical properties. Hydrophilic drugs tend to concentrate in skim milk, whereas lipophilic drugs tend to concentrate in cream. The concentration of a drug in casein is related to its degree of binding to milk proteins. Thus, we aimed to determine whether withdrawal time in whole milk differs from that in cream, casein, and skim milk. Amoxicillin and tylosin were selected as prototype hydrophilic and lipophilic drugs, respectively. The study was conducted in vitro and in vivo to determine whether in vitro conditions reflect the distribution of drugs in the different milk fractions in vivo. The in vivo study was conducted using a crossover design on 6 healthy Holstein dairy cattle. First, amoxicillin (i.m., single dose, 14 mg/kg) was administered to cows. Following a 1-wk washout period, tylosin (i.m., single dose, 15 mg/kg) was administered. Concentrations of amoxicillin and tylosin in milk and milk fractions were measured using HPLC-UV. In the in vitro study, 0.04 to 400 μg/g of amoxicillin and 0.05 to 50 μg/g of tylosin were spiked to drug-free milk and the concentrations in milk and milk fractions were measured. In addition, the percentage of total protein in milk and milk fractions was determined. Amoxicillin accumulated more in skim milk than in cream and casein, both in vitro (92%) and in vivo (73%, skim milk-to-whole milk ratio). The distribution of tylosin in whole and skim milk was similar to that of amoxicillin in the in vitro study, in contrast to the accumulation of tylosin in cream seen in vivo. However, the accumulation ratio of tylosin in cream was lower than expected. By either method, tylosin was less concentrated in casein than in skim milk and cream. The percentage of total protein was similar in skim milk and whole milk and higher than in cream. Thus, amoxicillin accumulates less in cream and casein, suggesting that these fractions would pose a lower risk to the consumer. Tylosin was still present at the maximum residue limit (50 μg/kg) 24 h after injection in the casein fraction and 48 h after injection in the cream fraction.
Dicle Üniversitesi Veteriner Fakültesi Dergisi, 2018
Antibakteriyal ilaçlar, veteriner klinikte en yaygın kullanılan ilaç grubudur. Bu ilaçlar çeşitli... more Antibakteriyal ilaçlar, veteriner klinikte en yaygın kullanılan ilaç grubudur. Bu ilaçlar çeşitli seviyelerde süte geçerler. Sütte kalıntı taranmasında kullanılan çok sayıda ticari kit mevcuttur. Bu kitler çalışma prensiplerine göre mikrobiyolojik, immunokimyasal ve biyosensörler olarak sınıflandırılır. Ticari test kitlerinde kolostrum ve mastitisli sütte doğal antibakteriyel maddelerin bulunması, mastitisli sütte yüksek somatik hücre sayısı ve pH, sütün yüksek oranda yağ, yağ asiti ve protein içermesi, sütteki deterjan ve dezenfektan kalıntıları, süt numunelerinin depolama ve saklama koşulları, mikrobiyolojik metotlarda inkübasyon süresi, sütte antiparaziter ilaç kalıntılarının bulunması, test sonuçlarının cihaz yerine görsel olarak yorumlanması gibi nedenlere bağlı olarak yanlış-pozitif sonuçlar alınabilmektedir. Antibakteriyellerin tanımlanması ve doğrulanmasında en güvenilir yöntem kromatografik metotlardır. Türkiye’de hayvansal gıdalarda antibiyotikler ve diğer kimyasallar “Kalıntı İzleme Programı” ile son 11 yıldır Gıda, Tarım ve Hayvancılık Bakanlığı tarafından sürdürülmektedir.
Milk is a food containing many biologically active substances that have an important place in the... more Milk is a food containing many biologically active substances that have an important place in the nourishment of newborns and adults. The transition of the drugs used in the treatment, as well as the environmental pollutants to milk cause a potential risk for consumer health as well as economical losses due to exceed of the legal limits of these compounds set by authorities. The transition of these chemicals to milk is complex; while active transport and passive diffusion play were found to have an important role. The transition abilities of the drugs into milk are defined by milk/plasma ratio. The M/P ratios of the drugs are affected by the composition of the milk and the physicochemical properties of the drug. The concentration of the drugs in the milk depends on the factors of the drug (protein binding, ionization, molecular weight, lipophilicity, drug-drug and drug-nutrient interactions) and organism (race, species, lactation period, parity, disease and nutrition). If the transition properties of the compounds of concern are known or able to be modelized in kinetic applications, it can be useful for preventing milk from drug residues.The success of mastitis treatment depends on the proper use of drugs and knowing of the behaviour of drugs in the milk.
This study aimed to determine the pharmacokinetics and pharmacokinetic interaction between oxfend... more This study aimed to determine the pharmacokinetics and pharmacokinetic interaction between oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered either alone or co-administered to goats orally. The study was carried out to the cross-over design into three periods, with a washout period of 21 days among administrations, on six healthy Alpine goats 1 year of age. The plasma concentrations of oxfendazole, oxfendazole metabolites fenbendazole and fenbendazole sulfone, and oxyclozanide were determined using HPLC-UV, and data were analyzed by the non-compartmental method. The plasma concentrations of oxfendazole were similar in both oxfendazole and combined groups. When oxfendazole was administered alone or in combination with oxyclozanide, the compounds recovered in plasma were oxfendazole, fenbendazole sulfone, and fenbendazole. Oxyclozanide did not change the plasma disposition of oxfendazole. In the oxyclozanide group, t1/ 2λz, Cmax, Tmax, and AUC0-∞ were estimated at 15.3 h, 11.6 μg/mL, 24 h, and 554 h × μg/mL, respectively. In the oxyclozanide plus oxfendazole treatment group, AUC0-∞ (1111 h×μg/mL), and Cmax (23.9 μg/mL) values were increased. In goats, the anthelmintic efficacy of oxfendazole and oxyclozanide should be determined by taking into account their pharmacokinetic data.
Journal of Veterinary Pharmacology and Therapeutics, 2023
The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gas... more The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gastrointestinal nematodes. This study aimed to determine both the pharmacokinetics of oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered orally to sheep and whether there is a pharmacokinetic interaction between these two drugs. The study was conducted in a three-period, crossover pharmacokinetic design and on six healthy Awassi sheep 1-3 years of age.
This study aimed to determine the effects of dexamethasone and minocycline alone and combined tre... more This study aimed to determine the effects of dexamethasone and minocycline alone and combined treatment with N-acetylcysteine (NAC) and vitamin E on serum coenzyme Q10 (CoQ10) and matrix metalloproteinase-9 (MMP-9) levels in rats administered aflatoxin B1 (AFB1). The study was carried out on 66 male Wistar rats. Following the intraperitoneal (IP) administration of AFB1 at dose of 2 mg/kg, minocycline (45 and 90 mg/kg, IP) and dexamethasone (5 and 20 mg/kg, IP) were administered alone and combined with NAC (200 mg/kg, IP) and vitamin E (600 mg/kg, IP). CoQ10 and MMP-9 levels were analyzed using the HPLC-UV method and a commercial kit by ELISA, respectively. AFB1 increased MMP-9 level and decreased CoQ10 level compared to the control group. After dexamethasone and minocycline administration, there is no increase in CoQ10 level, which is caused by AFB1. However, dexamethasone and minocycline combined with NAC+vitamin E caused significant increases in CoQ10 levels. Dexamethasone and minocycline alone and combined with NAC+vitamin E decreased MMP-9 levels compared to the single AFB1 treated group. The use of MMPs inhibitors and oxidative stress-reducing agents is anticipated to be beneficial in the poisoning with AFB1.
Journal of Veterinary Pharmacology and Therapeutics, 2022
This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used... more This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2-20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC-UV. The pharmacokinetic parameters were analyzed using the non-compartmental method. In healthy calves, the t 1/2ʎz , C max , T max, and AUC 0-12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves.
Türkiye Klinikleri Veteriner Bilimleri Dergisi, 2021
Canlı vücudunda tamamı sentezlenemeyen vitaminler, fizyolojik fonksiyonlar için gerekli olup kend... more Canlı vücudunda tamamı sentezlenemeyen vitaminler, fizyolojik fonksiyonlar için gerekli olup kendilerine özgü spesifik görevleri olan maddelerdir. İlaç-ilaç ve ilaç-gıda etkileşimleri, ilaçların istenmeyen etkilerinin ortaya çıkmasında büyük rol oynar. Farmakokinetik temelli ilaç etkileşimleri daha çok enzim ve taşıyıcı transmembran proteinler düzeyinde gözlenir. Metabolik reaksiyonların çoğu sitokrom P450 ailesi tarafından gerçekleştirilir. Enzim aktivitesinin, inhibisyonu veya indüksiyonu substrat ilacın konsantrasyonunu değiştirir. ATP-bağlayıcı kaset taşıyıcılarından, Pglikoprotein ve meme kanser direnç proteini toksik maddelerin ve ksenobiyotiklerin hücrelerden dışarı atılmasında ve ilaç-ilaç, ilaç-gıda etkileşimlerinde rol oynarlar. Çoğu ilaç etkileşimlerinde, sitokrom P450 ve P-glikoprotein birlikte rol oynar. Hem farmakokinetik ve hem de farmakodinamik etkileşimler, ilaçların farmakolojik etkinliğinde artış ve azalışa neden olabilir. Etkide artış ölüme yol açabilecek düzeyde bir etkileşim oluşturabilirken, etkide azalış ise tedavide başarısızlığa neden olabilir. İlaçlar arasındaki etkileşimin klinik önem arz edip etmeyeceği, etkileşime giren ilaçların terapötik indeks ve vücuttaki farmakokinetik davranış özelliklerinin bilinmesiyle ön görülebilir. Vitaminler, hem beşeri hem de veteriner hekimlikte en fazla suistimal edilen bileşikler arasındadır. İnsan ve hayvanların, besinlerle aldıkları vitaminlere ilave olarak kullanılan vitaminler sağlık açısından risk oluşturmakta ve ilaç etkileşimlerinde çoğu kez vitaminlerin etkisi göz ardı edilmektedir. Vitaminlerle ilaçlar arasındaki etkileşimleri belirlemeye yönelik daha çok deneysel ve klinik çalışmalara ihtiyaç vardır. Bu derlemede, yoğun kullanılan vitaminlerin ilaç etkileşimlerindeki önemi irdelenecektir.
This study was conducted to investigate the effects of matrix metalloproteinase (MMP) inhibitors ... more This study was conducted to investigate the effects of matrix metalloproteinase (MMP) inhibitors dexamethasone and minocycline administrations-both single and in combination with N-acetylcysteine (NAC) and vitamin E-on the tissue distribution and lethal dose (LD) 50 of aflatoxin (AF)B 1 in rats. We performed this study on male Wistar rats (8-10 weeks) in two phases. In the first phase, rats were administered dexamethasone (5 and 20 mg/ kg) and minocycline (45 and 90 mg/kg), both as single treatments and in combination with NAC (200 mg/kg) and vitamin E (600 mg/kg); these treatments followed AFB 1 administration (2 mg/kg). In the second phase, the therapeutic effect value (TEV) was calculated to determine the treatment effect on the LD 50 level of AFB 1. The tissue affinity of AFB1 from high to low was liver, kidney, intestine, brain, heart, spleen, lung, testis, and vitreous humor, respectively. Dexamethasone at the 20 mg/kg dose significantly reduced AFB 1 concentrations in the plasma and the other tissues, except for the vitreous humor. The effects of minocycline on the plasma and tissue concentrations of AFB 1 varied by dose and tissue. The combinations of dexamethasone or minocycline with NAC and vitamin E increased the AFB 1 concentrations in the plasma and all tissues, except for vitreous humor and liver. In male rats, the LD 50 value of AFB 1 was 11.86 mg/kg. The TEV of dexamethasone (20 mg/kg) was calculated to be 1.5. Dexamethasone can be administered in repeated doses at ≥20 mg/kg to increase survival in AFB 1 poisoning.
Kronik obstrüktif akciğer hastalığında kolinerjik sistemin aktivitesi artar, bu da solunum yolu d... more Kronik obstrüktif akciğer hastalığında kolinerjik sistemin aktivitesi artar, bu da solunum yolu düz kaslarını kasarak soluk alışverişini sınırlandırır. Bu nedenle kolinerjik sinir sistemi aktivitesinin arttığı kronik obstrüktif akciğer hastalığı gibi olguların tedavisinde, antikolinerjik ilaçlar kullanılmaktadır. Antikolinerjik ilaçların bu endikasyonda kullanımı, asetilkolinin bronkokonstriksiyon ve mukus salgısını artırıcı etkisinin azaltılmasına dayanmaktadır. Son yapılan deneysel çalışmalar, asetilkolinin yangıda da önemli rol oynadığını ortaya koymuştur. Muskarinik M3 reseptör-noksan fareler ve M3 selektif antagonistler kullanılarak yapılan çalışmalar, parankimal hücrelerdeki M3 reseptörlerinin asetilkolinin proinflamatuar etkisine aracılık ettiğini ortaya koymuştur. Beta-2 (β2) adrenerjik agonist ile muskarinik antagonist kombinasyonlarının kronik obstrüktif akciğer hastalığı tedavisinde kullanılması önerilmektedir. Bu öneri, β2 adrenerjik reseptör uyarımının M3 reseptörlerini antagonize ederek farklı bir yolakla inflamatuar hücrelerde inhibisyona yol açacağına dayanmaktadır ancak bu antiinflamatuar etkiler, kronik obstrüktif akciğer hastalığında açıkça ortaya konulamamıştır. Muskarinik reseptörler aracılığıyla, asetilkolinin proinflamatuar etkilerinin aksine parasempatik sinir sistemini içeren kolinerjik antiinflamatuar yol, doku hasarı ve enfeksiyon durumunda organları korumak için aşırı inflamatuar yanıtları düzenler. Diğer yandan asetilkolinin, α7 nikotinik asetilkolin reseptör aracılığıyla makrofajlar ve Tip 2 doğal lenfoid hücreler dâhil olmak üzere lökositler üzerinde inhibitör etki oluşturduğu ortaya konmuştur. Kronik obstrüktif akciğer hastalığında, asetilkolinin antiinflamatuar hücreler üzerindeki bu inhibe edici etkisi tam olarak ortaya konmasa da kolinerjik antiinflamatuar yolağı içeren nöroimmün etkileşimlerin terapötik bir hedef olabileceği belirtilmektedir.
Tromboembolik hastalıklar, hayvanlarda ve özellikle kedi ve köpeklerde hayati risk oluşturan pato... more Tromboembolik hastalıklar, hayvanlarda ve özellikle kedi ve köpeklerde hayati risk oluşturan patolojik bozukluklardır. Antitrombotik ilaçlar, trombozun oluşumu ve genişlemesini önlemek için kullanılırken, trombolitik (fibrinolitik) ilaçlar oluşan pıhtıyı eritmek için kullanılır. Tromboz riskli kedi ve köpeklerde hangi grup antitrombotik ilacın ve uygulanacak dozaj rejiminin belirlenmesi klinik açıdan önem taşımaktadır. Antiplatelet ilaçlardan aspirin, klopidogrel, tiklopidin, antikoagülan ilaçlardan varfarin, heparin, düşük molekül ağırlıklı heparinler ve rivaroksaban ile fibrinolitik ilaçlardan streptokinaz kedi ve köpeklerde en sık kullanılan antitrombotik ilaçlardır. Arteriyel tromboembolizm tedavisinde antiplateletler önerilirken, venöz tromboembolizm vakalarında antikoagülanlar önerilmektedir. Bazı arteriyel tromboembolizm vakalarında ise antiplatelet ve antikoagülan ilaçlarla kombine tedavi tercih edilmektedir. Ayrıca, antitrombotik tedavinin izlenmesi, ilacın klinik etkinliğini ve istenmeyen etkilerini belirlemek için çok önemlidir. Terapötik ilaç takibi, özellikle antikoagülan ilaçlardan varfarin ve heparin gibi ilaçlar için kullanılmaktadır. Bu çalışmada, antitrombotik ilaçların kedi ve köpeklerde kullanımı, bu alandaki mevcut bilgi ve çalışmalar ışığında değerlendirilmiştir. Kedi ve köpeklerde çeşitli patofizyolojik olguların tetiklediği ve ciddi sağlık problemlerine yol açabilen trombozun önlenmesinde kullanılan antitrombotik ilaçların etkin ve güvenli kullanımı için ilave çalışmalara ihtiyaç olduğu anlaşılmaktadır.
Journal of Veterinary Pharmacology and Therapeutics, 2019
The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.... more The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co‐administered to dogs after oral treatment. Twelve healthy cross‐bred dogs (weighing 18–21 kg, aged 1–3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15‐day washout period, respectively. Second group received tablet form of ivermectin plus praziquantel. The plasma concentrations of ivermectin and praziquantel were determined by high‐performance liquid chromatography using a fluorescence and ultraviolet detector, respectively. The pharmacokinetic parameters of ivermectin following oral alone‐administration were as follows: elimination half‐life (t1/2λz) 110 ± 11.06 hr, area under the plasma concentration–time curve (AUC0–∞) 7,805 ± 1,768 hr.ng/ml, maximum concentration (Cmax) 137 ± 48.09 ng/ml, and time to reach Cmax (Tmax) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone‐administration were as follows: t1/2λz 7.39 ± 3.86 hr, AUC0–∞ 4,301 ± 1,253 hr. ng/ml, Cmax 897 ± 245 ng/ml, and Tmax 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except Tmax of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.
İstenmeyen ilaç reaksiyonları, ölüm dahil ciddi sağlık problemleri ve ekonomik kayıplara neden ol... more İstenmeyen ilaç reaksiyonları, ölüm dahil ciddi sağlık problemleri ve ekonomik kayıplara neden olmaktadır. İlaç kullanımı ve sonrasında gözlenebilen bu etkiler; ilaç, canlı, çevre, genetik polimorfizm ve bireysel duyarlılık gibi faktörlerle ilişkilidir. İlaç yan etkilerinden korunmak için ilaç istenmeyen etkileriyle ilişkili biyomarkerların belirlenmesi çok önemlidir. Biyomarker, biyolojik bir olgunun ölçülebilir bir göstergesi olarak tanımlanabilir. Biyomarkerlar, ilaç seçimi ve riskli ırk ve türlerin izlenmesi için de kullanılmaktadır. Hasarlı dokulardan dolaşım ve idrara geçen çeşitli proteinler ve nükleik asitler biyomarker olarak değerlendirilmektedir. Genetik ve moleküler biyoloji alanındaki gelişmeler konvansiyonel biyomarkerlardan daha duyarlı ve spesifik olan, genomik (farmakogenetik) markerlar olarak da tanımlanan biyomarkerların belirlenmesine neden olmuştur. İdeal bir biyomarker için bazı nitelikler belirlenmiş ve bunların bazıları; istenmeyen etkiyi mümkün olduğunca erken belirlemeli, etkinin derecesi ve dozla ilişkisini ortaya koymalı, tüm tür ve ırklar için aynı güvenirlikte olmalı, istenmeyen etkinin kaynağını belirtmelidir. Mevcut makalede ilaç istenmeyen etkilerinin belirlenmesinde kullanılan biyomarkerlar alanındaki son gelişmeler değerlendirilmiştir.
Journal of Veterinary Pharmacology and Therapeutics, 2019
This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmaco... more This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmacokinetics in milk and plasma after intramuscular administration. Five healthy dairy cows (Holstein, weighing 450–500 kg, aged 2–4 years) were used in this study. They received single intramuscular amoxicillin at a dose of 14 mg/kg body weight. Blood and milk samples were collected prior to drug administration (0); after 15, 30, 45, 60, and 90 min; and 2, 3, 4, 6, 8, 10, and 12 hr after administration. The plasma and milk concentrations of amoxicillin were determined using high performance liquid chromatography with ultraviolet detection. The passage ratio of amoxicillin into milk and plasma was determined using both AUC-based calculation and milk and plasma concentrations at sampling times; it was calculated 0.46 and 0.52, respectively. The terminal half-life and mean residence time of amoxicillin were 6.05 and 8.60 hr in plasma and 2.62 and 5.35 hr in milk, respectively. The Cmax2 levels of amoxicillin in plasma and milk were measured as 1,096 and 457 ng/ml, respectively. It was observed that amoxicillin exhibited a secondary peak in plasma and milk. This study was the first to report on the passage ratio of amoxicillin into milk in lactating cows.
This study determined the distribution of drugs to different milk fractions according to their ph... more This study determined the distribution of drugs to different milk fractions according to their physicochemical properties. Hydrophilic drugs tend to concentrate in skim milk, whereas lipophilic drugs tend to concentrate in cream. The concentration of a drug in casein is related to its degree of binding to milk proteins. Thus, we aimed to determine whether withdrawal time in whole milk differs from that in cream, casein, and skim milk. Amoxicillin and tylosin were selected as prototype hydrophilic and lipophilic drugs, respectively. The study was conducted in vitro and in vivo to determine whether in vitro conditions reflect the distribution of drugs in the different milk fractions in vivo. The in vivo study was conducted using a crossover design on 6 healthy Holstein dairy cattle. First, amoxicillin (i.m., single dose, 14 mg/kg) was administered to cows. Following a 1-wk washout period, tylosin (i.m., single dose, 15 mg/kg) was administered. Concentrations of amoxicillin and tylosin in milk and milk fractions were measured using HPLC-UV. In the in vitro study, 0.04 to 400 μg/g of amoxicillin and 0.05 to 50 μg/g of tylosin were spiked to drug-free milk and the concentrations in milk and milk fractions were measured. In addition, the percentage of total protein in milk and milk fractions was determined. Amoxicillin accumulated more in skim milk than in cream and casein, both in vitro (92%) and in vivo (73%, skim milk-to-whole milk ratio). The distribution of tylosin in whole and skim milk was similar to that of amoxicillin in the in vitro study, in contrast to the accumulation of tylosin in cream seen in vivo. However, the accumulation ratio of tylosin in cream was lower than expected. By either method, tylosin was less concentrated in casein than in skim milk and cream. The percentage of total protein was similar in skim milk and whole milk and higher than in cream. Thus, amoxicillin accumulates less in cream and casein, suggesting that these fractions would pose a lower risk to the consumer. Tylosin was still present at the maximum residue limit (50 μg/kg) 24 h after injection in the casein fraction and 48 h after injection in the cream fraction.
Dicle Üniversitesi Veteriner Fakültesi Dergisi, 2018
Antibakteriyal ilaçlar, veteriner klinikte en yaygın kullanılan ilaç grubudur. Bu ilaçlar çeşitli... more Antibakteriyal ilaçlar, veteriner klinikte en yaygın kullanılan ilaç grubudur. Bu ilaçlar çeşitli seviyelerde süte geçerler. Sütte kalıntı taranmasında kullanılan çok sayıda ticari kit mevcuttur. Bu kitler çalışma prensiplerine göre mikrobiyolojik, immunokimyasal ve biyosensörler olarak sınıflandırılır. Ticari test kitlerinde kolostrum ve mastitisli sütte doğal antibakteriyel maddelerin bulunması, mastitisli sütte yüksek somatik hücre sayısı ve pH, sütün yüksek oranda yağ, yağ asiti ve protein içermesi, sütteki deterjan ve dezenfektan kalıntıları, süt numunelerinin depolama ve saklama koşulları, mikrobiyolojik metotlarda inkübasyon süresi, sütte antiparaziter ilaç kalıntılarının bulunması, test sonuçlarının cihaz yerine görsel olarak yorumlanması gibi nedenlere bağlı olarak yanlış-pozitif sonuçlar alınabilmektedir. Antibakteriyellerin tanımlanması ve doğrulanmasında en güvenilir yöntem kromatografik metotlardır. Türkiye’de hayvansal gıdalarda antibiyotikler ve diğer kimyasallar “Kalıntı İzleme Programı” ile son 11 yıldır Gıda, Tarım ve Hayvancılık Bakanlığı tarafından sürdürülmektedir.
Milk is a food containing many biologically active substances that have an important place in the... more Milk is a food containing many biologically active substances that have an important place in the nourishment of newborns and adults. The transition of the drugs used in the treatment, as well as the environmental pollutants to milk cause a potential risk for consumer health as well as economical losses due to exceed of the legal limits of these compounds set by authorities. The transition of these chemicals to milk is complex; while active transport and passive diffusion play were found to have an important role. The transition abilities of the drugs into milk are defined by milk/plasma ratio. The M/P ratios of the drugs are affected by the composition of the milk and the physicochemical properties of the drug. The concentration of the drugs in the milk depends on the factors of the drug (protein binding, ionization, molecular weight, lipophilicity, drug-drug and drug-nutrient interactions) and organism (race, species, lactation period, parity, disease and nutrition). If the transition properties of the compounds of concern are known or able to be modelized in kinetic applications, it can be useful for preventing milk from drug residues.The success of mastitis treatment depends on the proper use of drugs and knowing of the behaviour of drugs in the milk.
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mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered either alone or co-administered to goats
orally. The study was carried out to the cross-over design into three periods, with a washout period of 21 days
among administrations, on six healthy Alpine goats 1 year of age. The plasma concentrations of oxfendazole,
oxfendazole metabolites fenbendazole and fenbendazole sulfone, and oxyclozanide were determined using
HPLC-UV, and data were analyzed by the non-compartmental method. The plasma concentrations of oxfendazole
were similar in both oxfendazole and combined groups. When oxfendazole was administered alone or in combination
with oxyclozanide, the compounds recovered in plasma were oxfendazole, fenbendazole sulfone, and
fenbendazole. Oxyclozanide did not change the plasma disposition of oxfendazole. In the oxyclozanide group, t1/
2λz, Cmax, Tmax, and AUC0-∞ were estimated at 15.3 h, 11.6 μg/mL, 24 h, and 554 h × μg/mL, respectively. In the
oxyclozanide plus oxfendazole treatment group, AUC0-∞ (1111 h×μg/mL), and Cmax (23.9 μg/mL) values were
increased. In goats, the anthelmintic efficacy of oxfendazole and oxyclozanide should be determined by taking
into account their pharmacokinetic data.
mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered either alone or co-administered to goats
orally. The study was carried out to the cross-over design into three periods, with a washout period of 21 days
among administrations, on six healthy Alpine goats 1 year of age. The plasma concentrations of oxfendazole,
oxfendazole metabolites fenbendazole and fenbendazole sulfone, and oxyclozanide were determined using
HPLC-UV, and data were analyzed by the non-compartmental method. The plasma concentrations of oxfendazole
were similar in both oxfendazole and combined groups. When oxfendazole was administered alone or in combination
with oxyclozanide, the compounds recovered in plasma were oxfendazole, fenbendazole sulfone, and
fenbendazole. Oxyclozanide did not change the plasma disposition of oxfendazole. In the oxyclozanide group, t1/
2λz, Cmax, Tmax, and AUC0-∞ were estimated at 15.3 h, 11.6 μg/mL, 24 h, and 554 h × μg/mL, respectively. In the
oxyclozanide plus oxfendazole treatment group, AUC0-∞ (1111 h×μg/mL), and Cmax (23.9 μg/mL) values were
increased. In goats, the anthelmintic efficacy of oxfendazole and oxyclozanide should be determined by taking
into account their pharmacokinetic data.