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BACKGROUND: Capecitabine is an oral prodrug of the active metabolite 5-fluorouracil, which has been used effectively in human colorectal, head and neck, and mammary carcinomas. Capecitabine has several properties that make it an attractive treatment option for dogs: (i) it is relatively inexpensive, (ii) it has a short half-life in humans, allowing for rapid plasma concentration changes to be achieved with dosage adjustments, (iii) it is effective for treating carcinomas in humans, for which there are no widely-effective oral chemotherapy options in dogs, and (iv) it is thought to preferentially target cancer cells due to different expression of thymidine phosphorylase, thereby decreasing the risk of off-target side effects. However, capecitabine has not been widely explored as a chemotherapy agent for dogs. The goal of this study was to determine the plasma disposition of capecitabine in dogs following a single oral dose and to document any adverse events associated with capecitabine administration over the course of 5 weeks. RESULTS: Capecitabine was well tolerated throughout the 5-week study period when administered to 5 dogs with naturally occurring carcinomas at 750 mg/m[Formula: see text] by mouth once daily for 14 consecutive days in a 3-week cycle. No dogs withdrew from the study due to adverse events or other causes. The median AUC[Formula: see text] was 890 h[Formula: see text]ng/ml (range 750-1100 h[Formula: see text]ng/ml); however, the maximum blood concentration and time to reach that concentration of capecitabine was highly variable after a single dose. CONCLUSIONS: Capecitabine appears well-tolerated as an oral chemotherapy agent for dogs with carcinomas, although individualized dosing may be necessary, and further studies are warranted.
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Carcinoma , Doenças do Cão , Cães , Humanos , Animais , Capecitabina/uso terapêutico , Projetos Piloto , Desoxicitidina/efeitos adversos , Fluoruracila/efeitos adversos , Carcinoma/tratamento farmacológico , Carcinoma/veterinária , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Administração Oral , Doenças do Cão/etiologiaRESUMO
The feline MDR1 mutation (ABCB11930_1931delTC) has been associated with neurological toxicosis after topical application of eprinomectin products labeled for feline use. Information was collected from veterinarians who submitted samples for ABCB11930_1931delTC genotyping. In most cases, the submission form indicated an adverse event involving eprinomectin, in other cases submitting veterinarians were contacted to determine whether the patient had experienced an adverse drug event involving eprinomectin. If so, additional information was obtained to determine whether the case met inclusion criteria. 14 cases were highly consistent with eprinomectin toxicosis. Eight cats were homozygous for ABCB11930_1931del TC (3 died; 5 recovered). Six cats were homozygous wildtype (2 died; 4 recovered). The observed ABCB11930_1931delTC frequency (57%) was higher than the expected frequency (≤1%) in the feline population (Fisher Exact test, p < 0.01). Among wildtype cats, four were concurrently treated with potential competitive inhibitors of P-glycoprotein. Results indicate that topical eprinomectin products, should be avoided in cats homozygous for ABCB11930_1931delTC. This is a serious, preventable adverse event occurring in an identifiable subpopulation treated with FDA-approved products in accordance with label directions. Acquired P-glycoprotein deficiency resulting from drug interactions may enhance susceptibility to eprinomectin-induced neurological toxicosis in any cat, regardless of ABCB1 genotype.
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Doenças do Gato , Ivermectina , Ivermectina/análogos & derivados , Animais , Gatos , Ivermectina/administração & dosagem , Doenças do Gato/induzido quimicamente , Feminino , Masculino , Antiparasitários/administração & dosagem , Homozigoto , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genéticaRESUMO
OBJECTIVE: (1) To describe the computed tomography (CT) and gross anatomy of the equine extensor carpi radialis sheath (ECRS) and common digital extensor sheath (CDETS); (2) to describe a single-portal endoscopic examination of the ECRS and CDETS. STUDY DESIGN: Ex vivo experimental. SAMPLE POPULATION: Thirty clinically normal cadaver thoracic equine limbs severed at the humeral diaphysis. METHODS: Ten limbs underwent plain and intrathecal contrast CT examinations and gross dissection of the ECRS and CDETS. Single-portal endoscopic examination of ECRS and CDETS was attempted in 4 limbs and endoscopic examination was performed on 16 limbs. Endoscopic video recordings were reviewed by 3 observers for quality of visualization before dissection and examination for iatrogenic damage. Interobserver agreement for ECRS and CDETS visualization was determined with Fleiss' κ agreement. RESULTS: Extensor carpi radialis sheath and CDETS anatomy was consistent between gross dissection and CT examinations. The ECRS endoscopic portal was medial at the level of the intersection between the extensor carpi obliquus and extensor carpi radialis tendon. The CDETS endoscopic portal was lateral, 5 cm proximal to the lateral styloid process of the ulna. The ECRS and CDETS were well visualized and interobserver agreement was substantial (κ = .73; P < .0001) and moderate (κ = .53; P < .0001), respectively. CONCLUSION: Computed tomography examinations provided useful anatomical information, consistent with gross dissection of the ECRS and CDETS. The described single-portal endoscopic techniques allowed consistent tenoscopic examination of the majority of the ECRS and CDETS. CLINICAL SIGNIFICANCE: Awareness of the intrathecal anatomy of the ECRS and CDETS should facilitate the treatment of these tendon sheaths. The proposed portals provide good to excellent single-site endoscopic visualization of the majority of the ECRS and CDETS.
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Doenças dos Cavalos , Tendões , Animais , Cadáver , Endoscopia/veterinária , Cavalos , Tendões/diagnóstico por imagem , Tomografia Computadorizada por Raios X/veterinária , UlnaRESUMO
Metabolomics is the large-scale study of low-molecular-weight substances in a biological system in a given physiological state at a given time point. Metabolomics can be applied to identify predictors of inter-individual variability in drug response, provide clinicians with data useful for decision-making processes in drug selection, and inform about the pharmacokinetics and pharmacodynamics of a drug. It is, therefore, an exceptional approach for gaining new understanding effects in the field of comparative veterinary pharmacology. However, the incorporation of metabolomics into veterinary pharmacology and toxicology is not yet widespread, and this is probably, at least in part, a result of its highly multidisciplinary nature. This article reviews the potential applications of metabolomics in veterinary pharmacology and therapeutics. It integrates key concepts for designing metabolomics studies and analyzing and interpreting metabolomics data, providing solid foundations for applying metabolomics to the study of drugs in all veterinary species.
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Metabolômica , Farmacologia , AnimaisRESUMO
Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated.
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Proteínas Sanguíneas/metabolismo , Cães/genética , Genótipo , Orosomucoide/metabolismo , Polimorfismo Genético , Amitriptilina/farmacocinética , Anestésicos Locais/farmacocinética , Animais , Antiarrítmicos/farmacocinética , Antidepressivos Tricíclicos/farmacocinética , Cães/sangue , Cães/metabolismo , Regulação da Expressão Gênica/fisiologia , Inibidores da Protease de HIV/farmacocinética , Indinavir/farmacocinética , Lidocaína/farmacocinética , Orosomucoide/genética , Ligação Proteica , Verapamil/farmacocinéticaRESUMO
Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine-learning algorithms, partial least squares discriminant analysis (PLS-DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam- and saline-treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam-treated from saline-treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID-induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects.
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Anti-Inflamatórios não Esteroides/metabolismo , Gatos/metabolismo , Meloxicam/metabolismo , Metabolômica , Algoritmos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/sangue , Biomarcadores , Gatos/sangue , Análise Discriminante , Feminino , Meloxicam/administração & dosagem , Meloxicam/efeitos adversos , Meloxicam/sangueRESUMO
Interindividual variation in drug response occurs in canine patients just as it does in human patients. Although canine pharmacogenetics still lags behind human pharmacogenetics, significant life-saving discoveries in the field have been made over the last 20 years, but much remains to be done. This article summarizes the available published data about the presence and impact of genetic polymorphisms on canine drug transporters, drug-metabolizing enzymes, drug receptors/targets, and plasma protein binding while comparing them to their human counterparts when applicable. In addition, precision medicine in cancer treatment as an application of canine pharmacogenetics and pertinent considerations for canine pharmacogenetics testing is reviewed. The field is poised to transition from single pharmacogene-based studies, pharmacogenetics, to pharmacogenomic-based studies to enhance our understanding of interindividual variation of drug response in dogs. Advances made in the field of canine pharmacogenetics will not only improve the health and well-being of dogs and dog breeds, but may provide insight into individual drug efficacy and toxicity in human patients as well.
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Sistema Enzimático do Citocromo P-450/genética , Monitoramento de Medicamentos/veterinária , Proteínas de Membrana Transportadoras/genética , Polimorfismo Genético/genética , Medicina de Precisão/métodos , Animais , Cães , Humanos , Farmacogenética/métodosRESUMO
Drug binding to plasma proteins is routinely determined during drug development. Albumin polymorphisms c.1075G>T (p.Ala359Ser) and c.1422A>T (p.Glu474Asp) were previously shown to alter plasma protein binding of a drug candidate (D01-4582, 4-[1-[3-chloro-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid) in a colony of Beagles. Our study investigated the hypothesis that drug-protein binding in plasma from dogs with the albumin H1 (reference) allele would be greater than in plasma from dogs with the albumin H2 allele (c.1075G>T and c.1422A>T) (n = 6 per group). The plasma protein binding extent of four drugs (D01-4582, celecoxib, mycophenolic acid, and meloxicam) was evaluated using ultracentrifugation or equilibrium dialysis. Free and total drug concentrations were analyzed by liquid chromatography-mass spectrometry. The albumin gene coding region was sequenced in 100 dogs to detect novel gene variants, and H1/H2 allele frequency was determined in a large and varied population (n = 1446 from 61 breeds and mixed-breed dogs). For meloxicam, H1 allele plasma had statistically significant higher free drug fractions (P = 0.041) than H2 allele plasma. No significant difference was identified for plasma protein binding of D01-4582, celecoxib, or mycophenolic acid. c.1075G>T and c.1422A>T were the most common single nucleotide polymorphisms in canine albumin, present concurrently in most study dogs and occasionally identified independently. Our findings suggest a potential influence of c.1075G>T and c.1422A>T on plasma protein binding. This influence should be confirmed in vivo and for additional drugs. Based on our results, albumin genotyping should be considered for canine research subjects to improve interpretation of pharmacokinetic data generated during the drug development process for humans and dogs.
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Desenvolvimento de Medicamentos/métodos , Ligação Proteica/genética , Albumina Sérica/genética , Alelos , Animais , Celecoxib/farmacocinética , Cães , Feminino , Masculino , Meloxicam/farmacocinética , Ácido Micofenólico/farmacocinética , Compostos de Fenilureia/farmacocinética , Polimorfismo de Nucleotídeo Único , Pirrolidinas/farmacocinética , Albumina Sérica/metabolismoRESUMO
Plasmodium infections result in clinical presentations that range from asymptomatic to severe malaria, resulting in â¼1 million deaths annually. Despite this toll on humanity, the factors that determine disease severity remain poorly understood. Here, we show that the gut microbiota of mice influences the pathogenesis of malaria. Genetically similar mice from different commercial vendors, which exhibited differences in their gut bacterial community, had significant differences in parasite burden and mortality after infection with multiple Plasmodium species. Germfree mice that received cecal content transplants from "resistant" or "susceptible" mice had low and high parasite burdens, respectively, demonstrating the gut microbiota shaped the severity of malaria. Among differences in the gut flora were increased abundances of Lactobacillus and Bifidobacterium in resistant mice. Susceptible mice treated with antibiotics followed by yogurt made from these bacterial genera displayed a decreased parasite burden. Consistent with differences in parasite burden, resistant mice exhibited an elevated humoral immune response compared with susceptible mice. Collectively, these results identify the composition of the gut microbiota as a previously unidentified risk factor for severe malaria and modulation of the gut microbiota (e.g., probiotics) as a potential treatment to decrease parasite burden.
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Microbioma Gastrointestinal , Malária/microbiologia , Animais , Antibacterianos/uso terapêutico , Bifidobacterium/isolamento & purificação , Bifidobacterium/fisiologia , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Interações Hospedeiro-Parasita/imunologia , Humanos , Lactobacillus/isolamento & purificação , Lactobacillus/fisiologia , Malária/parasitologia , Malária/terapia , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Plasmodium yoelii , Probióticos/uso terapêuticoRESUMO
Repeated administration of meloxicam can cause kidney damage in cats by mechanisms that remain unclear. Metabolomics and lipidomics are powerful, noninvasive approaches used to investigate tissue response to drug exposure. Thus, the objective of this study was to assess the effects of meloxicam on the feline kidney using untargeted metabolomics and lipidomics approaches. Female young-adult purpose-breed cats were allocated into the control (n = 4) and meloxicam (n = 4) groups. Cats in the control and meloxicam groups were treated daily with saline and meloxicam at 0.3 mg/kg subcutaneously for 17 days, respectively. Renal cortices and medullas were collected at the end of the treatment period. Random forest and metabolic pathway analyses were used to identify metabolites that discriminate meloxicam-treated from saline-treated cats and to identify disturbed metabolic pathways in renal tissue. Our results revealed that the repeated administration of meloxicam to cats altered the kidney metabolome and lipidome and suggest that at least 40 metabolic pathways were altered in the renal cortex and medulla. These metabolic pathways included lipid, amino acid, carbohydrate, nucleotide and energy metabolisms, and metabolism of cofactors and vitamins. This is the first study using a pharmacometabonomics approach for studying the molecular effects of meloxicam on feline kidneys.
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Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças do Gato/induzido quimicamente , Córtex Renal/efeitos dos fármacos , Medula Renal/efeitos dos fármacos , Meloxicam/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças do Gato/patologia , Gatos , Esquema de Medicação , Feminino , Metabolismo dos Lipídeos , Meloxicam/administração & dosagem , MetabolômicaRESUMO
Plasmodium remains a major pathogen causing malaria and impairing defense against other infections. Defining how Plasmodium increases susceptibility to heterologous pathogens may lead to interventions that mitigate the severity of coinfections. Previous studies proposed that reduced T cell responses during coinfections are due to diminished recruitment of naive T cells through infection-induced decreases in chemokine CCL21. We found that, although Listeria infections reduced expression of CCL21 in murine spleens, lymphocytic choriomeningitis virus (LCMV)-specific T cell responses were not impaired during Listeria + LCMV coinfection, arguing against a major role for this chemokine in coinfection-induced T cell suppression. In our experiments, Plasmodium yoelii infection led to a reduced CD8(+) T cell response to a subsequent Listeria infection. We propose an alternative mechanism whereby P. yoelii suppresses Listeria-specific T cell responses. We found that Listeria-specific T cells expanded more slowly and resulted in lower numbers in response to coinfection with P. yoelii. Mathematical modeling and experimentation revealed greater apoptosis of Listeria-specific effector T cells as the main mechanism, because P. yoelii infections did not suppress the recruitment or proliferation rates of Listeria-specific T cells. Our results suggest that P. yoelii infections suppress immunity to Listeria by causing increased apoptosis in Listeria-specific T cells, resulting in a slower expansion rate of T cell responses.
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Coinfecção/imunologia , Imunidade Celular , Listeria monocytogenes/imunologia , Listeriose/imunologia , Malária/imunologia , Plasmodium yoelii/imunologia , Linfócitos T/imunologia , Animais , Apoptose/imunologia , Quimiocina CCL21/genética , Quimiocina CCL21/imunologia , Coinfecção/genética , Coinfecção/microbiologia , Coinfecção/parasitologia , Coinfecção/patologia , Listeriose/genética , Listeriose/parasitologia , Listeriose/patologia , Malária/genética , Malária/microbiologia , Malária/patologia , Camundongos , Camundongos TransgênicosRESUMO
Cats and dogs can suffer from multiple autoimmune diseases. Mycophenolic acid (MPA) is a potentially useful immunosuppressant drug in cats and dogs, because of its well-documented efficacy in controlling autoimmune disease in humans. However, the pharmacokinetics and pharmacodynamics in these species remain to be determined. We have developed and validated a sensitive, precise, accurate and reproducible method that provides consistent quantification of MPA and its major derivatives, MPA phenol glucoside and MPA phenol glucuronide, in canine and feline plasma using ultra-high-pressure liquid chromatography coupled to an ultraviolet detector. The main advantages of this novel method include a small sample volume, easy sample preparation, a short chromatographic analysis time and the option to select either phenolphthalein ß-d-glucuronide or mycophenolic acid carboxybutoxy ether as internal standard. Results of validation indicate that this analytical method is suitable to study the plasma disposition of MPA and its derivatives in dogs and cats.
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Gatos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Cães/sangue , Glucuronídeos/sangue , Glicosídeos/sangue , Imunossupressores/sangue , Ácido Micofenólico/sangue , Animais , Gatos/metabolismo , Cães/metabolismo , Glucuronídeos/metabolismo , Glicosídeos/metabolismo , Imunossupressores/metabolismo , Limite de Detecção , Ácido Micofenólico/metabolismoRESUMO
OBJECTIVE: To describe a transthecal approach to the palmar pouch of the distal interphalangeal joint (DIPJ) in horses and compare it with the conventional blind arthroscopic technique. STUDY DESIGN: Ex vivo study. SAMPLE POPULATION: Cadaver forelimbs (n = 26 pairs) from mature horses. METHODS: One limb from each pair was randomly assigned to each arthroscopic approach (conventional or transthecal). The conventional arthroscopic approach was performed as previously described and the transthecal approach was performed through sharp dissection of the distal reflection of the digital flexor tendon sheath (DFTS). The proportion (0-100%) of the navicular bone, palmar aspect of the condyles of the 2nd phalanx, collateral sesamoidean ligaments, and palmar synovial pouches of the DIPJ visualized by each approach was estimated. Limbs were dissected and iatrogenic damage of relevant structures was assessed. Nondirectional Mann-Whitney U-test was used to compare groups. Significance was set at P < .05. RESULTS: The transthecal approach provided greater visualization of the navicular bone (P < .001), palmar aspect of the 2nd phalanx (P < .001), and palmar synovial pouches of the DIPJ (P < .001) than the conventional approach. There were no significant differences in iatrogenic damage between approaches. CONCLUSION: The transthecal approach provides improved visualization of the palmar aspect of the DIPJ compared to the conventional blind approach and may be useful in nonseptic conditions of the DIPJ. However, because of the creation of communication with the DFTS, use of the transthecal approach for suspected synovial sepsis of the DIPJ may be contraindicated.
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Artroscopia/veterinária , Membro Anterior/anatomia & histologia , Cavalos/anatomia & histologia , Articulação do Dedo do Pé/anatomia & histologia , Animais , Artroscopia/instrumentação , Artroscopia/métodos , CadáverRESUMO
INTRODUCTION: Silica-sprayed tubes (SSTs) are often used to transport synovial fluid samples in equine practice. They promote the coagulation of the sample. The objective of the study is to evaluate the effect of SST on bacterial culture. MATERIALS AND METHODS: The study was divided into two parts: sterile saline (Part A) and synovial fluid (Part B). Four common bacteria associated with equine synovial sepsis were used: Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Three collection tubes were used: STT, plain (no-additives) and brain and heart infusion (BHI) broth. Bacteria were cultured in horse blood agar plates for 48 h. Outcome variables were negative culture, positive culture and total number of colony-forming units (CFUs). Statistical analysis was performed using Mann-Whitney U test, and significance was set at p < 0.05. RESULTS: The total number of agar plates read was 1557 (779 saline; 778 synovial fluid). Total negative cultures were 25/779 on saline and 3/778 on synovial fluid. In broth, maximum growth CFU was achieved after 8 h for both saline and synovial fluid for all bacteria. S. pyogenesand E. coli produced a significantly lower number of CFU when in SST compared to plain or broth after 4 h, whereas S. aureus (American Type Culture Collection [ATCC] and MRSA) only after 24 h. DISCUSSION: Silica-containing tubes reduced bacterial proliferation, whereas the use of a BHI broth provided the highest bacterial load in the sample. The use of SST may have a negative effect on bacterial proliferation in samples obtained from clinical cases.
Assuntos
Dióxido de Silício , Líquido Sinovial , Líquido Sinovial/microbiologia , Animais , Cavalos , Dióxido de Silício/química , Manejo de Espécimes/métodos , Manejo de Espécimes/veterinária , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Staphylococcus aureus/isolamento & purificação , Técnicas Bacteriológicas/veterinária , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificaçãoRESUMO
Introduction: Serum symmetric dimethylarginine (SDMA) and creatinine are commonly used biomarkers of renal function in cats. We hypothesize that the serum analytes creatinine and SDMA are equally effective at detecting impaired renal function caused by meloxicam-induced renal injury in cats. Our primary objective was to compare serum concentrations of SDMA and creatinine in cats before, during, and after induction of renal injury from repeated dosages of meloxicam in the context of a small pilot study. Methods: This follow-up study results from data collected in a well-controlled study that included 12 healthy female adult purpose-bred cats. Cats in the treatment group received meloxicam 0.3 mg/kg subcutaneously (SC) every 24 h for 31 days. Cats in the control group received saline (0.1 mL SC). Renal injury was defined as the presence of tubular damage, basement membrane damage, and/or interstitial inflammation in histological sections of kidney tissue. Serum creatinine and SDMA concentration were measured every 4 days. Results: In the control group, no cats developed renal azotemia. In the treatment group, four out of six cats developed elevated serum creatinine and histopathological evidence of renal injury. Three of these cats developed an elevation in serum SDMA. The time to the development of renal azotemia using serum creatinine or SDMA was not significantly different (p > 0.05). Discussion: In this pilot study, there was no evidence that serum SDMA was superior to serum creatinine at detecting impaired renal function caused by meloxicam-induced renal injury in cats.
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BACKGROUND: Theileria haneyi is one of the three known causative agents of equine piroplasmosis. While imidocarb is generally effective in the clearance of the highly pathogenic Theileria equi, it is ineffective in the treatment of T. haneyi. Moreover, co-infection with T. haneyi has been shown to impede the successful treatment of T. equi. Furthermore, tulathromycin and diclazuril have demonstrated inefficacy in eradicating T. haneyi. The absence of an effective therapeutic agent against this parasite represents a significant obstacle in managing equine piroplasmosis. METHODS: To address this issue, we evaluated the efficacy of buparvaquone in the treatment of T. haneyi in chronically infected horses. RESULTS: Our findings showed that treatment of horses with the recommended dose of 2.5 mg/kg of buparvaquone led to a rapid abatement of T. haneyi levels, to a level where the parasites were not detectable by nested PCR. Following treatment, the horses remained PCR negative for a minimum of seven weeks until recrudescence occurred. Subsequent re-administration of buparvaquone at an increased dosage of 6 mg/kg upon recrudescence failed to exert a theilericidal effect on T. haneyi. Throughout the treatment regimen, the hematological parameters of the horses and most components of the chemistry panel remained within the normal range, except for blood urea nitrogen levels, which fell below the normal range in certain instances. CONCLUSIONS: BPQ at 2.5 mg/kg and 6 mg/kg had a robust theilericidal effect but was ineffective in the clearance of the T. haneyi infection in persistently infected animals.
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Antiprotozoários , Doenças dos Cavalos , Naftoquinonas , Theileria , Theileriose , Animais , Theileriose/tratamento farmacológico , Theileriose/parasitologia , Cavalos , Theileria/efeitos dos fármacos , Doenças dos Cavalos/tratamento farmacológico , Doenças dos Cavalos/parasitologia , Naftoquinonas/uso terapêutico , Naftoquinonas/farmacologia , Naftoquinonas/administração & dosagem , Antiprotozoários/uso terapêutico , Antiprotozoários/administração & dosagem , Resultado do Tratamento , Doença Crônica , MasculinoRESUMO
Introduction: Theileria orientalis, an economically significant tick-borne hemoparasite, infects cattle globally. The T. orientalis Ikeda genotype, transmitted by Haemaphysalis longicornis ticks, is associated with clinical manifestations characterized by anemia, abortions, and mortality, although subclinical infections prevail. Despite the common occurrence of subclinical infections, therapeutic interventions targeting T. orientalis Ikeda in such cases are currently lacking, impeding effective parasite control measures. To address this critical knowledge gap, we assessed the efficacy of buparvaquone (BPQ) in eliminating the T. orientalis Ikeda, US isolate, in sub-clinically infected cattle. Methods: Twelve sub-clinically infected calves, identified by the presence of T. orientalis in peripheral blood alongside the absence of fever and anemia, were enrolled in the study. Six calves received two treatments of the BPQ label dose (2.5 mg/kg) at a 48-h interval, while additional three calves received the drug at a dosage of 6 mg/kg following the same regimen. Three untreated calves served as controls. Results and discussion: Endpoint and quantitative PCR analyses revealed that BPQ exerted a transient effect on T. orientalis parasitemia. Parasites remained undetectable in peripheral blood until weeks 4 and 11 post-treatment in animals administered 2.5 mg/kg and 6 mg/kg of BPQ, respectively. Intriguingly, following recrudescence, administering 6 mg/kg to animals previously treated with 2.5 mg/kg did not result in a reduction in parasite load. Pharmacokinetic analysis data suggested that escalating the dosage led to a less than proportional increase in serum concentrations of BPQ. Moreover, a significant yet reversible decrease (p < 0.05) in blood urea nitrogen was observed in animals treated with the drug, irrespective of the dosage. Despite parasitemia relapse, animals treated with 6 mg/kg BPQ exhibited a noteworthy decrease (p < 0.05) in IgG levels specific to the T. orientalis major piroplasm surface protein compared to controls and animals treated with 2.5 mg/kg of the drug. Conclusion: BPQ did not demonstrate efficacy in clearing subclinical T. orientalis Ikeda infection. Future investigations are warranted to explore innovative therapeutic modalities that, in synergy with vaccines and diagnostic assays, can facilitate the development of comprehensive programs aimed at controlling and eradicating this parasite.
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Introduction: B. bovis is an apicomplexan parasite responsible for bovine babesiosis, a tick-borne disease with a worldwide impact. The disease remains inefficiently controlled, and few effective drugs, including imidocarb dipropionate (ID), are currently available in endemic areas. The objective of this study was to evaluate whether buparvaquone (BPQ), a drug currently used to treat cattle infected with the Babesia-related Theileria spp. parasites, could be active against Babesia parasites. Herein, we compared the effect of ID and BPQ on B. bovis growth in vitro erythrocyte culture. Methods: We compared the effect of ID and BPQ on the culture-adapted Texas T2Bo strain of B. bovis. In vitro cultured parasites were incubated with ID and BPQ at two starting parasitemia levels (PPE), 0.2% and 1%. In vitro cultured parasites were treated with ID or BPQ at concentrations ranging from 10 to 300 nM, during 4 consecutive days. Parasitemia levels were daily evaluated using microscopic examination. Data was compared using the independent Student's t-test. Results and discussion: Both ID and BPQ significantly inhibited (p < 0.05) the growth of B. bovis, regardless of the initial parasitemia used. At 1% parasitemia, BPQ had lower calculated inhibitory concentration 50 (IC50: 50.01) values than ID (IC50: 117.3). No parasites were found in wells with 0.2% starting parasitemia, treated previously with 50 nM of BPQ or ID, after 2 days of culture without drugs. At 1% parasitemia, no parasite survival was detected at 150 nM of BPQ or 300 nM of ID, suggesting that both drugs acted as babesiacidals. Conclusion: Overall, the data suggests that BPQ is effective against B. bovis and shows a residual effect that seems superior to ID, which is currently the first-line drug for treating bovine babesiosis globally.
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Background: Acetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined. Objective: The objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles. Study design: Randomized study. Methods: Eight clinically healthy 7-9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis. Results: The median peak plasma concentrations (and range) occurred at 1.5 (0.5-2) hours, and 1.0 (1-2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9-17.4) µg/mL for the 20 mg/kg dose and 14 (11-18) µg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-µg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits. Conclusion: Plasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.
RESUMO
OBJECTIVE: To determine the pharmacokinetics and clinical safety of acetaminophen after oral administration of 40 mg/kg q 12 hours or 60 mg/kg q 24 hours for 14 days. ANIMALS: 12 healthy light-breed neonatal foals. PROCEDURES: 6 foals received acetaminophen at 40 mg/kg q 12 hours and 6 foals received 60 mg/kg q 24 hours for 14 days. The study dates were January 31 to April 15, 2023. Physical examinations were performed daily. Plasma disposition of acetaminophen was determined after the first, mid-point drug administration. Hematology and biochemistry analysis was performed before the study, day 7, and the last day of drug administration. Plasma acetaminophen concentrations were determined by high-performance liquid chromatography. Plasma pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS: No statistically significant changes occurred on hematology or biochemistry profiles. Elevations in γ-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were noted in 4 foals at various time points. The maximum plasma concentration (Cmax) occurred within 2 hours for both doses. The 60 mg/kg dose resulted in a larger median Cmax (range) at 28 µg/mL (22-32) than the 40 mg/kg dose at 23 µg/mL (19-27). The median area under the concentration-vs-time curve from 0 to 8 hours (AUC0-8 hour [range]) was 100 h⢵g/mL (82-100) at 40 mg/kg and 128 h⢵g/mL (120-168) for 60 mg/kg. Trough concentrations decreased over time for both regimens. CLINICAL RELEVANCE: Foals tolerate oral acetaminophen at 40 mg/kg q 12 hours or 60 mg/kg q 24 hours. Further analgesic and antipyretic studies will help to delineate optimal dosage regimens of acetaminophen to treat foals.