RESUMEN
A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0-8 h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0-8 h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.
Asunto(s)
Composición de Medicamentos , Glicoproteínas/química , Preparaciones Farmacéuticas/química , Calibración , Química Farmacéutica , Hospitales , Preparaciones Farmacéuticas/síntesis química , Espectroscopía Infrarroja Corta , Supositorios/síntesis química , Supositorios/químicaAsunto(s)
Cafeína/envenenamiento , Sobredosis de Droga/terapia , Hemoperfusión/métodos , Diálisis Renal/métodos , Cafeína/sangre , Bebidas Energéticas/efectos adversos , Hemoperfusión/economía , Humanos , Japón , Masculino , Diálisis Renal/economía , Intento de Suicidio , Resultado del Tratamiento , Adulto JovenRESUMEN
We prepared polypseudorotaxanes (PPRXs) composed of cyclodextrin (CyD) and polyethylene glycol (PEG) inside microspheres (MSs) by an emulsifying process using polypropylene glycol (PPG) that shows temperature-dependent hydrophilicity changes; PPG is hydrophobic at high temperatures but hydrophilic at low temperatures. An aqueous solution of CyD and PEG was dispersed as droplets in PPG at 60°C then cooled to 0°C to allow water of droplets to transfer into PPG. On removal of water in the droplets, CyD and PEG were left behind as a CyD/PEG PPRX inside the solid-state MSs. Examination of α-, ß-, and γ-CyD revealed that α-CyD was suitable for the formation of PPRX containing PEG in this MS preparation procedure. Interestingly, a new PPRX composed of α-CyD and PPG was formed in the α-CyD MSs when they were prepared in the absence of PEG from the aqueous solution of α-CyD. This MS fabrication procedure can control the size and shape of PPRX particles, and will contribute to the production of new types of CyD inclusion complexes.
Asunto(s)
Ciclodextrinas/química , Microesferas , Polímeros/química , Glicoles de Propileno/química , Rotaxanos/química , Portadores de Fármacos/química , Interacciones Hidrofóbicas e Hidrofílicas , Rotaxanos/síntesis química , TemperaturaRESUMEN
BACKGROUND: Several oxaliplatin-specific scales have been proposed in clinical practice to evaluate oxaliplatin-related neurotoxicity. We investigated whether there might be a discrepancy between the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) and the Neurotoxicity Criteria of Debiopharm (DEB-NTC), the commonly used oxaliplatin-specific scales, in the evaluation of peripheral neurotoxicity. PATIENTS AND METHODS: The subjects were 42 patients with metastatic colorectal cancer who received more than 6 cycles of first-line therapy with modified FOLFOX6 and more than 6 cycles of second-line therapy with FOLFIRI. The median number and cumulative dose of oxaliplatin administrations were 10.5 (range 6-22) and 889.4 mg/m(2) (range 484.5-1875.0 mg/m(2)), respectively. The peripheral neurotoxicity was evaluated during mFOLFOX6 therapy and after its discontinuation using NCI-CTCAE ver. 3.0 and DEB-NTC. Data were collected prospectively and analyzed retrospectively. RESULTS: The concordance rate of the peripheral neurotoxicity grade determined by these criteria was low: 48.8% during mFOLFOX6 and 47.3% after discontinuation of therapy. The cumulative dose of oxaliplatin-related peripheral neurotoxicity in 50% of the patients was lower when evaluated by DEB-NTC for both grades 1 (P = 0.09) and 2 (P < 0.001). The cumulative rate of improvement from grade 2 to 1 (P < 0.001) and from grade 2 to 0 (P < 0.05) after discontinuation of mFOLFOX6 therapy was higher when NCI-CTCAE was used for the evaluation. CONCLUSION: We found a discrepancy between the NCI-CTCAE and DEB-NTC scales in the evaluation of oxaliplatin-related neurotoxicity and suggest that the concomitant use of NCI-CTCAE and DEB-NTC would be useful to maintain oxaliplatin-based chemotherapy at higher quality.
Asunto(s)
Antineoplásicos/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Organoplatinos/toxicidad , Estándares de Referencia , Adulto , Anciano , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , National Cancer Institute (U.S.) , Metástasis de la Neoplasia , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Estados UnidosRESUMEN
The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 µM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Antineoplásicos/farmacología , Proteínas de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transporte Biológico , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Células HEK293 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleótido SimpleRESUMEN
CASE: Is fomepizole necessary after massive ingestion of a mixture of methanol and ethanol? We report the case of a 37-year-old man who was transported to our Poison Center 12 h after ingesting 500 mL of fuel alcohol containing 70% methanol and 30% ethanol in a suicide attempt. On admission, he presented only with somnolence and mild metabolic acidosis. We hypothesized that most of the ethanol had been metabolized. OUTCOME: As the estimated serum concentration of methanol was lethal (242.6 mg/dL), fomepizole was given i.v. and hemodialysis was carried out twice, resulting in complete recovery. Later, the serum concentrations of both methanol and ethanol on admission were found to be 224.1 and 0.51 mg/dL, respectively. CONCLUSION: Therapeutic intervention was delayed by half a day after ingestion of a product containing methanol and ethanol in the present case. If the patient had arrived earlier, he may have only been treated with hemodialysis, but not fomepizole.
RESUMEN
CASE PRESENTATION: A 91-year-old woman was transferred to our Emergency Medical Center and Poison Center with somnolence, hypertension (186/61 mm Hg), and repeated vomiting. Three hours later, 10 transdermal patches, each containing 18 mg of rivastigmine (9.5 mg/24 h), were found on her lower back and both thighs, when miosis, facial and trunk sweating, enhanced bowel sound, hypertension, and sinus tachycardia were noted. She was diagnosed with acute cholinergic syndrome due to rivastigmine poisoning. Her hypertension and sinus tachycardia peaked 8 and 5 h after all the patches were removed, respectively. Her symptoms subsided spontaneously after 17 h. DISCUSSION: In the present case, our patient was presented with acute cholinergic syndrome due to carbamate intoxication after massive transdermal exposure to rivastigmine. Toxicological analysis revealed a remarkably high estimated serum rivastigmine concentration (150.6 ng/ml) and notably low serum butyrylcholinesterase activity (35 IU/l) on admission, with a markedly prolonged calculated elimination half-life of 6.5 h. CONCLUSIONS: Emergency physicians should consider acetylcholinesterase inhibitor exposure (e.g., rivastigmine) when patients are present with acute cholinergic syndrome.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/envenenamiento , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/inducido químicamente , Síndromes de Neurotoxicidad/etiología , Rivastigmina/envenenamiento , Taquicardia Sinusal/inducido químicamente , Administración Cutánea , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Presión Sanguínea/efectos de los fármacos , Inhibidores de la Colinesterasa/administración & dosificación , Sobredosis de Droga , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Síndromes de Neurotoxicidad/diagnóstico , Síndromes de Neurotoxicidad/fisiopatología , Rivastigmina/administración & dosificación , Índice de Severidad de la Enfermedad , Taquicardia Sinusal/diagnóstico , Taquicardia Sinusal/fisiopatología , Parche TransdérmicoAsunto(s)
Sobredosis de Droga/complicaciones , Síndrome de QT Prolongado/inducido químicamente , Parasimpatolíticos/envenenamiento , Propiofenonas/envenenamiento , Torsades de Pointes/inducido químicamente , Electrocardiografía , Femenino , Humanos , Persona de Mediana Edad , Parasimpatolíticos/sangre , Propiofenonas/sangreRESUMEN
We evaluated a needle-free injector (NFI), which has been studied as an administration device to the subcutaneous tissue, as a device to deliver drugs into skin tissues. ShimaJet used for self-injection of insulin was selected as a spring-powered NFI in this study. Weak (NFI-w) and strong (NFI-s) injectors were evaluated. Rhodamine 6G, as a model compound, was injected onto the skin surface of hairless rats and the skin distribution and amount released from the skin of the compound were followed. A modified nozzle (able to inject at an angle of 45 degrees ) was prepared in addition to the conventional dedicated nozzle. The spring constants, nozzle shapes and penetration enhancer, 1-[2-(decylthio)ethyl] azacyclopentane-2-one (HPE-101), affected not only the skin distribution, but also the release profiles of rhodamine 6G. In addition, the release profiles of rhodamine 6G after injection using NFI-w or NFI-s obeyed diffusion-controlled or membrane-controlled kinetics, respectively. This difference was probably due to the skin site (depth) of rhodamine 6G delivered by the NFI. Furthermore, HPE-101 increased the retention time of rhodamine 6G in the epidermis. The present results suggested that an NFI can be a useful tool for enhanced drug delivery into skin.
Asunto(s)
Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Inyecciones a Chorro/instrumentación , Inyecciones a Chorro/métodos , Absorción Cutánea/efectos de los fármacos , Animales , Epidermis/metabolismo , Colorantes Fluorescentes/farmacocinética , Cinética , Pirroles/farmacología , Ratas , Ratas sin Pelo , Rodaminas/farmacocinéticaRESUMEN
In the present study, we investigated whether poly-(DL-lactide-co-glycolide) (50:50) microspheres (PLG MS) containing a model antigen, ovalbumin (OVA), were delivered into mouse skin and the immune responses induced using a microparticulate bombardment system, Helios gene gun system, which can painlessly deliver the powdered drug through the stratum corneum to the epidermal-dermal interface using a high velocity supersonic flow of helium gas to accelerate the particles. The introduction of OVA-loaded PLG MS shows helium pressure-dependence, so that improved introduction can be achieved by a higher helium pressure used, thereby inducing sufficient anti-OVA IgG level. Moreover, in order to determine the type of immune system induced using particle bombardment, we investigated helper T-cell response characterized by the cytokine production in the isolated splenocytes 6 weeks after immunization and consequent production of the anti-OVA IgG subclasses in the serum in mice. As a result, IL-4 production in splenocytes and anti-OVA IgG1 level were preferentially elicited by particle bombardment with OVA-loaded PLG MS compared with IFN-gamma and anti-OVA IgG2a level. It seemed likely that particle bombardment using this system led to a Th-2 type immune response, i.e. a humoral immune response. In conclusion, this microparticulate bombardment system is a promising immunization method, expected to become an alternative to needle injection used to administer a broad range of vaccines for the treatment of various diseases.