RESUMO
Imidacloprid (IDP) is an active ingredient of the Admire brand pesticide used to control the vector (Asian citrus psyllid) that transmits the causative organism Candidatus Liberibacter asiaticus (CLas) for citrus greening or huanglongbing disease. Imidacloprid products are applied via soil drench where citrus roots are mostly concentrated which is between 0 and 60 cm depth. These soil depths exhibit different characteristics that may affect IDP leaching beyond the rooting zone. Representative soil samples were collected from Entisols and Ultisols, which are the dominant soil orders under citrus production in central Florida, at 15 cm increments up to 60 cm to estimate and understand the batch sorption, kinetics, equilibria, and degradation of IDP. Results showed that the equilibrium time for IDP at 0-15 cm depth (10 hours) was 2 times faster than at 15-60 cm (20 hours) for the Entisol. Nevertheless, all depths reached equilibrium within 24 hours for the Entisol. The 0-30 cm depth adsorbed 2 times more IDP than the 30-60 cm depth for both soils. Nevertheless, the adsorption coefficient was approximately ≤ 1 mL g-1 for both soils. The half-life of IDP in both soils ranged from 10 to 17 days. The Entisol showed higher adsorption than the Ultisol at both depths, probably due to relatively lower organic carbon (OC) content in the Ultisol compared to the Entisol. Thus, the Ultisol showed high IDP leaching vulnerability compared to the Entisol. Movement of IDP is affected by the amount of OC in the citrus critical zone.
Assuntos
Citrus , Neonicotinoides , Nitrocompostos , Poluentes do Solo , Solo , Neonicotinoides/química , Neonicotinoides/metabolismo , Nitrocompostos/química , Nitrocompostos/metabolismo , Florida , Solo/química , Adsorção , Poluentes do Solo/química , Poluentes do Solo/metabolismo , Citrus/química , Cinética , Meia-Vida , Inseticidas/química , Inseticidas/metabolismo , Imidazóis/química , Imidazóis/metabolismoRESUMO
Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.
Assuntos
Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Adulto , Masculino , Método Duplo-Cego , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Relação Dose-Resposta a Droga , Epóxido Hidrolases/antagonistas & inibidores , Jejum/sangue , Adolescente , Administração Oral , Meia-VidaRESUMO
INTRODUCTION: Ulcerative colitis is a chronic inflammatory bowel disease, affecting the colorectal mucosae, with a relapsing-remitting course, characterized by the trafficking and gathering of lymphocytes in the inflammatory intestinal mucosa. Sphingosine-1-phosphate (S1P) receptor modulators preventing lymphocytes egress from lymphoid tissues to the active inflammation site is an alternative therapeutic option in this condition. AREA COVERED: We carried out a comprehensive review of the literature available on Medline, Scopus and Embase regarding the pharmacokinetics of S1P receptor modulators. For each compound, we reviewed the mechanism of action, pharmacokinetic data and efficacy and safety data from phase 3 studies and real-life studies when available. EXPERT OPINION: S1P receptor modulators, including ozanimod and etrasimod (both currently on the market) as well as VTX002 (under development), are a new class of drugs for the treatment of moderate to severe ulcerative colitis, inducing and maintaining the remission. Due to its pharmacokinetic features, this class of drugs has certain advantages such as an oral administration, a short half-life, a high volume of distribution, and no immunogenicity. On the other hand, there are risks of cardiological and ophthalmological side-effects, as well as drug-drug interactions risk, that require special attention from the healthcare providers.
Assuntos
Colite Ulcerativa , Moduladores do Receptor de Esfingosina 1 Fosfato , Humanos , Colite Ulcerativa/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacocinética , Moduladores do Receptor de Esfingosina 1 Fosfato/administração & dosagem , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversos , Animais , Oxidiazóis/farmacocinética , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacologia , Oxidiazóis/efeitos adversos , Meia-Vida , Índice de Gravidade de Doença , Interações Medicamentosas , Mucosa Intestinal/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Linfócitos/metabolismo , Linfócitos/efeitos dos fármacos , IndanosRESUMO
Agonists of thyroid hormone receptor ß (THR-ß) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent and selective compound ALG-055009 (14) as a potential best in class THR-ß agonist. The high metabolic stability and good permeability translated well in vivo to afford a long in vivo half-life pharmacokinetic profile with limited liability for DDI, and it overcomes certain drawbacks seen in recent clinical candidates.
Assuntos
Receptores beta dos Hormônios Tireóideos , Receptores beta dos Hormônios Tireóideos/agonistas , Receptores beta dos Hormônios Tireóideos/metabolismo , Humanos , Animais , Ratos , Relação Estrutura-Atividade , Masculino , Descoberta de Drogas , Camundongos , Meia-VidaRESUMO
Matrix metalloproteinases (MMPs) are significant drivers of many diseases, including cancer, and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties for drug candidates, such as complete MMP inhibition, low toxicity, low immunogenicity, and high tissue permeability. However, a major challenge with TIMPs is their rapid clearance from the bloodstream due to their small size. This study explores a method for extending the plasma half-life of the N-terminal domain of TIMP2 (N-TIMP2) by appending it with a long, intrinsically unfolded tail containing Pro, Ala, and Thr (PATylation). We designed and produced two PATylated N-TIMP2 constructs with tail lengths of 100 and 200 amino acids (N-TIMP2-PAT100 and N-TIMP2-PAT200). Both constructs demonstrated higher apparent molecular weights and retained high inhibitory activity against MMP-9. N-TIMP2-PAT200 significantly increased plasma half-life in mice compared to the non-PATylated variant, enhancing its therapeutic potential. PATylation offers distinct advantages for half-life extension, such as fully genetic encoding, monodispersion, and biodegradability. It can be easily applied to N-TIMP2 variants engineered for high affinity and selectivity toward individual MMPs, creating promising candidates for drug development against MMP-related diseases.
Assuntos
Metaloproteinase 9 da Matriz , Inibidor Tecidual de Metaloproteinase-2 , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/química , Animais , Meia-Vida , Camundongos , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Peptídeos/química , Peptídeos/farmacologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/química , Desdobramento de Proteína/efeitos dos fármacosAssuntos
Antipsicóticos , Síndrome Maligna Neuroléptica , Humanos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Síndrome Maligna Neuroléptica/diagnóstico , Síndrome Maligna Neuroléptica/epidemiologia , Síndrome Maligna Neuroléptica/etiologia , Síndrome Maligna Neuroléptica/terapia , Haloperidol/administração & dosagem , Haloperidol/efeitos adversos , Haloperidol/farmacocinética , Variantes Farmacogenômicos , Receptores de Dopamina D2/metabolismo , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/efeitos adversos , Antagonistas dos Receptores de Dopamina D2/farmacocinética , Receptores de Dopamina D4/antagonistas & inibidores , Receptores de Dopamina D4/metabolismo , Diagnóstico Diferencial , Meia-VidaRESUMO
INTRODUCTION: Rapid excretion of drug derivatives often results in short drug half-lives, necessitating frequent administrations. Catalytic compartments, also known as nano- and microreactors, offer a solution by providing confined environments for in situ production of therapeutic agents. Inspired by natural compartments, polymer-based catalytic compartments have been developed to improve reaction efficiency and enable site-specific therapeutic applications. AREAS COVERED: Polymer-based compartments provide stability, permeability control, and responsiveness to stimuli, making them ideal for generating localized compounds/signals. These sophisticated systems, engineered to carry active compounds and enable selective molecular release, represent a significant advancement in pharmaceutical research. They mimic cellular functions, creating controlled catalytic environments for bio-relevant processes. This review explores the latest advancements in synthetic catalytic compartments, focusing on design approaches, building blocks, active molecules, and key bio-applications. EXPERT OPINION: Catalytic compartments hold transformative potential in precision medicine by improving therapeutic outcomes through precise, on-site production of therapeutic agents. While promising, challenges like scalable manufacturing, biodegradability, and regulatory hurdles must be addressed to realize their full potential. Addressing these will be crucial for their successful application in healthcare.
Assuntos
Sistemas de Liberação de Medicamentos , Polímeros , Humanos , Catálise , Polímeros/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/administração & dosagem , Medicina de Precisão , Animais , Meia-Vida , Desenho de FármacosRESUMO
The pharmacokinetic profile of selected NSAIDs in southern black rhinoceros (Diceros bicornis minor) were studied. Phenylbutazone (PBZ), meloxicam (MEL), and firocoxib (FIR) were administered orally to five captive, black rhinoceros, and blood was collected at predetermined time points for NSAID quantification and noncompartmental pharmacokinetic (PK) analysis. Phenylbutazone 4.0 mg/kg PO q12h for three doses, MEL 0.3 mg/kg PO q24h administered twice, and a single oral dose of FIR 0.1 mg/kg, were tested with a minimum washout time of 2 wk. PBZ reached a median (range) peak concentration (Cmax) of 9.42 (2.74-11.5) g/ml at a mean (range) time (Tmax) of 6.00 (4.00 to >12.00) h, and the median (range) elimination half-life (T1/2) was 6.07 (3.95-6.49) h. Phenylbutazone pharmacokinetic parameters for black rhinoceros in this study were similar to domestic horses. Meloxicam reached a median (range) Cmax of 0.576 (0.357-0.655) µg/ml at a median (range) time (Tmax) of 6.00 (4.00-12.00) h; the median (range) T1/2 of MEL was 14.0 (12.4-17.9) h. These results demonstrate that once-daily administration of MEL at 0.3 mg/kg resulted in a serum concentration of greater than 0.200 µg/ml from 2 to 24 h in four animals, which is within the analgesic range (0.200-0.400 µg/ml) for this drug in other species postulated by other studies. A single dose of firocoxib (0.1 mg/kg) reached a median (range) peak concentration (Cmax) of 15.7 (9.65-17.3) ng/ml at a median (range) Tmax of 4.00 (4.00-6.00) h. The median (range) elimination T1/2 of FIR was 4.96 (4.47-6.51) h, which is faster than in the horse. The data suggest that extrapolation from equine FIR dosage recommendations is inappropriate for black rhinoceros.
Assuntos
4-Butirolactona , Anti-Inflamatórios não Esteroides , Meloxicam , Perissodáctilos , Fenilbutazona , Sulfonas , Animais , Meloxicam/farmacocinética , Meloxicam/administração & dosagem , Meloxicam/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , 4-Butirolactona/farmacocinética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/administração & dosagem , 4-Butirolactona/sangue , Perissodáctilos/sangue , Fenilbutazona/farmacocinética , Fenilbutazona/administração & dosagem , Fenilbutazona/sangue , Masculino , Feminino , Meia-Vida , Sulfonas/farmacocinética , Sulfonas/administração & dosagem , Sulfonas/sangue , Administração Oral , Área Sob a CurvaRESUMO
Cefpodoxime proxetil is commonly used to treat cetacean patients with suspected or confirmed bacterial infections; however, pharmacokinetic data are needed to guide proper dosing in these species. Cefpodoxime proxetil is a time-dependent, semisynthetic, third-generation cephalosporin, appropriate for once-daily dosing and U.S. Food and Drug Administration-approved for use in dogs with a broad spectrum of activity including gram-positive and gram-negative species. The objective of this study was to evaluate the population pharmacokinetics of cefpodoxime in bottlenose dolphins (Tursiops truncatus). A sparse-sampling design was used, with serum from dolphins receiving cefpodoxime proxetil at 10 mg/kg orally every 24 h to treat suspected or confirmed bacterial infections. Serum samples (n = 57) from 24 dolphins were analyzed at 12 time points from 0 to 96 h postdose. Serum samples were analyzed using liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment linear models with first order absorption were tested. Covariates including weight, age, and sex were considered for inclusion in the model, and between-subject variability was incorporated. A two-compartment model performed best, where following an oral dose of 10 mg/kg, serum concentration reached a mean maximum concentration of 23.0 µg/ml, mean time to maximum concentration of 5.0 h, and mean half-life of 11.4 h. With daily dosing, accumulation was approximately 18% and steady state was reached by the second dose. Serum protein binding was 82.8% as determined by equilibrium dialysis, similar to plasma protein binding reported in dogs. Based on the population pharmacokinetic model, once-daily oral dosing was systemically absorbed and quickly reached maximum concentrations. The half-life in dolphins appears to be longer than other species studied to date. Given the paucity of antimicrobial pharmacokinetic studies in dolphins, and limited once-daily oral antibiotic options for this species, these data are helpful for clinicians to make informed antimicrobial choices.
Assuntos
Antibacterianos , Golfinho Nariz-de-Garrafa , Animais , Golfinho Nariz-de-Garrafa/sangue , Feminino , Antibacterianos/farmacocinética , Antibacterianos/sangue , Antibacterianos/administração & dosagem , Masculino , Meia-Vida , Ceftizoxima/farmacocinética , Ceftizoxima/análogos & derivados , Ceftizoxima/administração & dosagem , Ceftizoxima/sangue , Cefpodoxima , Área Sob a CurvaRESUMO
Objective: The aim of this study was to determine the plasma pharmacokinetics of oxytetracycline (OTC) in rainbow trout (Oncorhynchus mykiss) of different body sizes. Methods: The research was carried out on three groups as small (30-50 g), medium (90-110 g) and large (185-215 g) body sizes at 8 ± 0.5 °C. OTC was administered orally at a dose of 60 mg/kg to all groups. Blood samples were taken at 19 different sampling times until the 384 h after oxytetracycline administration. The plasma concentrations of OTC were measured using high pressure liquid chromatography-ultraviolet and pharmacokinetic parameters were evaluated using non-compartmental analysis. Results: OTC was detected in small-body sized fish until the 336 h and in medium and large-body sized fish until the 384 h. The elimination half-life of OTC was 85.46, 87.24 and 86.98 h in the small, medium and large body size groups, respectively. The peak plasma concentration increased from 0.66 to 1.11 µg/mL, and the area under the plasma concentration-versus time curve from zero (0) h to infinity (∞) increased from 87.86 to 151.52 h*µg/mL, in tandem with the increase in fish body size. As fish body size increased, volume of distribution and total body clearance decreased. Conclusion: These results show that the pharmacokinetics of OTC vary depending on fish size. Therefore, there is a need to reveal the pharmacodynamic activity of OTC in rainbow trout of different body sizes.
Assuntos
Antibacterianos , Tamanho Corporal , Oncorhynchus mykiss , Oxitetraciclina , Animais , Oncorhynchus mykiss/metabolismo , Oxitetraciclina/farmacocinética , Oxitetraciclina/sangue , Oxitetraciclina/administração & dosagem , Administração Oral , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Meia-Vida , Cromatografia Líquida de Alta PressãoRESUMO
The objective of this phase 1 single-dose study was to evaluate the safety, tolerability, and pharmacokinetics of mirikizumab in Chinese healthy adults. Sixty participants were randomized within 5 planned dose cohorts: intravenous (IV) 300 mg, IV 600 mg, IV 1200 mg, subcutaneous (SC) 200 mg, and SC 400 mg to receive mirikizumab (10 participants in each cohort) or placebo (2 participants in each cohort). No death or serious adverse events occurred. Twenty-eight (56.0%) participants who received mirikizumab reported 49 treatment-emergent adverse events (TEAEs) and 8 (80.0%) participants who received placebo reported 18 TEAEs. The majority of TEAEs were mild in severity. Following IV 300-1200 mg mirikizumab, the arithmetic mean of both area under the concentration versus time curve from time 0 to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) increased by approximately 3.5-fold, and the arithmetic mean half-life (t1/2) ranged from 9.64 to 12.0 days. Following SC 200 and 400 mg mirikizumab, the arithmetic mean of both AUC0-∞ and Cmax increased by approximately 1.6-fold, the median time to Cmax (tmax) was 2.98 days for both, and the arithmetic mean t1/2 was 10.6 and 10.5 days, respectively. Absolute bioavailability based on pooled SC and IV dose data was 38.2%. In this study, the safety and pharmacokinetic profile of mirikizumab were consistent with what has been reported in other studies.
Assuntos
Área Sob a Curva , Voluntários Saudáveis , Humanos , Masculino , Adulto , Feminino , Injeções Subcutâneas , Meia-Vida , Adulto Jovem , Povo Asiático , Método Duplo-Cego , Relação Dose-Resposta a Droga , Pessoa de Meia-Idade , China , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Administração IntravenosaRESUMO
The chemical UV filter 2-ethylhexyl salicylate (EHS) is used in various personal-care products. The dermal and oral metabolism of EHS have already been targeted by different studies. However, toxicokinetic data after a single dermal exposure to EHS was missing. In our study, three volunteers were dermally exposed to a commercial EHS-containing sunscreen for 9 h with an application dose of 2 mg sunscreen per cm2 body surface area. The exposure was performed indoors, and sunscreen was applied on about 75% of the total skin area. Complete urine voids were collected over 72 h and eight blood samples were drawn from each subject. Urine samples were analyzed for EHS and seven known metabolites (5OH-EHS, 4OH-EHS, 2OH-EHS, 6OH-EHS, 4oxo-EHS, 5oxo-EHS, and 5cx-EPS) by online-SPE UPLC MS/MS. The peaks of urinary elimination occurred 10-11 h after application. The elimination half-lives (Phase 1) were between 6.6 and 9.7 h. The dominant urinary biomarkers were EHS itself, followed by 5OH-EHS, 5cx-EPS, 5oxo-EHS, and 4OH-EHS. 2OH-EHS, 6OH-EHS, and 4oxo-EHS were detected only in minor amounts. An enhanced analysis of conjugation species revealed marginal amounts of unconjugated metabolites and up to 40% share of sulfate conjugates for 5OH-EHS, 5oxo-EHS, and 5cx-EPS. The results demonstrated a delayed systemic resorption of EHS via the dermal route. Despite an extensive metabolism, the parent compound occurred as main urinary parameter. The delayed dermal resorption as well as the slow elimination of EHS indicate an accumulation up to toxicological relevant doses during daily repeated dermal application to large skin areas.
Assuntos
Administração Cutânea , Salicilatos , Protetores Solares , Toxicocinética , Humanos , Salicilatos/farmacocinética , Salicilatos/toxicidade , Protetores Solares/farmacocinética , Protetores Solares/toxicidade , Protetores Solares/administração & dosagem , Protetores Solares/metabolismo , Adulto , Masculino , Espectrometria de Massas em Tandem , Feminino , Meia-Vida , Absorção Cutânea , Pele/metabolismo , Pele/efeitos dos fármacosRESUMO
Imatinib is an oral molecular targeted therapy that acts as a tyrosine kinase inhibitor. Silkworms present a promising experimental model for elucidating the pharmacokinetic and toxicity profiles of various compounds. This study aimed to establish an experimental paradigm for investigating the pharmacokinetics of imatinib in silkworms. A comparative analysis of imatinib pharmacokinetic parameters across silkworms, humans, mice, and rats revealed similarities in time to maximum concentration (Tmax) and apparent clearance values between silkworms and humans. However, differences in elimination half-life (t1/2) and apparent volume of distribution between silkworms and humans remained within 5- and 4-fold ranges, respectively. Importantly, mice demonstrated pharmacokinetic parameters closer to those of humans than rats during imatinib studies. Additionally, silkworms and mice exhibit similar Tmax and t1/2 values. This study highlights the potential of silkworms as valuable tools for investigating imatinib metabolism in pharmacokinetic studies. Furthermore, it underscores the applicability of silkworms in elucidating the pharmacokinetic parameters of various molecular-targeted drugs, thus facilitating advancements in drug development and evaluation.
Assuntos
Antineoplásicos , Bombyx , Mesilato de Imatinib , Mesilato de Imatinib/farmacocinética , Animais , Antineoplásicos/farmacocinética , Camundongos , Humanos , Meia-Vida , Ratos , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Modelos AnimaisRESUMO
Sulfonamides (S) are old bacteriostatic antibiotics which are widely prescribed in combination with trimethoprim (TMP) for the treatment of various diseases in food-producing animals such as poultry. Nowadays, the 1:5 dose ratio of TMP/S used in broilers is a direct transposition of the ratio determined in Human decades ago for TMP/sulfamethoxazole (SMX), aiming to obtain a supposed synergistic plasma concentration ratio of 1:19. However, major pharmacokinetics (PK) differences exist according to the sulfonamide used in the combination. Here, we generated new PK data in broilers after a cross-over design with IV and the oral administration of 2 major sulfonamides, sulfadiazine (SDZ) and SMX, in combination with TMP, and analyzed the data via a population pharmacokinetic (popPK) modeling approach. Results showed that TMP has a greater plasma to tissue distribution than both sulfonamides with a higher volume of distribution (0.51 L/kg for SDZ, 0.62 L/kg for SMX and 3.14 L/kg for TMP). SMX has the highest elimination half-life (2.83 h) followed by SDZ and TMP (2.01 h and 1.49 h, respectively). The oral bioavailability of the 3 molecules was approximately 100%. Bodyweight could explain some of the inter-individual variability in the volume of distribution of SDZ and SMX and the clearance of SDZ and TMP, as heavier broilers have higher typical values. Monte Carlo simulations of a large virtual broiler population (n = 1,000) showed that the targeted plasma ratio of TMP:S of 1:19 was rarely or never reached at the individual level for both combinations at the marketed doses and greatly varies over time and between individuals, questioning the relevance of the 1:5 dose ratio for current formulations of TMP/S.
Assuntos
Galinhas , Sulfadiazina , Combinação Trimetoprima e Sulfametoxazol , Trimetoprima , Animais , Galinhas/metabolismo , Sulfadiazina/farmacocinética , Sulfadiazina/administração & dosagem , Trimetoprima/farmacocinética , Trimetoprima/administração & dosagem , Combinação Trimetoprima e Sulfametoxazol/farmacocinética , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Administração Oral , Combinação de Medicamentos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Estudos Cross-Over , Masculino , Modelos Biológicos , Meia-Vida , Feminino , BenzenossulfonamidasRESUMO
Knowledge of amoxicillin (AMX) pharmacokinetics (PK) and tissue residues in fish, which is necessary for prudent drug use, remains limited. The study aimed to explore the PK characteristics of AMX in Nile tilapia (Oreochromis niloticus) reared at 25 and 30 °C as well as to determine optimal dosages and drug withdrawal time (WDT). In the PK investigation, the fish received a single dose of 40 mg/kg AMX via oral gavage, and the optimal dosage was determined by the pharmacokinetic-pharmacodynamic approach. In the tissue residue study, the fish were orally gavaged with 40 mg/kg/day AMX once daily for 5 days and the WDT was established by the linear regression analysis. The results revealed the temperature-dependent drug elimination; the clearance relative to bioavailability (CL/F) and elimination half-life at 30 °C (0.180 L/kg/h and 6.06 h, respectively) were about twice those at 25 °C (0.090 L/kg/h and 10.49 h, respectively). The optimal dosages at the minimum inhibitory concentration (MIC) of 2 µg/mL were 10.97 (25 °C) and 41.03 (30 °C) mg/kg/day, respectively. Finally, following the multiple oral administration, the muscle/skin residue of AMX on day 1 after the last dosing at 25 and 30 °C were 548 and 264 ng/g, respectively. The average tissue residues were depleted below the maximum residue limits (MRL) of 50 µg/kg on day 5 (25 °C) and 3 (30 °C), respectively, and the WDT were 6 and 4 days when rearing at 25 and 30 °C, respectively. This knowledge serves as a practical guideline for responsible use of AMX in treating bacterial diseases in Nile tilapia aquaculture.
Assuntos
Amoxicilina , Antibacterianos , Ciclídeos , Temperatura , Animais , Amoxicilina/farmacocinética , Amoxicilina/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Resíduos de Drogas , Testes de Sensibilidade Microbiana , Meia-Vida , Relação Dose-Resposta a DrogaRESUMO
Robenacoxib (RX) is a non-steroidal anti-inflammatory drug (NSAID) of the coxib class. This study aimed to evaluate the plasma dispositions and faecal excretion profiles of RX in Alpine and Saanen goats following oral and subcutaneous routes. Two different goat breeds were allocated into two treatment groups concerning the breed. RX was administered subcutaneously to animals at a dose of 4â¯mg/kg b.w. Following a one-week washout period, RX was administered by oral route to the same animals at the same dose. Heparinized blood samples were collected from all animals before drug administration (0â¯h) and subsequently up to 24â¯h. Faecal samples were collected at various times between 8â¯h and 36â¯h. The concentrations of RX in plasma and faeces were determined by HPLC. The plasma half-life (T1/2λz) of RX in Saanen goats (1.21â¯h) was significantly longer (P < 0.017) than in Alpine goats (0.90â¯h) after subcutaneous administration. In both goat breeds, statistical differences were observed between subcutaneous and oral administration of RX for T1/2λz, Tlast, Cmax, AUC0-∞, and MRT0-∞. Faecal Cmax and Tmax parameters following oral administrations were 0.92⯵g/g and 0.85⯵g/g at 30â¯h and at 24â¯h in Alpine and Saanen goats, respectively. The difference in plasma protein ratio between Alpine and Saanen goats may have affected the T1/2λz of the drug. NSAIDs are among the drug groups frequently detected in aquatic and terrestrial ecosystems around the world and there are data on the effects of NSAID residues on wildlife and aquatic species. Therefore, revealing the excretion of NSAIDs, which are frequently used in the veterinary field, in faeces and urine should be considered for ecological sustainability.
Assuntos
Anti-Inflamatórios não Esteroides , Fezes , Cabras , Fenilacetatos , Animais , Cabras/metabolismo , Cabras/sangue , Fezes/química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Injeções Subcutâneas/veterinária , Administração Oral , Fenilacetatos/farmacocinética , Fenilacetatos/sangue , Fenilacetatos/administração & dosagem , Meia-Vida , Difenilamina/farmacocinética , Difenilamina/análogos & derivados , Difenilamina/administração & dosagem , Feminino , Masculino , Área Sob a CurvaRESUMO
This study investigates the pharmacokinetics (PK) of montelukast (MTK), a cysteinyl leukotriene receptor antagonist increasingly being considered in veterinary medicine. In dogs, MTK has found indications mainly for treating atopic dermatitis as an off-label use. Six male Labrador dogs underwent a single oral administration of MTK (40â¯mg/dog) in both fasted and fed conditions according to an open, single-dose, two-treatment, two-phase, cross-over design, with a washout period of one week. Blood was withdrawn to heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24â¯hr. MTK plasma concentrations were quantified using a validated HPLC method, and the data were analysed using PKanalix™ software with a non-compartmental approach. Concentrations remained quantifiable at 24â¯hr after administration, under both conditions. No significant differences were observed in the PK parameters between the fasted and fed states. MTK was relatively eliminated slowly, with t1/2 values of 8.10 and 7.68â¯hr after fasted and fed states, respectively. The attainment of maximum concentration (Cmax) occurred at a Tmax of 4â¯hr, with mean values of 1.98⯵g/mL and 2.80⯵g/mL under fasted and fed conditions, respectively. Given the unknown therapeutic range of MTK in dogs and the absence of controlled studies proving its efficacy in this species, further dosing adjustments and refinements should be considered based on both the current PK data and the need to establish an effective therapeutic range, if present. Future research should focus on efficacy studies, multiple-dose investigations, and pharmacodynamic assessments to evaluate the suitability of MTK use in dogs.
Assuntos
Acetatos , Estudos Cross-Over , Ciclopropanos , Jejum , Antagonistas de Leucotrienos , Quinolinas , Sulfetos , Animais , Cães , Sulfetos/farmacocinética , Sulfetos/administração & dosagem , Masculino , Quinolinas/farmacocinética , Quinolinas/administração & dosagem , Ciclopropanos/farmacocinética , Ciclopropanos/administração & dosagem , Acetatos/farmacocinética , Acetatos/administração & dosagem , Administração Oral , Antagonistas de Leucotrienos/farmacocinética , Antagonistas de Leucotrienos/administração & dosagem , Área Sob a Curva , Meia-VidaRESUMO
Relaxin-2 is a peptide hormone with important roles in human cardiovascular and reproductive biology. Its ability to activate cellular responses such as vasodilation, angiogenesis, and anti-inflammatory and antifibrotic effects has led to significant interest in using relaxin-2 as a therapeutic for heart failure and several fibrotic conditions. However, recombinant relaxin-2 has a very short serum half-life, limiting its clinical applications. Here, we present protein engineering efforts targeting the relaxin-2 hormone in order to increase its serum half-life while maintaining its ability to activate the G protein-coupled receptor RXFP1. To achieve this, we optimized a fusion between relaxin-2 and an antibody Fc fragment, generating a version of the hormone with a circulating half-life of around 3 to 5 days in mice while retaining potent agonist activity at the RXFP1 receptor both in vitro and in vivo.
Assuntos
Receptores Acoplados a Proteínas G , Receptores de Peptídeos , Relaxina , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Animais , Relaxina/farmacologia , Receptores de Peptídeos/agonistas , Receptores de Peptídeos/metabolismo , Camundongos , Humanos , Meia-Vida , Engenharia de Proteínas/métodos , Células HEK293 , Fragmentos Fc das Imunoglobulinas/farmacologia , Camundongos Endogâmicos C57BL , MasculinoRESUMO
Imazethapyr is the most common herbicide used for weed management in pulses. A field trial was carried out with imazethapyr 10% SL formulation at 100 and 150 g a.i./ha application rates, as pre-and post-emergence, to study dissipation of imazethapyr in soil, persistence in urdbean plant, terminal residues in urdbean grains and effect on soil microbes. An acetate buffered- quick, easy, cheap, effective, rugged, and safe (QuEChERS) method in combination with high-performance liquid chromatography (HPLC) was validated for imazethapyr residue analysis. The half-life of imazethapyr in soil ranged from 15.12 to 18.02 days. The residues of imazethapyr persist up to 60 days in soil and up to 7-15 days in urdbean plant. Residues were not detected in grains at the time of harvest. Persistence of imazethapyr residues in soil significantly impact soil microbial populations depending on herbicide application rates and timing.
Assuntos
Herbicidas , Ácidos Nicotínicos , Resíduos de Praguicidas , Microbiologia do Solo , Poluentes do Solo , Solo , Vigna , Herbicidas/análise , Poluentes do Solo/análise , Vigna/química , Ácidos Nicotínicos/análise , Resíduos de Praguicidas/análise , Solo/química , Cinética , Cromatografia Líquida de Alta Pressão , Meia-VidaRESUMO
INTRODUCTION: Hemophilia B is a X-linked rare inherited bleeding disorder characterized by coagulation factor IX (FIX) deficiency. Therapy for hemophilia B is aimed at replacing the FIX deficiency by means of several plasma-derived or recombinant FIX products. The recent availability of recombinant FIX concentrates with a prolonged FIX half-life represented a great technological advance, permitting more spaced drug infusions and reducing treatment burden among hemophilia B patients. AREAS COVERED: This review summarizes the main preclinical and phase 1/2 studies investigating the innovative hemostatic products for hemophilia B replacement therapy. EXPERT OPINION: The significant recent technological advantages in the treatment of hemophilia B has led to the development of innovative FIX products aimed at further extending FIX half-life and using increasingly effective and convenient modes of administration. These novel hemostatic agents, currently in the preclinical or early clinical phase of development, carry the potential of improving patients' health status and quality of life. Continuous research is anyway needed to offer such patients a concrete chance of conducting a normal existence, like to non-affected age-matched individuals.