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INTRODUCTION: Definitive management of non-compressible intra-abdominal hemorrhage (NCIAH) currently requires a surgeon and operating room capable of performing damage control surgery. In a wartime scenario or a geographically remote environment, these may not be readily available. In this study, we sought to test the safety of 2 emerging injectable hemostatic agents (CounterFlow and Fast Onset Abdominal Management, or FOAM, poloxamer component) versus normal saline control over a prolonged monitoring duration following administration by a non-surgical provider. MATERIALS AND METHODS: The Institutional Animal Care and Use Committee approved all research conducted in this study. We randomized male New Zealand white rabbits into 2 monitoring cohorts of 24 hours and 2 weeks. Each cohort contained 3 treatment groups (n = 4 rabbits/group): CounterFlow, the testable poloxamer component of FOAM, and normal saline control. We injected each treatment intraperitoneally in the left lower abdominal quadrant. Doses were 15 mL/kg for CounterFlow, 6.3 mL/kg for the poloxamer component of FOAM, and 15 mL/kg for normal saline. We conducted all injections under isoflurane anesthesia monitored by trained veterinary staff. Animals were euthanized at each cohort end point, and a veterinary pathologist blinded to treatment type performed necropsy. The primary outcome was incidence of intra-abdominal adhesions at necropsy. Quantitatively, adhesions when present were graded by the veterinary pathologist on a 1 to 4 scale, where "1" represented adhesions involving from 1 to 25% of the examined abdomen, "2" represented from 26 to 50%, "3" represented from 51 to 75%, and "4" represented from 76 to 100%. Qualitatively, adhesions present were graded by degree ("1" = minimal, "2" = mild, "3" = moderate, and "4" = severe) and chronicity ("1" = acute, "2" = subacute, and "3" = chronic). We also drew d-dimer blood values and measured body weights for each animal. Statistical analysis included either repeated measures 2-way ANOVA or a mixed-effects model (in the case of missing data) with Geisser-Greenhouse correction. We adjusted multiple comparisons using Tukey statistical hypothesis tests. RESULTS: In the 2-week cohort, 3 CounterFlow animals showed adhesions judged to be "1" quantitatively. Qualitatively, 2 of these were assessed as "1" for degree of adhesions and the other demonstrated a "2." On the chronicity of adhesions scale, 1 animal demonstrated a "2" and 2 demonstrated a "3." No animals in other groups (FOAM and control) demonstrated adhesions. CounterFlow-treated animals showed a statistically significant rise in d-dimer values in the 24-hour cohort only. In the 2-week cohort, CounterFlow-treated animals showed a decrease in body weight at 24 hours after injection but returned to their baseline (normal) body weights at 7 days. CONCLUSIONS: Findings from this study demonstrate that the tested ingredients of FOAM poloxamer component are safe for intraperitoneal injection and hold potential for further study directed toward prehospital non-compressible intra-abdominal hemorrhage management by non-surgical providers. Although CounterFlow produced abdominal adhesions in 3 of 4 rabbits in the 2-week cohort, these were determined to be "minimal" or "mild" in degree.
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Hemostáticos , Animales , Conejos , Adherencias Tisulares , Masculino , Hemostáticos/administración & dosificación , Inyecciones Intraperitoneales , Poloxámero/efectos adversos , Poloxámero/administración & dosificación , Incidencia , Abdomen/cirugíaRESUMEN
OBJECTIVES: To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain tissueMETHODS: Citicoline, cytidine diphosphocholine, designated as CDP-choline, was purchased as a white powder with the molecular weight of 510.31 g/mol. The triblock copolymers of polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol (PEG-PPG-PEG), branded as Pluronic F127, was used. RESULTS: When instilled into the nasal cavity, Pluronic F127 for intranasal administration is transformed into a gel that remains retained for 45-55 minutes, which promotes better penetration of drugs into the brain tissue. CONCLUSION: The polymer's gelling and adhesive properties performed well, which is crucial for further research at the preclinical stage (Tab. 1, Fig. 5, Ref. 28).
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Administración Intranasal , Encéfalo , Sistemas de Liberación de Medicamentos , Poloxámero , Poloxámero/administración & dosificación , Encéfalo/metabolismo , Animales , Citidina Difosfato Colina/administración & dosificación , Citidina Difosfato Colina/farmacocinética , Geles , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Mucosa Nasal/metabolismoRESUMEN
Synthetic lifting media, ORISE™ gel and Eleview®, are increasingly used in gastrointestinal endoscopy, but neither comparative features nor pitfalls are well-established. Media histopathology, morphologic mimics, and complications are described, along with helpful stains and endoscopist media preference. A 3-year retrospective search was performed. A total of 123 cases (108 endoscopies and 15 subsequent surgeries) were identified. ORISE gel was used in 86 (79.6%), Eleview in 20 (13.9%), and others in 7 (6.5%). ORISE gel was histologically identified in 58.1% (n = 50) of endoscopic specimens and all 15 resections. Eleview media were not detected histologically. ORISE gel mimicked mucin in hematoxylin and eosin-stained biopsies, concerning for adenocarcinoma misdiagnosis and/or upstaging, but did not stain for mucin. Acid-fast bacterial staining highlights ORISE gel for specific and definitive identification. In resections, ORISE evolves into an amorphous eosinophilic material, often with exuberant giant cell reaction and transmural bowel penetration. Polyp formation leads to polypectomy in one patient, and operative lesions concerning for adenocarcinoma resulted in frozen sections in two patients. ORISE gel mimics mucin, malignant masses, amyloid, pulse granulomata, elastofibromas, and infectious granulomata. No significant endoscopist media preference was identified. Recognition of ORISE gel in tissues eliminates multiple pitfalls. Eleview was not detectable, yielded none of the pitfalls seen with ORISE gel, and, on our survey, has equivalent endoscopist acceptance. In this largest published series to date, Eleview is clearly preferable to ORISE gel.
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Artefactos , Endoscopía Gastrointestinal/efectos adversos , Tracto Gastrointestinal/patología , Poloxámero/efectos adversos , Anciano , Anciano de 80 o más Años , Biopsia , Color , Errores Diagnósticos , Femenino , Tracto Gastrointestinal/cirugía , Geles , Humanos , Masculino , Persona de Mediana Edad , Poloxámero/administración & dosificación , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Procedimientos InnecesariosRESUMEN
Anterior uveitis is a sight-threatening inflammation inside the eyes. Conventional eye drops for anti-inflammatory therapy need to be administered frequently owing to the rapid elimination and corneal barrier. To address these issues, polypseudorotaxane hydrogels were developed by mixing Soluplus micelles (99.4 nm) and cyclodextrins solution. The optimized hydrogels exhibited shear-thinning and sustained release properties. The hydrogels exhibited higher transcorneal permeability coefficient (Papp, 1.84 folds) than that of drug solutions. Moreover, animal study indicated that the hydrogels significantly increased the precorneal retention (AUC, 21.2 folds) and intraocular bioavailability of flurbiprofen (AUCAqueous humor, 17.8 folds) in comparison with drug solutions. Importantly, the hydrogels obviously boosted anti-inflammatory efficacy in rabbit model of endotoxin-induced uveitis at a reduced administration frequency. Additionally, the safety of hydrogels was confirmed by cytotoxicity and ocular irritation studies. In all, the present study demonstrates a friendly non-invasive strategy based on γ-CD-based polypseudorotaxane hydrogels for ocular drug delivery.
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Ciclodextrinas/uso terapéutico , Flurbiprofeno/uso terapéutico , Hidrogeles/uso terapéutico , Soluciones Oftálmicas/uso terapéutico , Poloxámero/uso terapéutico , Rotaxanos/uso terapéutico , Uveítis Anterior/tratamiento farmacológico , gamma-Ciclodextrinas/uso terapéutico , Administración Oftálmica , Animales , Ciclodextrinas/administración & dosificación , Ciclodextrinas/química , Sistemas de Liberación de Medicamentos , Flurbiprofeno/administración & dosificación , Flurbiprofeno/química , Hidrogeles/administración & dosificación , Hidrogeles/química , Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/química , Poloxámero/administración & dosificación , Poloxámero/química , Conejos , Rotaxanos/administración & dosificación , Rotaxanos/química , gamma-Ciclodextrinas/administración & dosificación , gamma-Ciclodextrinas/químicaRESUMEN
Hyperlipidemia is one of the leading causes of, atherosclerosis, and cardiovascular disease. In this study, we evaluated the protective role of hesperidin (HES) against lipidemic stress in a hyperlipidemic model of rats. We developed a hyperlipidemic model of the rat through an i.p dose of poloxamer-407, 0.5 g/kg body weight for 3 alternative days in a week for 30 days and rats were supplemented with HES orally (100 mg/kg body weight) once daily. Bodyweight, fasting glucose, insulin, HOMA-IR index, triglyceride, cholesterol, ROS, FRAP, GSH, PMRS, AGE, MDA, PCO, AOPP, PON-1, TNF-α and IL-6, SGPT and SGOT were estimated in blood and plasma, and histopathology was done in liver tissue. Our data show that oxidative stress, inflammatory markers were increased in the P-407 treated group. Liver tissue histology also changes in the hyperlipidemic groups of rats.HES supplementation protects against P-407 induced alterations and maintains the redox homeostasis. Our results provide evidence that HES protects against lipidemic stress and redox imbalance induced by P-407 in rats.
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Hesperidina/farmacología , Hiperlipidemias/tratamiento farmacológico , Poloxámero/efectos adversos , Factores Protectores , Animales , Modelos Animales de Enfermedad , Hesperidina/uso terapéutico , Hiperlipidemias/sangre , Hiperlipidemias/etiología , Estrés Oxidativo/efectos de los fármacos , Poloxámero/administración & dosificación , Sustancias Protectoras/metabolismo , RatasRESUMEN
The purpose of this study was to design silver nanoparticles (AgNPs) poloxamer thermoreversible gel (AgNPs-PL) and investigate whether this gel could provide sustained antibacterial activity against Enterococcus faecalis (E. faecalis) in the root canal. The gels fabricated were characterized in terms of gelatin temperature, particle size, in-vitro Ag+ release, and elemental content. Cytotoxicity of AgNPs-PL on primary human periodontal ligament fibroblasts (HPDLFs) was examined by CCK-8 assay. Characterization of AgNPs-PL gel revealed that it contained particles existing as large clumps/fused aggregates of different shapes, with a mean diameter of 21.624 ± 14.689 nm, exhibited sustained release of Ag+ for 9 days, and non-toxic to HPDLFs at a low dose (4-32 µg/mL) through 24, 48, and 72 h exposures. The antibacterial effect of 16 and 32 µg/mL concentrations of AgNPs-PL was compared with blank poloxamer gel (PL) and calcium hydroxide (CH) using three methods: (I) agar counting plate, (II) scanning electron microscope (SEM) observations, and (III) confocal laser scanning microscope (CLSM) analysis. AgNPs-PL at the two doses above was more effective than PL and CH in removing E. faecalis biofilm at 1, 3, 9 days. Thus, AgNPs-PL exhibits strong activity against E. faecalis and is easy to produce, with a continuous release profile of Ag+. AgNPs-PL gel may be a candidate for a new root canal disinfection.
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Biopelículas/efectos de los fármacos , Nanopartículas del Metal/química , Poloxámero/química , Irrigantes del Conducto Radicular/administración & dosificación , Antibacterianos/química , Antibacterianos/farmacología , Hidróxido de Calcio/química , Cavidad Pulpar/efectos de los fármacos , Cavidad Pulpar/microbiología , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/patogenicidad , Femenino , Humanos , Masculino , Poloxámero/administración & dosificación , Irrigantes del Conducto Radicular/química , Plata/químicaRESUMEN
The present study reports the performance of the pigment hypericin (HYP)-loaded poloxamer-based mucoadhesive in situ gelling liquid crystalline precursor system (LCPS) for the treatment of vulvovaginal candidiasis (VVC) in mice. LCPS composed of 40% of ethoxylated and propoxylated cetyl alcohol, 30% of oleic acid and cholesterol (7:1), 30% of a dispersion of 16% poloxamer 407 and 0.05% of HYP (HYP-LCPS) was prepared and characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS) and ex vivo permeation and retention studies across vaginal porcine mucosa were performed. In addition, the antifungal properties of the HYP-LCPS were evaluated in a murine in vivo model; for this, infected C57BL female mice groups were treated with both HYP in solution and HYP-LCPS, and after 6 days colony forming unit (CFU)/ml count was performed. PLM and SAXS confirmed that HYP-LCPS is a microemulsion situated in boundary transition region confirming its action as an LCPS. When in contact with simulated vaginal fluid, HYP-LCPS became rigid and exhibited maltase crosses and bragg peaks characteristics of lamellar phase. Ex vivo permeation and retention studies showed that HYP-LCPS provides a localized treatment on the superficial layers of porcine vaginal mucosa. HYP-LCPS induced a significant reduction in the number of CFU/ml in the mice; thus this formulation indicated it is as effective as a commercial dosage form. It was concluded that LCPS maintains the biological activity of HYP and provides an adequate drug delivery system for this lipophilic molecule at the vaginal mucosa, being a promising option in cases of VVC.
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Antracenos/administración & dosificación , Antifúngicos/administración & dosificación , Candida albicans/efectos de los fármacos , Candidiasis Vulvovaginal/tratamiento farmacológico , Perileno/análogos & derivados , Vagina/metabolismo , Adhesivos/administración & dosificación , Animales , Antracenos/metabolismo , Antifúngicos/metabolismo , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Microscopía de Polarización , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiología , Membrana Mucosa/patología , Perileno/administración & dosificación , Perileno/metabolismo , Poloxámero/administración & dosificación , Fármacos Sensibilizantes a Radiaciones , Dispersión del Ángulo Pequeño , Porcinos , Vagina/microbiología , Vagina/patología , Difracción de Rayos XRESUMEN
Lidocaine is widely used as a local anesthetic for alleviation of post-operative pain and for management of acute and chronic painful conditions. Although several approaches are currently used to prolong the duration of action, an effective strategy to achieve neural blockage for several hours remains to be identified. In this study, a lidocaine-loaded Pluronic® F68-reduced graphene oxide hydrogel was developed to achieve sustained release of lidocaine. Fourier transform infrared spectroscopy, X-ray diffraction, and Raman spectroscopy confirmed the synthesis of Pluronic® F68-reduced graphene oxide. Transmission electron microscopy showed wrinkled, flat nanosheets with micelles attached. The developed hydrogel showed desirable pH, viscosity, adhesiveness, hardness, and cohesiveness for topical application. The ex vivo release study demonstrated the ability of the Pluronic® F68-reduced graphene oxide hydrogel to prolong release up to 10 h, owing to the strong π-π interactions between the graphene oxide and the lidocaine. In comparison with a commercial lidocaine ointment, the developed graphene oxide hydrogel showed sustained anesthetic effect in the radiant heat tail flick test and sciatic nerve block model. Thus, this study demonstrates the potential of using Pluronic® F68-reduced graphene oxide nanocarriers to realize prolonged effects of local anesthesia for effective pain management.
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Anestesia Local/métodos , Grafito/química , Hidrogeles/química , Lidocaína/química , Administración Tópica , Animales , Preparaciones de Acción Retardada , Liberación de Fármacos , Grafito/administración & dosificación , Grafito/farmacología , Hidrogeles/administración & dosificación , Hidrogeles/farmacología , Lidocaína/administración & dosificación , Lidocaína/farmacología , Poloxámero/administración & dosificación , Poloxámero/química , Poloxámero/farmacología , Conejos , Ratas , Nervio Ciático/efectos de los fármacos , Pruebas de Irritación de la Piel , ViscosidadRESUMEN
Resveratrol is a very promising anti-oxidant drug candidate with low oral bioavailability due to its intrinsic poor water solubility, intestinal efflux and metabolization mechanisms. Resveratrol solubility high-throughput screening with different carriers was performed showing an enhancement above 2000-fold with Soluplus® and Tween® 80. The former was selected as a carrier at the ratio of resveratrol: Soluplus® (1:2). Then, third-generation solid dispersions were developed with Gelucire® and poloxamer 407 at 5 and 15% to resveratrol: Soluplus® (1:2). All formulations enhanced solubility around 2-fold when compared to resveratrol: Soluplus® (1:2) solid dispersion. Caco-2 cells permeability studies showed that both surfactants increased drug permeability and the fraction recovered (2-fold) suggesting that these could reduce efflux mechanism and metabolism. Formulation with 15% poloxamer 407 demonstrated most promising results and was selected for further studies. In in vivo studies, resveratrol:Soluplus®: poloxamer 407 (1:2-15%) third generation solid dispersion presented an AUCo-t of 279 ± 54 ng.h/mL and a Cmax of 134 ± 78 ng/mL, 2.5 fold higher than solid dispersion without poloxamer 407. This work reports the development of third-generation solid dispersion that significantly improved resveratrol bioavailability. This was accomplished by an increased solubility and most probably by reducing intestinal efflux and metabolism mechanisms.
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Antioxidantes/farmacocinética , Composición de Medicamentos/métodos , Poloxámero/química , Polietilenglicoles/química , Polivinilos/química , Resveratrol/farmacocinética , Administración Oral , Animales , Antioxidantes/administración & dosificación , Antioxidantes/química , Disponibilidad Biológica , Células CACO-2 , Rastreo Diferencial de Calorimetría , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Humanos , Masculino , Microscopía Electrónica de Rastreo , Permeabilidad , Poloxámero/administración & dosificación , Poloxámero/farmacocinética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Polivinilos/administración & dosificación , Polivinilos/farmacocinética , Ratas , Ratas Wistar , Resveratrol/administración & dosificación , Resveratrol/química , Solubilidad , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Simvastatin is a translational drug that may be used to induce local bone formation. In this study, simvastatin microcrystals were made by a wet media milling method, and then we verified the osteogenic effect of the microcrystals in rat ovariectomy (OVX)-induced osteoporosis and femur defect models. For the osteoporosis model, we delivered simvastatin microcrystals to the tibia with poloxamer hydrogels via an intraosseous injection. Bone mineral density and the ultimate force of the treated tibia were significantly improved after injection of simvastatin microcrystals at 0.5 and 1 mg compared with the OVX or 0-mg control groups. For the femur defect model, simvastatin microcrystals were incorporated in clinically used calcium phosphate cements (CPCs) as an implant. Quantitative analysis of bone regeneration by microcomputed tomography (µCT) showed improved bone morphology with simvastatin microcrystals at 50 and 100 µg, compared with the CPC vehicle. A semiquantitative scale for histology assessment further demonstrated a higher bone regeneration score in the drug-loaded groups. Our study shows that simvastatin microcrystals can promote bone formation by local delivery using a poloxamer hydrogel or CPC, which may be translationally useful.
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Osteoporosis/tratamiento farmacológico , Simvastatina/administración & dosificación , Simvastatina/farmacología , Animales , Densidad Ósea/efectos de los fármacos , Cristalización , Modelos Animales de Enfermedad , Composición de Medicamentos/métodos , Femenino , Fémur/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteoporosis/patología , Ovariectomía , Tamaño de la Partícula , Poloxámero/administración & dosificación , Poloxámero/química , Poloxámero/farmacología , Ratas , Ratas Sprague-Dawley , Simvastatina/química , Microtomografía por Rayos XRESUMEN
Background: In this study, we sought to provide an idea for establishing a novel mouse model for Parkinson's disease (PD) through intranasal administration of paraquat instead of the conventional method of intraperitoneal injection. Intranasal administration has the potential to lower mortality caused by intraperitoneal paraquat administration.Methods: A paraquat-loaded thermosensitive hydrogel composed of poloxamer 407 and poloxamer 188 was prepared. The survival rate of the animals was monitored upon paraquat administration nasally and intraperitoneally. The animals' behavior was also observed. Immunofluorescence staining of tyrosine hydroxylase (TH) - positive cells and western blotting of α-synuclein (α-syn)in striatum were performed. HPLC method with electrochemical detection was used to quantify monoamine neurotransmitters in striatum. Real-time RT-PCR analysis of type 1 collagen, type 3 collagen and fibronectin expression was used to evaluate pulmonary fibrosis in mice after paraquat administration.Results: The results indicated that intranasal administration of paraquat-loaded thermosensitive hydrogel can elicit Parkinsonism-like symptoms in mice. Relative to the conventional intraperitoneal injection, this strategy significantly improves survival when modeling PD and resulted in a higher loss of TH positive neurons in substantia nigra pars compacta (SNpc) and more aggregation of α-syn in striatum. Moreover, animals receiving paraquat hydrogel nasally exhibited motor disorder as well as lower levels of dopamine and dopamine metabolites in striatum when compared to those receiving paraquat intraperitoneally. The mRNA expression of collagen and fibronectinindicated that intranasal administration of paraquat was not associated with lung fibrosis.Conclusion: This strategy provides a new idea and more convenient operation for the future study of mouse model of PD.
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Administración Intranasal/métodos , Cuerpo Estriado/efectos de los fármacos , Paraquat/administración & dosificación , Paraquat/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Poloxámero/administración & dosificación , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patologíaRESUMEN
PURPOSE: Restricted shoulder mobility is a major upper extremity dysfunction associated with lower quality of life and disability after breast cancer surgery. We hypothesized that a poloxamer and sodium alginate mixture (Guardix-SG®) applied after axillary lymph node dissection (ALND) would significantly improve shoulder range of motion (ROM) in patients with breast cancer. METHODS: We conducted a double-blind, randomized, prospective study to evaluate the clinical efficacy and safety of Guardix-SG® for the prevention of upper extremity dysfunction after ALND. The primary outcome measure was shoulder ROM at baseline (T0) and 3 (T1), 6 (T2), and 12 months (T3) after surgery. Secondary outcome measures were the Disabilities of the Arm, Shoulder, and Hand score(DASH), pain associated with movement, which was assessed using a numeric rating scale, and lymphedema assessed using body composition analyzer. RESULTS: A total of 83 women with breast cancer were randomly assigned to either the Guardix-SG® group or the control group. In the Guardix-SG® group (n = 37), Guardix-SG® was applied to the axillary region after ALND. In the control group (n = 46), ALND was performed without using Guardix-SG®. Comparing ROM for shoulder flexion before surgery (178.2°) and 12 months after surgery (172.3°), that was restored 12 months after surgery in the Guardix-SG® group, and there was no statistically significant difference between that at before surgery and 12 months after surgery (p = 0.182). No adverse effect was observed in either group. CONCLUSIONS: The results of this study have shown that Guardix-SG® help improve shoulder ROM without causing adverse effects in patients who underwent breast cancer surgery. However, there was no statistically significant difference from the control group. A further large-scale study is needed to obtain a more conclusive conclusion. TRIAL REGISTRATION: CRISKCT0003386; https://cris.nih.go.kr (20181207).
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Neoplasias de la Mama/cirugía , Carboximetilcelulosa de Sodio/administración & dosificación , Ácido Hialurónico/administración & dosificación , Escisión del Ganglio Linfático/efectos adversos , Mastectomía/efectos adversos , Poloxámero/administración & dosificación , Rango del Movimiento Articular/efectos de los fármacos , Hombro/patología , Axila , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Método Doble Ciego , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Tensoactivos/administración & dosificaciónRESUMEN
The use of nanoscale materials (NMs) could cause problems such as cytotoxicity, genomic aberration, and effects on human health, but the impacts of NM exposure during pregnancy remain uncharacterized in the context of clinical applications. It was sought to determine whether nanomaterials pass through the maternal-fetal junction at any stage of pregnancy. Quantum dots (QDs) coated with heparinized Pluronic 127 nanogels and polyethyleneimine (PEI) were administered to pregnant mice. The biodistribution of QDs, as well as their biological impacts on maternal and fetal health, was evaluated. Encapsulation of QDs with a nanogel coating produces a petal-like nanotracer (PNt), which could serve as a nano-carrier of genes or drugs. PNts were injected through the tail vein and accumulated in the liver, kidneys, and lungs. QD accumulation in reproductive organs (uterus, placenta, and fetus) differed among phases of pregnancy. In phase I (7 days of pregnancy), the QDs did not accumulate in the placenta or fetus, but by phase III (19 days) they had accumulated at high levels in both tissues. Karyotype analysis revealed that the PNt-treated pups did not have genetic abnormalities when dams were treated at any phase of pregnancy. PNts have the potential to serve as carriers of therapeutic agents for the treatment of the mother or fetus and these results have a significant impact on the development and application of QD-based NPs in pregnancy.
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Portadores de Fármacos/administración & dosificación , Heparina/administración & dosificación , Poloxámero/administración & dosificación , Polietileneimina/administración & dosificación , Puntos Cuánticos/administración & dosificación , Animales , Portadores de Fármacos/farmacocinética , Femenino , Heparina/farmacocinética , Humanos , Cariotipo , Intercambio Materno-Fetal , Células Madre Mesenquimatosas , Ratones Endogámicos ICR , Poloxámero/farmacocinética , Polietileneimina/farmacocinética , Embarazo , Distribución TisularRESUMEN
Surfactants can improve the hydrophobicity of poorly water-soluble drugs and increase the stability of microparticles by reducing surface tension. This study describes that surfactant-engineered florfenicol instant microparticles (FIMs) increase bioavailability through a micellar solubilization mechanism. The FIMs were prepared by a modified emulsification method, and the optimal prescription was obtained by a combination of single factor investigation and response surface methodology. The microparticles prepared in this study reduce the polymer materials while increasing the drug content. FIM has a smaller particle size and modification of poloxamer, resulting in better solubility and higher bioavailability. The in vitro solubility of FIM is 1.43 times higher than that of the bulk drug, and the dissolution equilibrium can be achieved in 10â¯minutes. Compared with florfenicol, FIM showed a decrease in Tmax in the plasma concentration curve, with a peak concentration of 1.43 times and an area of 1.41 times. Considering the advantages of in vitro/in vivo performance and ease of preparation, FIMs may have great application prospects in pharmacy research.
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Poloxámero/farmacocinética , Tianfenicol/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Tamaño de la Partícula , Poloxámero/administración & dosificación , Poloxámero/química , Conejos , Solubilidad , Propiedades de Superficie , Tianfenicol/administración & dosificación , Tianfenicol/sangre , Tianfenicol/farmacocinéticaRESUMEN
BACKGROUND: Minimally invasive intratumoural administration of thermoresponsive hydrogels, that transition from liquid to gel in response to temperature, has been proposed as a potential treatment modality for solid tumours. The aim of this study was to assess the inherent cytotoxicity of a poloxamer-based thermoresponsive hydrogel in a murine xenograft model of lung cancer. METHODS: In vitro viability assessment was carried out in a lung cancer (A549) and non-cancerous (Balb/c 3T3 clone A31) cell line. Following intratumoural administration of saline or the thermoresponsive hydrogel to an A549 xenograft model in female Athymic Nude-Foxn1nu mice (n = 6/group), localisation was confirmed using IVIS imaging. Tumour volume was assessed using callipers measurements over 14 days. Blood serum was analysed for liver and kidney damage and ex vivo tissue samples were histologically assessed. RESULTS: The thermoresponsive hydrogel demonstrated a dose-dependent cancer cell-specific toxicity in vitro and was retained in situ for at least 14 days in the xenograft model. Tumour volume increase was statistically significantly lower than saline treated control at day 14 (n = 6, p = 0.0001), with no associated damage of hepatic or renal tissue observed. CONCLUSIONS: Presented is a poloxamer-based thermoresponsive hydrogel, suitable for intratumoural administration and retention, which has demonstrated preliminary evidence of local tumour control, with minimal off-site toxicity.
Asunto(s)
Hidrogeles/administración & dosificación , Neoplasias Pulmonares/terapia , Poloxámero/administración & dosificación , Células A549 , Técnicas de Ablación , Animales , Células 3T3 BALB , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidrogeles/efectos adversos , Hidrogeles/farmacocinética , Neoplasias Pulmonares/sangre , Ratones , Poloxámero/efectos adversos , Poloxámero/farmacocinética , Termodinámica , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Loading of gatifloxacin in contact lenses affects critical lens properties (optical and swelling) owing to drug precipitation in the contact lens matrix. The presence of Pluronic® F-68 in the packaging solution creates in-situ micelles in the contact lens to dissolve gatifloxacin precipitates and provide sustained drug release. The micelles further improved the drug uptake from the drug-packaging solution to create an equilibrium of drug between the lens matrix and the packaging solution. In this study, we optimized gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and gatifloxacin loading capacity as well as sustained drug delivery. Optimization of gatifloxacin-pluronic-loaded contact lens was carried out using a 32 factorial design by tailoring the concentration of Pluronic® F-68 in the packaging solution (X1) and the amount of gatifloxacin in the monomer solution (X2) to achieve the desired lens properties. The optimized batch (X1 = 0.3%w/v and X2 = 0.3%w/v) showed an optical transmittance of 92.84%, swelling of 92.36% and gatifloxacin loading capacity of 92.56 µg. The in vitro flux data of the optimized batch (GT-Pl-CL) showed sustained release up to 72 h, whereas soaked contact lenses (SM-CL) and direct gatifloxacin-loaded contact lenses (DL-CL) showed a sustained release up to 48 h. The in vivo gatifloxacin release data for rabbit tear fluid showed sustained release with a high gatifloxacin level for the GT-Pl-CL lens in comparison to the SM-CL and the eye drop solution. This study demonstrates the application of the 32 full factorial design to optimize gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and drug loading capacity.
Asunto(s)
Lentes de Contacto Hidrofílicos , Sistemas de Liberación de Medicamentos/métodos , Gatifloxacina/farmacocinética , Absorción Ocular/efectos de los fármacos , Soluciones Oftálmicas/farmacocinética , Poloxámero/farmacocinética , Animales , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos/efectos de los fármacos , Liberación de Fármacos/fisiología , Excipientes/administración & dosificación , Excipientes/química , Excipientes/farmacocinética , Femenino , Gatifloxacina/administración & dosificación , Gatifloxacina/química , Masculino , Absorción Ocular/fisiología , Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/química , Poloxámero/administración & dosificación , Poloxámero/química , ConejosRESUMEN
Budesonide is a glucocorticoid for the treatment of ulcerative colitis (UC). The current study aims to develop a thermosensitive in situ and adhesive gel for rectal delivery of budesonide. HPMC K4M was selected as the adhesive agent based on the adhesive force and the effect on gel performance. The formulation of gel was optimized by using the central composite design-response surface methodology (CCD-RSM); a mathematical model was successfully developed to predict desired formulations as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, and HPMC K4M and the performances of gel. Based on CCD-RSM, a thermosensitive in situ and adhesive gel consisting of 0.002% budesonide, 0.74% HPMC, 4.87% F-68, and 19.0% F-127 was developed. Furthermore, the in vivo behavior of gel was evaluated in Sprague-Dawley rats. In comparison with budesonide solution, rectal administration of budesonide gel at 0.1 mg/kg in rats showed relative bioavailability of 230% with significant increase in rectum uptake.
Asunto(s)
Adhesivos/administración & dosificación , Antiinflamatorios/administración & dosificación , Budesonida/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Adhesivos/metabolismo , Administración Rectal , Animales , Antiinflamatorios/metabolismo , Disponibilidad Biológica , Budesonida/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Femenino , Geles , Masculino , Poloxámero/administración & dosificación , Poloxámero/metabolismo , Ratas , Ratas Sprague-Dawley , Recto/efectos de los fármacos , Recto/metabolismoRESUMEN
PURPOSE: Vepoloxamer (VEPO), a rheologic agent, repairs damaged cell membranes, thus inhibiting unregulated Ca2+ entry into cardiomyocytes. This study examined the effects of i.v. infusion of VEPO on LV function in dogs with coronary microembolization-induced heart failure (HF) (LV ejection fraction, EF ~ 30%). METHODS: Thirty-five HF dogs were studied. Study 1: 21 of 35 dogs were randomized to 2-h infusion of VEPO at dose of 450 mg/kg (n = 7) or VEPO at 225 mg/kg (n = 7) or normal saline (control, n = 7). Hemodynamics were measured at 2 h, 24 h, 1 week, and 2 weeks after infusion. Study 2: 14 HF dogs were randomized to 2-h infusions of VEPO (450 mg/kg, n = 7) or normal saline (control, n = 7). Each dog received 2 infusions of VEPO or saline (pulsed therapy) 3 weeks apart and hemodynamics measured at 24 h, and 1, 2, and 3 weeks after each infusion. In both studies, the change between pre-infusion measures and measures at other time points (treatment effect, Δ) was calculated. RESULTS: Study 1: compared to pre-infusion, high dose VEPO increased LVEF by 11 ± 2% at 2 h, 8 ± 2% at 24 h (p < 0.05), 8 ± 2% at 1 week (p < 0.05), and 4 ± 2% at 2 weeks. LV EF also increased with low-dose VEPO but not with saline. Study 2: VEPO but not saline significantly increased LVEF by 6.0 ± 0.7% at 2 h (p < 0.05); 7.0 ± 0.7%% at 1 week (p < 0.05); 1.0 ± 0.6% at 3 weeks; 6.0 ± 1.3% at 4 weeks (p < 0.05); and 5.9 ± 1.3% at 6 weeks (p < 0.05). CONCLUSIONS: Intravenous VEPO improves LV function for at least 1 week after infusion. The benefits can be extended with pulsed VEPO therapy. The results support development of VEPO for treating patients with acute on chronic HF.
Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Poloxámero/administración & dosificación , Volumen Sistólico/efectos de los fármacos , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Animales , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Infusiones Intravenosas , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
The objective of the present study was to screen the effect of increased simvastatin (SVS) solubility, through mixed micelles as a model approach, on in vitro anticancer efficacy in combination with hydrophilic alendronate sodium (ADS) as a strategy to improve therapeutic efficacy and to repositioning the existing drugs. The SVS-loaded mixed micelles (SVS-MMs) composed of TPGS and Poloxamer-407 were prepared using the film dispersion method and characterized for SVS loading and mean particle size. The optimized SVS-MMs were physically mixed with plain ADS (SVS + ADS MMs) and screened for in vitro cytotoxicity using MTT assay and cell cycle arresting and apoptotic activities using FACS technique. The optimized SVS-MMs showed maximum SVS loading (97.3 ± 2.3%) with minimum particle size (206 ± 8 nm). The SVS + ADS MM treatment significantly (P < 0.001) inhibited the cell growth with low IC50 values against all cells (A549: 0.037 ± 0.028 µg/mL, MDAMB-231: 0.172 ± 0.031 µg/mL, PC-3: 0.022 ± 0.015 µg/mL). Further, the SVS + ADS MM treatment significantly inhibited the cell multiplication in the S phase and resulted in high % of late apoptotic and necrotic cells at low concentration (0.05 and 0.15 µg/mL) as compared other test samples. The above results revealed the significance of encapsulating SVS in the core of MMs (improved solubility), and high efficacy and quick effect of SVS + ADS MM treatment against all cell lines screened. Graphical abstract.
Asunto(s)
Alendronato/administración & dosificación , Antineoplásicos/administración & dosificación , Simvastatina/administración & dosificación , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Micelas , Poloxámero/administración & dosificaciónRESUMEN
Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of -10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.