RESUMO
SIGNIFICANCE: Fluorocoxib D, N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a water-soluble optical imaging agent to detect cyclooxygenase-2 (COX-2)-expressing cancer cells. AIM: We evaluated the pharmacokinetic and safety properties of fluorocoxib D and its ability to detect cancer cells in vitro and in vivo. APPROACH: Pharmacokinetic parameters of fluorocoxib D were assessed from plasma collected at designated time points after intravenous administration of 1 mg / kg fluorocoxib D in six research dogs using a high-performance liquid chromatography analysis. Safety of fluorocoxib D was assessed for 3 days after its administration using physical assessment, complete blood count, serum chemistry profile, and complete urinalysis in six research dogs. The ability of fluorocoxib D to detect COX-2-expressing cancer cells was performed using human 5637 cells in vitro and during rhinoscopy evaluation of specific fluorocoxib D uptake by canine cancer cells in vivo. RESULTS: No evidence of toxicity and no clinically relevant adverse events were noted in dogs. Peak concentration of fluorocoxib D (114.8 ± 50.5 ng / ml) was detected in plasma collected at 0.5 h after its administration. Pretreatment of celecoxib blocked specific uptake of fluorocoxib D in COX-2-expressing human 5637 cancer cells. Fluorocoxib D uptake was detected in histology-confirmed COX-2-expressing head and neck cancer during rhinoscopy in a client-owned dog in vivo. Specific tumor-to-normal tissue ratio of detected fluorocoxib D signal was in an average of 3.7 ± 0.9 using Image J analysis. CONCLUSIONS: Our results suggest that fluorocoxib D is a safe optical imaging agent used for detection of COX-2-expressing cancers and their margins during image-guided minimally invasive biopsy and surgical procedures.
Assuntos
Antineoplásicos , Neoplasias , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Cães , Neoplasias/diagnóstico por imagem , Imagem ÓpticaRESUMO
Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that has been used orally and intramuscularly in numerous avian species, but not studied to date, in African penguins ( Spheniscus demersus). The study describes the pharmacokinetic parameters of meloxicam after oral and intramuscular administration to African penguins. Several pilot studies were conducted initially where meloxicam (1, 0.5, and 0.25 mg/kg) was given intramuscularly to 4 birds, and orally (1 mg/kg) to 2 birds. Based on pilot study results, one group of 8 penguins was given meloxicam 0.5 mg/kg intramuscularly and one group of 8 penguins was given 1 mg/kg orally. Blood samples were collected at baseline and at 11 time intervals per group after administration of meloxicam. Meloxicam time to maximum plasma concentration (Tmax), maximum concentration (Cmax), and half-life (t1/2) after intramuscular administration were 1.00 hour, 8.03 µg/mL, and 31.87 hours, respectively, while oral administration produced a Tmax, Cmax, and t1/2 of 12.00 hours, 10.84 µg/mL, and 28.59 hours, respectively. Based on plasma meloxicam concentrations found to be therapeutic in other bird species and humans, the recommended dosage and frequency for African penguins is 1 mg/kg orally every 48 hours and 0.5 mg/kg intramuscularly every 24 hours. Further studies are needed to determine the multiple-dose pharmacokinetics of meloxicam in African penguins.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Aves/metabolismo , Meloxicam/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Disponibilidade Biológica , Aves/sangue , Espécies em Perigo de Extinção , Feminino , Injeções Intramusculares/veterinária , Masculino , Meloxicam/administração & dosagem , Meloxicam/sangue , Projetos Piloto , Especificidade da EspécieRESUMO
OBJECTIVE: To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. ANIMALS: 5 healthy purpose-bred hounds. PROCEDURES: The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses. RESULTS: Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ngâ¢h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ngâ¢h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.
Assuntos
Cães/sangue , Sirolimo/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Cromatografia Líquida/métodos , Meia-VidaRESUMO
Neuropathic pain is a manifestation of chronic pain that arises with damage to the somatosensory system. Pharmacologic treatment recommendations for alleviation of neuropathic pain are often multimodal, and the few reports communicating treatment of suspected neuropathic pain in avian patients describe the use of gabapentin as part of the therapeutic regimen. To determine the pharmacokinetics of gabapentin in Hispaniolan Amazon parrots ( Amazona ventralis ), compounded gabapentin suspensions were administered at 30 mg/kg IV to 2 birds, 10 mg/kg PO to 3 birds, and 30 mg/kg PO to 3 birds. Blood samples were collected immediately before and at 9 different time points after drug administration. Plasma samples were analyzed for gabapentin concentration, and pharmacokinetic parameters were calculated with both a nonlinear mixed-effect approach and a noncompartmental analysis. The best compartmental, oral model was used to simulate the concentration-time profiles resulting from different dosing scenarios. Mild sedation was observed in both study birds after intravenous injection. Computer simulation of different dosing scenarios with the mean parameter estimates showed that 15 mg/kg every 8 hours would be a starting point for oral dosing in Hispaniolan Amazon parrots based on effective plasma concentrations reported for human patients; however, additional studies need to be performed to establish a therapeutic dose.
Assuntos
Amazona/metabolismo , Aminas/farmacocinética , Analgésicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácido gama-Aminobutírico/farmacocinética , Administração Oral , Amazona/sangue , Aminas/administração & dosagem , Aminas/química , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/química , Relação Dose-Resposta a Droga , Gabapentina , Injeções Intravenosas , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/químicaRESUMO
SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.
Assuntos
Anticarcinógenos/farmacocinética , Anticarcinógenos/toxicidade , Cromanos/farmacocinética , Cromanos/toxicidade , Tionas/farmacocinética , Tionas/toxicidade , Administração Oral , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Animais , Anticarcinógenos/administração & dosagem , Área Sob a Curva , Cromanos/administração & dosagem , Cães , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Tionas/administração & dosagem , Testes de Toxicidade , Aumento de Peso/efeitos dos fármacosRESUMO
We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1 mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1 mg/kg showed a peak of fluorocoxib A (92±28 ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.
Assuntos
Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Ciclo-Oxigenase 2/metabolismo , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Indóis/administração & dosagem , Indóis/farmacocinética , Imagem Óptica/métodos , Rodaminas/administração & dosagem , Rodaminas/farmacocinética , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/veterinária , Inibidores de Ciclo-Oxigenase 2/toxicidade , Doenças do Cão/tratamento farmacológico , Doenças do Cão/metabolismo , Cães , Feminino , Corantes Fluorescentes/toxicidade , Indóis/toxicidade , Injeções Intravenosas , Masculino , Modelos Animais , Fenômenos Ópticos , Projetos Piloto , Rodaminas/toxicidadeRESUMO
9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.
Assuntos
Anticarcinógenos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Ácidos Graxos Insaturados/toxicidade , Naftalenos/toxicidade , Administração Oral , Animais , Anticarcinógenos/farmacocinética , Cães , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ácidos Graxos Insaturados/farmacocinética , Feminino , Masculino , Naftalenos/farmacocinética , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Ratos , Especificidade da Espécie , Testes de Toxicidade CrônicaRESUMO
Carboplatin is an antineoplastic drug administered to treat different tumoral conditions in canine oncology. The objective of this study was to validate a high-performance chromatographic (HPLC) method which could be applied in canine pharmacokinetic studies. Following ultrafiltration using a Centrifree device, standards, quality controls and plasma samples were separated by isocratic reversed-phase HPLC on an Inertsil ODS-2 (250 x 4.6 mm i.d.) analytical column and quantified using UV detection at 220 nm. The mobile phase was potassium phosphate (pH 4.5), with a flow-rate of 1.0 mL/min. The procedure produced a linear curve (r(2) > 0.999) over the concentration range 1-200 microg/mL. The lower limit of quantification was 1 microg/mL. The intra-assay and inter-assay precision was approximately 90%. The overall recovery was approximately 90%. The method was illustrated with a preliminary pharmacokinetic analysis on nine dogs treated with carboplatin at our hospital. Carboplatin disposition followed a monocompartmental structure in dogs and was characterized by a short half-life (50 min).
Assuntos
Antineoplásicos/sangue , Carboplatina/sangue , Cromatografia Líquida de Alta Pressão/métodos , Animais , Antineoplásicos/farmacocinética , Carboplatina/farmacocinética , Cromatografia Líquida de Alta Pressão/veterinária , Cães , Drogas Veterinárias/sangue , Drogas Veterinárias/farmacocinéticaRESUMO
Analgesia is becoming increasingly important in veterinary medicine, and little research has been performed that examined pain control in avian species. Tramadol is a relatively new drug that provides analgesia by opioid (mu), serotonin, and norepinephrine pathways, with minimal adverse effects. To determine the pharmacokinetics of tramadol and its major metabolite O-desmethyltramadol (M1) in eagles, 6 bald eagles (Haliaeetus leucocephalus) were each dosed with tramadol administered intravenously (4 mg/kg) and orally (11 mg/kg) in a crossover study. Blood was collected at various time points between 0 and 600 minutes and then analyzed with high-performance liquid chromatography to determine levels of tramadol and M1, the predominate active metabolite. The terminal half-life of tramadol after intravenous dosing was 2.46 hours. The maximum plasma concentration, time of maximum plasma concentration, and terminal half life for tramadol after oral dosing were 2156.7 ng/ml, 3.75 hours, and 3.14 hours, respec vely. In addition, the oral bioavailability was 97.9%. Although plasma concentrations of ramadol and M1 associated with analgesia in any avian species is unknown, based on the obtained data and known therapeutic levels in humans, a dosage of 5 mg/kg PO q12h is recommended for bald eagles. Pharmacodynamic studies are needed to better determine plasma levels of tramadol and M1 associated with analgesia in birds.