RESUMEN
Donepezil (DPZ), a piperidine-based reversible cholinesterase inhibitor, finds extensive use in treating Alzheimer's disease (AD). Originally designed as an oral formulation, DPZ encounters drawbacks such as a brief duration of action and reduced treatment effectiveness in elderly patients with memory impairment or difficulty swallowing medications. To address these issues and improve patient compliance, researchers are actively exploring alternative DPZ formulations. Consequently, reliable methods are necessary to quantitate DPZ in biological samples for in vivo assessment. Therefore, we propose an efficient, sensitive, wide-dynamic, and cost-effective method for quantitating DPZ in rat plasma. Our method employs liquid-liquid extraction (LLE) followed by liquid chromatography and tandem mass spectrometry, enabling in vivo evaluation of novel DPZ formulations. Notably, our method requires only 20 µL of rat plasma and employs icopezil as the internal standard-a cost-effective compound with chemical similarity to DPZ. We meticulously optimized LLE conditions, taking into account factor interactions through design of experiments (DOE). Our rapid and straightforward extraction and purification involved using 500 µL of pure methyl tert-butyl ether to extract DPZ from the sample within five minutes. The dynamic range of the method extends from 0.5 ng/mL to 1,000 ng/mL, demonstrating excellent sensitivity and suitability for pharmacokinetic studies across diverse DPZ formulations. Following the FDA guidelines, we rigorously validated the developed method, evaluating selectivity, linearity (with a coefficient of determination ≥0.9999), accuracy (ranging from 96.0% to 109.6%), precision (≤13.9%), matrix effect (92.2% to 103.8%), recovery (98.5% to 106.8%), the lower limit of quantitation (0.5 ng/mL), and stability. Finally, we effectively employed the validated method for the long-term pharmacokinetic assessment of a DPZ formulation. We expect that this approach will make a substantial contribution to the advancement of new DPZ formulations, ultimately benefiting individuals afflicted by AD.
Asunto(s)
Donepezilo , Extracción Líquido-Líquido , Piperidinas , Espectrometría de Masas en Tándem , Donepezilo/sangre , Donepezilo/farmacocinética , Animales , Espectrometría de Masas en Tándem/métodos , Extracción Líquido-Líquido/métodos , Ratas , Cromatografía Liquida/métodos , Piperidinas/sangre , Piperidinas/farmacocinética , Piperidinas/química , Inhibidores de la Colinesterasa/sangre , Inhibidores de la Colinesterasa/farmacocinética , Indanos/sangre , Indanos/farmacocinética , Masculino , Reproducibilidad de los Resultados , Ratas Sprague-Dawley , Cromatografía Líquida con Espectrometría de MasasRESUMEN
ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.
Asunto(s)
Administración Intranasal , Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Donepezilo , Liposomas , ARN Interferente Pequeño , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Donepezilo/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/farmacología , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Indanos/administración & dosificación , Indanos/farmacocinética , Péptidos beta-Amiloides/metabolismoRESUMEN
Liquid-phase microextraction (LPME) possesses a high potential to isolate organic substances from different sample matrices. In this work, LPME was applied for the first time to investigate the biodistribution of diphenidol in different biofluids, organs, and brain regions using a fatal poisoning case. Since the LPME of diphenidol hasn't been reported, the effect of supported liquid membrane (SLM), acceptor and donor phases, and extraction time on LPME performance was investigated first. The solvents of 2-nonanone and 2-nitrophenyl octyl ether (NPOE) were found to be stable and efficient SLMs for LPME of diphenidol from biofluids and tissue samples, respectively. At steady state, the LPME recoveries for different sample matrices were in the range of 87 %-91 %. Due to the clean-up capability of LPME and the relatively high concentration of diphenidol in the fatal poisoning case, the proposed LPME systems were validated with related sample matrices using HPLC-UV for the determination. The methods displayed good linearity (R² ≥ 0.9943), and the limits of detection were 0.30 mg L-1, 0.28 mg L-1, and 2.7 µg g-1 for blood, urine, and liver samples, respectively. Meanwhile, the precision (≤13%), accuracy (90-110%), and matrices effect (±15%) were satisfactory at low, medium, and high concentrations. In addition, the stability, carryover, and dilution integrity met the requirements of ASB Standard 036. Finally, the proposed method was successfully applied to evaluate the biodistribution of diphenidol in five different biofluids, five organs, and six brain regions from a fatal poisoning case. Generally, the distribution of diphenidol in biofluids was lower than that in the organs and brain regions, and the highest concentration of diphenidol was observed in the liver, which is very important for the selection of inspection samples in forensic toxicological analysis. Therefore, LPME was proved to be a powerful tool for the investigation of biodistribution and postmortem redistribution in the fields of forensics.
Asunto(s)
Microextracción en Fase Líquida , Piperidinas , Humanos , Cromatografía Líquida de Alta Presión/métodos , Límite de Detección , Microextracción en Fase Líquida/métodos , Piperidinas/sangre , Piperidinas/farmacocinética , Piperidinas/envenenamiento , Reproducibilidad de los Resultados , Distribución TisularRESUMEN
Inhibiting O-GlcNAcase and thereby up-regulation of the O-GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC50 = 4.93 ± 2.05 nM) and cellular potency (EC50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O-GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores Enzimáticos , Piperidinas , beta-N-Acetilhexosaminidasas , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacocinética , Humanos , Relación Estructura-Actividad , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , beta-N-Acetilhexosaminidasas/metabolismo , Ratas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Ratones , Células PC12 , Descubrimiento de Drogas , Ratones Transgénicos , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , MasculinoRESUMEN
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.
Asunto(s)
Adenina , Benzamidas , Química Farmacéutica , Lípidos , Nitrilos , Feniltiohidantoína , Piperidinas , Solubilidad , Temperatura , Nitrilos/química , Nitrilos/administración & dosificación , Piperidinas/química , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Adenina/análogos & derivados , Adenina/química , Adenina/administración & dosificación , Feniltiohidantoína/farmacocinética , Feniltiohidantoína/administración & dosificación , Lípidos/química , Animales , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Masculino , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/administración & dosificación , Estabilidad de Medicamentos , Cristalización/métodos , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/administración & dosificación , Lipólisis/efectos de los fármacos , RatasRESUMEN
Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize 99mTc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with 99mTc, the optimum radiolabeling condition was determined as 200 ppm SnCl2 and 0.5 mg ascorbic acid, and both 99mTc-MS/TOFA-9 and 99mTc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide , Quitosano , Geles , Microesferas , Piperidinas , Pirimidinas , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/diagnóstico por imagen , Pirimidinas/química , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Piperidinas/química , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Quitosano/química , Humanos , Tecnecio/química , Inyecciones Intraarticulares , Pirroles/química , Pirroles/administración & dosificación , Animales , Poloxámero/química , Tamaño de la Partícula , Liberación de FármacosRESUMEN
Drug solubility and dissolution remain a significant challenge in pharmaceutical formulations. This study aimed to formulate and evaluate repanglinide (RPG) nanosuspension-based buccal fast-dissolving films (BDFs) for dissolution enhancement. RPG nanosuspension was prepared by the antisolvent-precipitation method using multiple hydrophilic polymers, including soluplus®, polyvinyl alcohol, polyvinyl pyrrolidine, poloxamers, and hydroxyl propyl methyl cellulose. The nanosuspension was then directly loaded into BDFs using the solvent casting technique. Twelve formulas were prepared with a particle size range of 81.6-1389 nm and PDI 0.002-1 for the different polymers. Nanosuspensions prepared with soluplus showed a favored mean particle size of 82.6 ± 3.2 nm. The particles were spherical and non-aggregating, as demonstrated by SEM imaging. FTIR showed no interaction between soluplus and RPG. Faster dissolution occurred for the nanosuspension in comparison with pure RPG (complete release vs 60% within 30 min). The nanosuspension was successfully incorporated into BDFs. The optimum film formula showed 28 s disintegration time, and 97.3% RPG released within 10 min. Ex-vivo permeation profiles revealed improved RPG nanosuspension permeation with the cumulative amount of RPG permeated is103.4% ± 10.1 and a flux of 0.00275 mg/cm2/min compared to 39.3% ± 9.57 and a flux of 0.001058 mg/cm2/min for pure RPG. RPG was successfully formulated into nanosuspension that boosted drug dissolution and permeation. The selection of the ultimate NP formula was driven by optimal particle size, distribution, and drug content. Soluplus NPs were shown to be the successful formulations, which were further incorporated into a buccal film. The film was evaluated for ex-vivo permeation, confirming successful RPG formulation with improved performance compared to pure drugs.
Asunto(s)
Carbamatos , Nanopartículas , Tamaño de la Partícula , Piperidinas , Solubilidad , Suspensiones , Nanopartículas/química , Piperidinas/química , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Carbamatos/química , Carbamatos/administración & dosificación , Carbamatos/farmacocinética , Animales , Química Farmacéutica/métodos , Liberación de Fármacos , Polivinilos/química , Polímeros/química , Administración Bucal , Polietilenglicoles/química , Composición de Medicamentos/métodosRESUMEN
Ibrutinib, an antineoplastic agent tackling chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's Macroglobulinemia, falls under the category of BCS class II drugs, characterized by a puzzling combination of low solubility and high permeability. Its oral bioavailability remains a perplexing challenge, merely reaching 2.9 % due to formidable first-pass metabolism hurdles. In a bid to surmount this obstacle, researchers embarked on a journey to develop ibrutinib-loaded NLCs (Nanostructured Lipid Carriers) using a methodology steeped in complexity: a Design of Experiments (DoE)-based hot melted ultrasonication approach. Despite a plethora of methods for analyzing ibrutinib in various matrices, the absence of a spectrofluorimetric method for assessing it in rat plasma added to the enigma. Thus emerged a spectrofluorimetric method, embodying principles of white analytical chemistry and analytical quality by design, employing a Placket-Burman design for initial method exploration and a central composite design for subsequent refinement. This method underwent rigorous validation in accordance with ICH guidelines, paving the way for its application in scrutinizing the in-vivo pharmacokinetics of ibrutinib-loaded NLCs, juxtaposed against commercially available formulations. Surprisingly, the optimized NLCs exhibited a striking 1.82-fold boost in oral bioavailability, shedding light on their potential efficacy. The environmental impact of this method was scrutinized using analytical greenness tools, affirming its eco-friendly attributes. In essence, the culmination of these efforts has not only propelled advancements in drug bioavailability but also heralded the dawn of a streamlined and environmentally conscious analytical paradigm.
Asunto(s)
Adenina , Lípidos , Piperidinas , Pirimidinas , Espectrometría de Fluorescencia , Animales , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/química , Adenina/sangre , Piperidinas/farmacocinética , Piperidinas/química , Piperidinas/sangre , Lípidos/química , Masculino , Espectrometría de Fluorescencia/métodos , Ratas , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/sangre , Portadores de Fármacos/química , Nanoestructuras/química , Pirazoles/farmacocinética , Pirazoles/química , Pirazoles/sangre , Pirazoles/administración & dosificación , Reproducibilidad de los Resultados , Ratas WistarRESUMEN
Inflammatory skin diseases are typically managed with semi-solid formulations such as creams and ointments. These treatments often fail to remain on the skin for long, as they can be easily wiped off by clothing, necessitating frequent reapplication throughout the day and resulting in poor patient adherence. Therefore, this study sought to fabricate an electrospun dressing as an alternative dosage form that provides a sustained release of the anti-inflammatory agent tofacitinib over three days. In this study, three types of electrospun fiber dressings - uniaxial, coaxial, and layer-by-layer - were produced and examined for their morphological, mechanical, and release characteristics. In addition to a comprehensive characterization, another objective was to analyze the drug permeation behavior from these fiber dressings on porcine skin, comparing their performance to that of a tofacitinib cream. The layer-by-layer system notably exhibited a delayed drug release, while the uniaxial and coaxial systems demonstrated an initial burst release. However, the permeation studies revealed no significant differences between these systems, underscoring the necessity of conducting such studies - a crucial aspect often overlooked in research on electrospun fiber dressings. Overall, this study highlights the potential of electrospun, drug-loaded dressings for the treatment of inflammatory skin diseases.
Asunto(s)
Vendajes , Preparaciones de Acción Retardada , Liberación de Fármacos , Piperidinas , Pirimidinas , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/química , Animales , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Porcinos , Preparaciones de Acción Retardada/administración & dosificación , Piel/metabolismo , Piel/efectos de los fármacos , Administración Cutánea , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Absorción Cutánea , Enfermedades de la Piel/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Pirroles/administración & dosificación , Pirroles/química , Pirroles/farmacocinéticaRESUMEN
PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.
Asunto(s)
Relación Dosis-Respuesta a Droga , Indazoles , Neoplasias Ováricas , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Indazoles/farmacocinética , Indazoles/efectos adversos , Indazoles/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Piperidinas/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Supervivencia sin Progresión , Trombocitopenia/inducido químicamente , Ensayos Clínicos como AsuntoRESUMEN
Repaglinide (RPG) belongs to the class of drugs known as meglitinides and is used for improving and maintaining glycemic control in the treatment of patients with Type 2 diabetes. RPG is a Class II drug (BCS) because of its high permeability and low water solubility. It also undergoes hepatic first-pass metabolism. The oral bioavailability of RPG is low (about 56 %) due to these drawbacks. Our aim in this study is to prepare two different nano-sized drug carrier systems containing RPG (nanoparticle: RPG-PLGA-Zein-NPs or nanoemulsion: RPG-NE) and to carry out a pharmacokinetic study for these formulations. We prepared NPs using PLGA and Zein. In addition, a single NE formulation was developed using Tween 80 and Pluronic F68 as surfactants and Labrasol as co-surfactant. The droplet size values of the blank-NE and RPG-NE formulations were found to be less than 120 nm. The mean particle sizes of blank-Zein-PLGA-NPs and RPG-Zein-PLGA-NPs were less than 260 nm. The Cmax and tmax values of RPG-Zein-PLGA-NPs and RPG-NE (523 ± 65 ng/mL and 770 ± 91 ng/mL; 1.41 ± 0.46 h and 1.61 ± 0.37 h, respectively) were meaningfully higher than those of free RPG (280 ± 33 ng/mL; 0.72 ± 0.28 h) (p < 0.05). The AUC0-∞ values calculated for RPG-Zein-PLGA-NPs and RPG-NE were approximately 4.04 and 5.05 times higher than that calculated for free RPG. These nanosized drug delivery systems were useful in increasing the oral bioavailability of RPG. Moreover, the NE formulation was more effective than the NP formulation in improving the oral bioavailability of RPG (p < 0.05).
Asunto(s)
Carbamatos , Emulsiones , Hipoglucemiantes , Nanopartículas , Piperidinas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Carbamatos/farmacocinética , Carbamatos/química , Carbamatos/administración & dosificación , Nanopartículas/química , Nanopartículas/administración & dosificación , Masculino , Piperidinas/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacocinética , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Tamaño de la Partícula , Ratas , Zeína/química , Zeína/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Disponibilidad Biológica , Tensoactivos/química , Tensoactivos/farmacocinética , Ratas Sprague-Dawley , Ratas Wistar , Poloxámero/química , Poloxámero/farmacocinética , Glicéridos/química , Glicéridos/farmacocinética , Composición de Medicamentos/métodosRESUMEN
OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation. ANIMALS: 4 healthy horses without evidence of forelimb lameness. METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 µg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points. RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point. CLINICAL RELEVANCE: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.
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Preparaciones de Acción Retardada , Flavonoides , Enfermedades de los Caballos , Piperidinas , Líquido Sinovial , Animales , Caballos , Inyecciones Intraarticulares/veterinaria , Flavonoides/administración & dosificación , Flavonoides/farmacocinética , Enfermedades de los Caballos/tratamiento farmacológico , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Artropatías/veterinaria , Artropatías/tratamiento farmacológico , Masculino , Femenino , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Estudios LongitudinalesRESUMEN
Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become an attractive target for cancer therapy in recent years. Given that niraparib has good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled niraparib derivatives for tumor imaging to detect PARP expression and improve the accuracy of stratified patient therapy. The niraparib isonitrile derivative (CNPN) was designed, synthesized, and radiolabeled to obtain the [99mTc]Tc-CNPN complex with high radiochemical purity (>95%). It was lipophilic and stable in vitro. In HeLa cell experiments, the uptake of [99mTc]Tc-CNPN was effectively inhibited by the ligand CNPN, indicating the binding affinity for PARP. According to the biodistribution studies of HeLa tumor-bearing mice, [99mTc]Tc-CNPN has moderate tumor uptake and can be effectively inhibited, demonstrating its specificity for targeting PARP. The SPECT imaging results showed that [99mTc]Tc-CNPN had tumor uptake at 2 h postinjection. All of the results of this study indicated that [99mTc]Tc-CNPN is a promising tumor imaging agent that targets PARP.
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Indazoles , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Humanos , Ratones , Piperidinas/química , Piperidinas/farmacocinética , Indazoles/química , Indazoles/farmacocinética , Células HeLa , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único/métodos , Radiofármacos/farmacocinética , Radiofármacos/química , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Femenino , Tecnecio/química , Nitrilos/química , Nitrilos/farmacocinética , Ratones Desnudos , Ratones Endogámicos BALB CRESUMEN
Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant potential in therapeutic applications for treating alopecia areata; however, the systemic adverse effects of oral administration and low absorption rate at the target site limit its application. Hence, to address this issue, we designed topical formulations of tofacitinib-loaded cationic lipid nanoparticles (TFB-cNLPs) with particle sizes of approximately 200 nm. TFB-cNLPs promoted percutaneous absorption and hair follicle targeting in an ex vivo pig ear model. TFB-cNLP decreased IFN-γ-induced alopecia areata symptoms in an in vitro follicle model by blocking the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. It also reduced the number of CD8+NKG2D+T cells in a C3H mouse model of alopecia areata in vivo, thereby inhibiting the progression of alopecia areata and reversing hair loss. These findings suggest that TFB-cNLP enhanced hair follicle targeting and has the potential for topical treatment or prevention of alopecia areata.
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Alopecia Areata , Portadores de Fármacos , Folículo Piloso , Lípidos , Piperidinas , Pirimidinas , Absorción Cutánea , Animales , Alopecia Areata/tratamiento farmacológico , Folículo Piloso/metabolismo , Folículo Piloso/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Porcinos , Lípidos/química , Lípidos/administración & dosificación , Portadores de Fármacos/química , Ratones Endogámicos C3H , Nanopartículas/administración & dosificación , Ratones , Nanoestructuras/administración & dosificación , Femenino , LiposomasRESUMEN
Objective: Curcuminoids, the major component of which is curcumin, are natural polyphenolic compounds from the rhizome of Curcuma longa Linn. and possess extensive biopharmacological properties that are limited in humans due to poor bioavailability. Currently, most commercial bioavailable turmeric extracts use synthetic excipients or the addition of piperine to enhance bioavailability, and are needed in multiple daily doses to achieve clinical efficacy. This study was conducted to compare the bioavailability of a natural, water-dispersible turmeric extract containing 60% natural curcuminoids, the test product, WDTE60N (1 × 250 mg per day), with the reference product, turmeric extract capsules (500 mg curcuminoids and 5 mg piperine, CPC; 3 × 500 mg per day). Methods: Sixteen healthy adult male subjects fasted overnight for 10 hours and then were dosed with either one capsule of the test product WDTE60N or three capsules of reference product CPC orally (One capsule administered at every 6 hours interval i.e. at 0.00 hrs, 6.00 hrs and at 12.00 hrs) in each study period. Blood sampling before and after dosing was carried out at defined time points at -12.00, -02.00, 00.00 (within 10 minutes prior to dosing) hours in morning before dosing and post-dose (First dose) at 00.50, 01.00, 02.00, 03.00, 04.00, 05.00, 06.50, 07.00, 08.00, 09.00, 10.00, 11.00, 12.50, 13.00, 14.00, 16.00, 18.00, 20.00 and 24.00 hours in each period. Plasma concentration of curcuminoids was determined using a validated liquid chromatography with tandem mass spectrometry bioanalytical method. Results: The Cmax (GLSM) for the test product WDTE60N was observed to be 74.56 ng/mL; and same for the reference CPC was 22.75 ng/mL. AUC0-t (GLSM) for test WDTE60N was 419.00 hâng/mL; and for reference CPC it was 359.86 hâng/mL for total curcuminoids. Conclusion: The test formulation WDTE60N showed improved relative absorption and equivalent exposure at a 10-fold-lower dose of actives than the reference formulation CPC.
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Alcaloides , Benzodioxoles , Estudios Cruzados , Curcuma , Curcumina , Piperidinas , Extractos Vegetales , Humanos , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/farmacocinética , Curcuma/química , Adulto , Alcaloides/farmacocinética , Alcaloides/farmacología , Benzodioxoles/farmacocinética , Benzodioxoles/farmacología , Curcumina/farmacocinética , Curcumina/farmacología , Piperidinas/farmacocinética , Piperidinas/farmacología , Disponibilidad Biológica , Adulto Joven , Alcamidas Poliinsaturadas/farmacología , Alcamidas Poliinsaturadas/farmacocinéticaRESUMEN
Tofacitinib can effectively improve the clinical symptoms of rheumatoid arthritis (RA) patients. In this current study, a recombinant human CYP2C19 and CYP3A4 system was operated to study the effects of recombinant variants on tofacitinib metabolism. Moreover, the interaction between tofacitinib and myricetin was analyzed in vitro. The levels of M9 (the main metabolite of tofacitinib) was detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The findings revealed that 11 variants showed significant changes in the levels of M9 compared to CYP3A4.1, while the other variants didn't reveal any remarkable significances. Compared with CYP2C19.1, 11 variants showed increases in the levels of M9, and 10 variants showed decreases. Additionally, it was demonstrated in vitro that the inhibition of tofacitinib by myricetin was a non-competitive type in rat liver microsomes (RLM) and human liver microsomes (HLM). However, the inhibitory mechanism was a competitive type in CYP3A4.18, and mixed type in CYP3A4.1 and .28, respectively. The data demonstrated that gene polymorphisms and myricetin had significant effects on the metabolism of tofacitinib, contributing to important clinical data for the precise use.
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Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Flavonoides , Microsomas Hepáticos , Piperidinas , Pirimidinas , Humanos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Flavonoides/farmacología , Flavonoides/metabolismo , Pirimidinas/farmacología , Pirimidinas/metabolismo , Animales , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Ratas , Piperidinas/farmacología , Piperidinas/farmacocinética , Piperidinas/metabolismo , Polimorfismo Genético , Pirroles/farmacología , Pirroles/metabolismoRESUMEN
Pritelivir is a novel viral helicase-primase inhibitor active against herpes simplex virus. In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Sistema Enzimático del Citocromo P-450 , Interacciones Farmacológicas , Humanos , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Femenino , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Masculino , Adulto , Bupropión/farmacología , Bupropión/farmacocinética , Sulfonamidas/farmacología , Persona de Mediana Edad , Rosuvastatina Cálcica/farmacología , Rosuvastatina Cálcica/farmacocinética , Flurbiprofeno/farmacología , Flurbiprofeno/farmacocinética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Carbamatos/farmacología , Midazolam/farmacocinética , Midazolam/farmacología , Adulto Joven , Piperidinas/farmacología , Piperidinas/farmacocinéticaRESUMEN
Niraparib is a potent and orally bioavailable inhibitor of poly (ADP-ribose) polymerase (PARP) with high specificity for isoforms 1 and 2. It has been approved by the U.S. Food and Drug Administration for ovarian cancer maintenance therapy and is currently under development for various cancers, including glioblastoma. To assess central nervous system (CNS) penetration of niraparib in glioblastoma patients, a novel bioanalytical method was developed to measure total and unbound niraparib levels in human brain tumor tissue and cerebrospinal fluid (CSF). The method was validated using plasma as a surrogate matrix over the concentration range of 1-10,000â¯nM on an LC-MS/MS system. The MS/MS detection was conducted in positive electrospray ionization mode, while chromatography was performed using a Kinetex™ PS C18 column with a total 3.5-minute gradient elution run time. The maximum coefficient of variation for both intra- and inter-day precision was 10.6%, with accuracy ranging from 92.8% - 118.5% across all matrices. Niraparib was stable in human brain homogenate for at least 6â¯hours at room temperature (RT) and 32 days at -20°C, as well as in stock and working solutions for at least 21â¯hours (RT) and 278 days (4°C). Equilibrium dialysis experiments revealed the fractions unbound of 0.05 and 0.16 for niraparib in human brain and plasma, respectively. The validated method is currently employed to assess niraparib levels in human glioblastoma tissue, CSF, and plasma in an ongoing trial on newly diagnosed glioblastoma and recurrent IDH1/2(+) ATRX mutant glioma patients (NCT05076513). Initial results of calculated total (Kp) and unbound (Kp,uu) tumor-to-plasma partition coefficients indicate significant brain penetration ability of niraparib in glioblastoma patients.
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Neoplasias Encefálicas , Indazoles , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Espectrometría de Masas en Tándem , Humanos , Piperidinas/farmacocinética , Piperidinas/sangre , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Indazoles/farmacocinética , Indazoles/administración & dosificación , Indazoles/uso terapéutico , Espectrometría de Masas en Tándem/métodos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacocinética , Cromatografía Liquida/métodos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Reproducibilidad de los Resultados , Encéfalo/metabolismo , Sulfonamidas/farmacocinética , Sulfonamidas/análisis , Sulfonamidas/administración & dosificación , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[18F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([18F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [18F]VAT. [3H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BPND). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [18F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [3H]VAT autoradiography-specific binding and PET [18F]VAT uptake were low in white matter. [18F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BPND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BPND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BPND calculations and demonstrate the viability, reproducibility, and utility of using the [18F]VAT tracer in humans to quantify cholinergic pathways.
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Encéfalo , Piperidinas , Tomografía de Emisión de Positrones , Humanos , Adulto , Persona de Mediana Edad , Anciano , Masculino , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodos , Femenino , Reproducibilidad de los Resultados , Adulto Joven , Anciano de 80 o más Años , Piperidinas/farmacocinética , Piperidinas/metabolismo , Envejecimiento/metabolismo , Radiofármacos/farmacocinética , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. METHODS: This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily dose on days 1-11, and (3) daily dose on days 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. RESULTS: For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. CONCLUSIONS: The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. GOV IDENTIFIER: NCT04577833.