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Many vaccines require multiple doses for full efficacy, posing a barrier for patient adherence and protection. One solution to achieve full vaccination may be attained with single-administration vaccines containing multiple controlled release doses. In this study, delayed-release vaccines were generated using atomic layer deposition (ALD) to coat antigen-containing powders with alumina. Using in vitro and in vivo methods, we show that increasing the coat thickness controls the kinetics of antigen release and antibody response, ranging from weeks to months. Our results establish an in vitro-in vivo correlation with a level of tunable control over the antigen release and antibody response times with the potential to impact future vaccine design.
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INTRODUCTION: With a limited global supply of vaccines and an increasing vaccine hesitancy, improving vaccination coverage has become a priority. Current vaccination regimes require multiple doses to be administered in a defined schedule where missed doses may lead to incomplete vaccine coverage and failure of immunization programmes. As such, there is an ever-increasing demand to convert multi-dose injectable vaccines into single-dose formats, often called single administration vaccines (SAVs). AREAS COVERED: This review summarizes recent developments in the field of SAVs, with a focus on pulsatile or controlled-release formulations. It will identify the technical challenges, translational as well as commercial barriers to SAVs development. Furthermore, the progress of SAV formulations for hepatitis B and polio vaccines will be reviewed thoroughly as case studies, with a focus on the development challenges and the preclinical immunogenicity/reactogenicity data. EXPERT OPINION: Despite the efforts to develop SAVs, few attempts have advanced to Phase-I trials. Considering the SAV development journey and bottlenecks, including commercial barriers from the early stages, may overcome some of the hurdles around the technology. The renewed global focus on vaccines since the COVID-19 pandemic could facilitate development of a new generation of technologies for pandemic preparedness including strategies for SAVs.
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COVID-19 , Vacunas , Humanos , Pandemias , COVID-19/prevención & control , Inmunización , VacunaciónRESUMEN
Immunotherapy has significantly improved treatment outcomes in various cancer entities. To enhance immunogenicity and efficacy, and to further broaden its applicability, co-administration of anti-tumor vaccines is considered as a promising strategy. Here, we introduce adeno-associated virus (AAV) vectors, widely used for in vivo gene therapy, as a potent cancer vaccine platform. Our AAV vector-based vaccine combines antigen display on the capsid surface with a vector-mediated antigen overexpression targeting different components of the immune system in a unique chronological order by a single intramuscular application. Thereby, both profound and long-lasting antigen-specific T and B cell immune responses were induced. Moreover, mice receiving the vaccine were protected against tumor growth, demonstrating its efficacy in two tumor models, including the low immunogenic and aggressive B16/F10-Ova melanoma model. Remarkably, this approach was even effective in conditions of a late tumor challenge, i.e., 80 days post-vaccination, between 88% (B16/F10-Ova melanoma) and 100% (EG7 thymoma) of mice remained tumor free. Thus, decorating AAV vector particles with antigens by capsid engineering represents a potent vaccine concept for applications in cancer immunotherapy. Its modular and versatile "plug-and-play" framework enables the use of tumor antigens of choice and the easy implementation of additional modifications to enhance immunogenicity further.
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La presente investigación realiza un recorrido por el concepto de confiabilidad como una de las propiedades psicométricas fundamentales en la Teoría Clásica de los Test. Se desarrolla el concepto y cuáles son sus diferentes aplicaciones prácticas para indagar el grado de confiabilidad de un instrumento de medición. Se centra el estudio en el cálculo de la consistencia interna a partir del alfa y el omega como los coeficientes más utilizados y la importancia de calcularlos mediante la utilización de matrices de correlaciones policoricas (MCP). Como objetivo principal se presenta una guía en español para el cálculo de coeficientes ordinales de confiabilidad al utilizar el programa R/RStudio. Se brinda un ejemplo a nivel empírico que da cuenta la relevancia de calcular este tipo decoeficientes para el cálculo de la confiabilidad de un instrumento. Al emplear una muestra de 266 adultos entre 18 y 63 años (M = 31.91, DE = 11.50), se administró la versión adaptada a argentina del Inventario de Ansiedad de Beck y el Cuestionario de Regulación Emocional. De esta manera, se exponen coeficientes para estimar la confiabilidad de los instrumentos que dan cuenta de sus ventajas y desventajas, al realizar el cálculo mediante MCP, matriz de correlaciones de Pearson y matriz de covarianzas de Pearson. A partir de los resultados, se evidencia que el cálculo mediante MCP proporcionó grados de confiabilidades mayores respecto al cálculo mediante las otras dos matrices. Se espera que el presente documento sea de importancia para investigadores no familiarizados con R.
The present study takes a tour of the concept of reliability as one of the fundamental psychometric properties in Classical Tests Theory. The concept and its different practical applications are developed to investigate the degree of reliability of a measuring instrument. Focusing on the calculation of internal consistency from alpha and omega as the most used coefficients and the importance of calculating these coefficients by using polychoric correlation matrices (PCM). The main objective is to present a guide in Spanish for the calculation of ordinal reliability coefficients using the R/Rstudio program. Providing an example at the empirical level that shows the relevance of calculating this type of coefficients for calculating the reliability of an instrument. Using a sample of 266 adults between the ages of 18 and 63 years (M = 31.91 SD = 11.50), the version adapted to Argentina of the Beck Anxiety Inventory and the Emotional Regulation Questionnaire were administered. In this way, coefficients are exposed to estimate the reliability of the instruments that account for their advantages and disadvantages, performing the calculation using MCP, Pearson's correlation matrix and Pearson's covariance matrix. From the results, it is evident that the calculation using MCP provided higher degrees of reliability compared to the calculation using the other two matrices. This document is expected to be of importance to researchers unfamiliar with R.
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Humanos , Adolescente , Adulto , Persona de Mediana Edad , Ansiedad/psicología , Reproducibilidad de los Resultados , Confianza/psicología , Pruebas NeuropsicológicasRESUMEN
Glutamine is an amino acid that is mainly used for the treatment of gastrointestinal diseases in clinic, but there is a lack of such medicine in veterinary clinic, and its research in dogs has never been seen. This study aimed to investigate the pharmacokinetics of single and multiple administration of glutamine (Gln) tablets in Beagles. Twenty-four healthy Beagles were randomly selected for the pharmacokinetic study of a single dose of low (120 mg/kg), medium (240 mg/kg), and high (360 mg/kg) Gln tablets. After 7 days of washout period, six Beagles in the medium group were selected for a multiple-dose pharmacokinetic study, 240 mg/kg twice a day for 7 days. The Gln concentration in plasma was determined by a validated UPLC-MS/MS method. The results of single oral administration of different doses of Gln tablets showed that Cmax, AUC0ât, AUC0ââ had a certain linear relationship with the dosage. T-tests were performed for single and multiple administration of Tmax, Cmax, t1/2λz, AUC0ât, and AUC0ââ, and the results showed no significant differences (p > 0.05). Therefore, Gln tablets were absorbed quickly by oral administration, and there was no accumulation in Beagles after 7 days of administration.
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Tibetan medicine is one of the oldest traditional medicine systems in the world. Taking the Ruyi Zhenbao tablet (RYZB) as an example, which is a widely used classic oral Tibetan medicine, this article discusses the pharmacokinetics of single administration and long-term treatment and analyzed its metabolic properties and tissue distribution in vivo. After single administration, blood samples were collected before administration and at different time points after administration in different groups of rats. In the study of long-term treatment effects, blood samples were collected from the animals in each group on days 1, 15, and 30 and on day 15 after withdrawal. The results showed that after a single administration, the dose change had no significant effect on the T1/2 and Tmax of agarotetrol, isoliquiritigenin, and piperine (p > 0.05). There was a certain correlation between the increase in AUC0-t and the Cmax of agarotetrol, isoliquiritigenin, piperine, and the increase in dosage, with a dose range of 0.225-0.900 g/kg. There were no significant differences in Cmax and AUC0-t of ferulic acid at different doses (p > 0.05). Meanwhile, there was no significant sex-based difference in the pharmacokinetic parameters of these four components in rats. After long-term administration, the distribution agarotetrol in various tissues of rats was kidney > liver > heart > brain; the tissue distribution in low- and medium-dose groups of isoliquiritigenin was liver > kidney > heart > brain, and in the high-dose group, kidney > liver > heart > brain. The tissue distribution of piperine in each dose group was liver > kidney > heart > brain, and that of ferulic acid in each dose group was kidney > liver > heart > brain. Through the establishment of the previously developed methodology, the pharmacokinetic properties of RYZB were analyzed after a single administration and long-term administration. Our findings confirmed this approach for the exploration and establishment of a pharmacokinetic evaluation of Tibetan medicine, to support its guiding role in clinical application, but also to accelerate research into Tibetan medicine theory and medicine and to provide a solid foundation for the translation of Tibetan medicine throughout the world.
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Multiple vaccines can be mixed into a single combination to be a single product. However, combination vaccines have problems of complexity. In this study, microneedles were utilized in a compartmental microneedle array (CMA) to deliver two influenza vaccine strains without mixing. In this study, the CMA had two compartments, and two rectangular structures were attached to each end of the array to enable integration of the compartments with the coating equipment. The coating solution, which contained influenza vaccines for B/Yamagata (B-Y) and B/Victoria (B-V), was filled into the two reservoirs of the container. The CMA was aligned with the container for dipping the first compartment of the array into the first reservoir and the second compartment into the second reservoir. The CMA containing B-Y and B-V separately was administered to mice, and weight change and survival were compared with other groups of mice administered (a) combination vaccines with microneedles, (b) two monovalent vaccines with microneedles, (c) intramuscularly with a combination vaccine, and (d) intramuscularly with two monovalent vaccines. Plaque reduction neutralization tests were also performed to compare the CMA group with the other groups. The CMA showed a relative standard error of less than 7% between samples in dose uniformity. It also showed comparable antibody-forming efficacy compared to other groups, especially by B/Yamagata virus challenge. The CMA mice group showed better survival and weight change than mice that received intramuscular (IM) injection of the combination vaccine. In the neutralizing antibody experiment, all microneedle groups showed a higher neutralizing antibody than the IM groups. Vaccines were administered without mixing by a single administration using a CMA, and the CMA showed comparable efficacy with IM administration of the combination vaccine. Multivalent vaccines can be delivered without mixing as a single product by using a CMA.
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Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Animales , Anticuerpos Antivirales , Ratones , Agujas , Vacunación , Vacunas CombinadasRESUMEN
Poorly managed postoperative pain decreases patient satisfaction, impedes early patient mobilization, lengthens inpatient hospital stay, and increases healthcare costs. Multimodal analgesia with local anesthetics is considered most effective for postoperative pain management. This study compared patients undergoing lumbar fusion who received plain bupivacaine from May 2011 until August 2012 with those who received liposomal bupivacaine from September 2012 until May 2013. The aim was to determine which preparation reduced postoperative opioid use the most. All lumbar spinal fusion surgeries in the periods indicated were included in the study. Ninety-three patient charts were reviewed: 47 for the plain bupivacaine group and 46 for the liposomal bupivacaine group. The study found no statistical difference between liposomal and plain bupivacaine in providing postoperative pain control from lumbar fusion surgery. Liposomal bupivacaine is as effective as plain bupivacaine for postoperative pain control after lumbar fusion. However, a continuous infusion system carries substantial inherent drawbacks: need for training and setup, pump cost, risk of infection at the insertion site, or catheter migration. Therefore, liposomal bupivacaine becomes the logical and attractive choice to manage postoperative pain following lumbar fusion.
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Anestésicos Locales/administración & dosificación , Bupivacaína/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Fusión Vertebral , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Vértebras Lumbares , Masculino , Persona de Mediana Edad , Manejo del Dolor , Dimensión del Dolor , Distribución Aleatoria , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We report a case of a 73-year-old man diagnosed with pulmonary pleomorphic carcinoma who showed profound durable response after a single treatment with pembrolizumab. The patient underwent a diagnostic workup in our hospital due to a hoarseness of voice. Chest computed tomography revealed a massive pulmonary tumor in the left upper lobe and multiple nodules in the both lung fields. Histological examination of a transbronchial lung biopsy specimen revealed pulmonary pleomorphic carcinoma. First-line treatment with pembrolizumab was discontinued after a single administration due to treatment-related pneumonitis. However, durable response has been observed over 17 months to date.
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OBJECTIVE： To study the effects of berberine hydrochloride on the pharmacokinetics of tacrolimus in rats after single or multiple administration， and to provide reference for clinical combination therapy. METHODS： 30 rats were randomly divided into 5 groups， with 6 rats in each group： group one was treated with single administration of tacrolimus； group two was treated with tacrolimus intragastrically， twice a day， for consecutive 1 week； group three was treated with single administration of berberine hydrochloride， 5 min later given single administration of tacrolimus； group four was treated with tacrolimus intragastrically， twice a day， for consecutive 1 week， and then given tacrolimus intragastrically once 5 min after intragastric administration of berberine hydrochloride on the 8th day； group five was treated with berberine hydrochloride intragastrically， twice a day， and given tacrolimus intragastrically every 5 min， for consecutive 8 d. The doses of berberine hydrochloride and tacrolimus were 200 mg/kg and 0.945 mg/kg. The blood samples 0.3 mL were collected from posterior orbital venous plexus of rats 0， 5， 15， 30 min and 1， 2， 3， 4， 6， 8， 12 h after last intragastric administration of tacrolimus. The concentration of tacrolimus in rat whole blood was determined by LC-MS/MS. DAS 2.0 software was used for pharmacokinetic study. RESULTS： Compared with group one， the pharmacokinetic parameters AUC0-12 h， AUC0-∞ and MRT0-12 h of tacrolimus in rats were decreased significantly in group three （P＜0.05），while there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group four （P＞0.05）. Compared with group two， AUC0-12 h of tacrolimus was decreased significantly while CLz was increased significantly in group four （P＜0.05）； there was no statistical significance in all pharmacokinetic parameters of tacrolimus in group five （P＞0.05）. CONCLUSIONS： Single and multiple intragastric administration of berberine hydrochloride has a certain effect on the pharmacokinetics of tacrolimus in rats， it shows that there is a downward trend in blood drug concentration and needs to be used with caution.
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Vaccination in the developing world is hampered by limited patient access, which prevents individuals from receiving the multiple injections necessary for protective immunity. Here, we developed an injectable microparticle formulation of the inactivated polio vaccine (IPV) that releases multiple pulses of stable antigen over time. To accomplish this, we established an IPV stabilization strategy using cationic polymers for pH modulation to enhance traditional small-molecule-based stabilization methods. We investigated the mechanism of this strategy and showed that it was broadly applicable to all three antigens in IPV. Our lead formulations released two bursts of IPV 1 month apart, mimicking a typical vaccination schedule in the developing world. One injection of the controlled-release formulations elicited a similar or better neutralizing response in rats, considered the correlate of protection in humans, than multiple injections of liquid vaccine. This single-administration vaccine strategy has the potential to improve vaccine coverage in the developing world.
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Esquemas de Inmunización , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacunación/métodos , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Inyecciones/métodos , Microesferas , Poliomielitis/prevención & control , Ratas , Ratas WistarRESUMEN
Niemann-Pick type C2 (NPC2) disease is a rare, neurodegenerative disorder caused by mutations in the NPC2 gene, leading to lysosomal accumulation of unesterified cholesterol and other lipids. It is characterized by hepatosplenomegaly, liver dysfunction and severe neurological manifestations, resulting in early death. There is no effective therapy for NPC2 disease. Here, we evaluated the effectiveness of an adeno-associated virus (AAV), serotype rh.10 gene transfer vector expressing the mouse Npc2 gene (AAVrh.10-mNpc2-HA, HA tagged to facilitate analysis) to treat the disease in an Npc2-/- mouse model. A single intracisternal administration of the AAVrh.10-mNpc2-HA to 6 week old Npc2-/- mice mediated vector DNA, transgene mRNA and protein expression in brain and other organs. Compared to untreated Npc2-/- mice, AAV-treated Npc2-/- mice demonstrated amelioration of disease pathology in the brain, reduced lysosomal storage, reduced Purkinje cell death, decreased gliosis, and improved performance in behavioral tasks. Treatment-related reduction in serum disease markers was detected early and this effect persisted. Liver and spleen pathology were improved with significant reduction of liver cholesterol and sphingomyelin levels in treated Npc2-/- mice. Finally, administration of AAVrh.10-mNpc2-HA significantly extended life-span. Taken together, these data demonstrate the benefit of a one-time intracisternal administration of AAVrh.10-mNpc2-HA as a life-long treatment for NPC2 disease.
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Terapia Genética/métodos , Enfermedad de Niemann-Pick Tipo C/terapia , Proteínas de Transporte Vesicular/genética , Animales , Cisterna Magna , Dependovirus/genética , Expresión Génica , Vectores Genéticos , Esperanza de Vida , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Microinyecciones , Actividad Motora , Enfermedad de Niemann-Pick Tipo C/patología , Enfermedad de Niemann-Pick Tipo C/psicología , Fenotipo , Desempeño Psicomotor , Bazo/patologíaRESUMEN
Viral nanoparticles have been utilized as a platform for vaccine development and are a versatile system for the display of antigenic epitopes for a variety of disease states. However, the induction of a clinically relevant immune response often requires multiple injections over an extended period of time, limiting patient compliance. Polymeric systems to deliver proteinaceous materials have been extensively researched to provide sustained release, which would limit administration to a single dose. Melt-processing is an emerging manufacturing method that has been utilized to create polymeric materials laden with proteins as an alternative to typical solvent-based production methods. Melt-processing is advantageous because it is continuous, solvent-free, and 100% of the therapeutic protein is encapsulated. In this study, we utilized melt-encapsulation to fabricate viral nanoparticle laden polymeric materials that effectively deliver intact particles and generate carrier specific antibodies in vivo. The effects of initial processing and postprocessing on particle integrity and aggregation were studied to develop processing windows for scale-up and the creation of more complex materials. The dispersion of particles within the PLGA matrix was studied, and the effect of additives and loading level on the release profile was determined. Overall, melt-encapsulation was found to be an effective method to produce composite materials that can deliver viral nanoparticles over an extended period and elicit an immune response comparable to typical administration schedules.
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Implantes Absorbibles , Allolevivirus/química , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Virión/química , Allolevivirus/inmunología , Animales , Inmunización/métodos , Masculino , Ratones Endogámicos BALB C , Vacunas Virales/administración & dosificación , Vacunas Virales/inmunología , Virión/inmunologíaRESUMEN
In nonhumans, the sex steroid testosterone regulates reproductive behaviors such as fighting between males and mating. In humans, correlational studies have linked testosterone with aggression and disorders associated with poor impulse control, but the neuropsychological processes at work are poorly understood. Building on a dual-process framework, we propose a mechanism underlying testosterone's behavioral effects in humans: reduction in cognitive reflection. In the largest study of behavioral effects of testosterone administration to date, 243 men received either testosterone or placebo and took the Cognitive Reflection Test (CRT), which estimates the capacity to override incorrect intuitive judgments with deliberate correct responses. Testosterone administration reduced CRT scores. The effect remained after we controlled for age, mood, math skills, whether participants believed they had received the placebo or testosterone, and the effects of 14 additional hormones, and it held for each of the CRT questions in isolation. Our findings suggest a mechanism underlying testosterone's diverse effects on humans' judgments and decision making and provide novel, clear, and testable predictions.
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Testosterona/farmacología , Pensamiento/efectos de los fármacos , Adulto , Humanos , Masculino , Testosterona/administración & dosificación , Testosterona/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: A DNA-human Ad5 (HuAd5) prime-boost malaria vaccine has been shown to protect volunteers against a controlled human malaria infection. The potency of this vaccine, however, appeared to be affected by the presence of pre-existing immunity against the HuAd5 vector. Since HuAd5 seroprevalence is very high in malaria-endemic areas of the world, HuAd5 may not be the most appropriate malaria vaccine vector. This report describes the evaluation of the seroprevalence, immunogenicity and efficacy of three newly identified gorilla adenoviruses, GC44, GC45 and GC46, as potential malaria vaccine vectors. RESULTS: The seroprevalence of GC44, GC45 and GC46 is very low, and the three vectors are not efficiently neutralized by human sera from Kenya and Ghana, two countries where malaria is endemic. In mice, a single administration of GC44, GC45 and GC46 vectors expressing a murine malaria gene, Plasmodium yoelii circumsporozoite protein (PyCSP), induced robust PyCSP-specific T cell and antibody responses that were at least as high as a comparable HuAd5-PyCSP vector. Efficacy studies in a murine malaria model indicated that a prime-boost regimen with DNA-PyCSP and GC-PyCSP vectors can protect mice against a malaria challenge. Moreover, these studies indicated that a DNA-GC46-PyCSP vaccine regimen was significantly more efficacious than a DNA-HuAd5-PyCSP regimen. CONCLUSION: These data suggest that these gorilla-based adenovectors have key performance characteristics for an effective malaria vaccine. The superior performance of GC46 over HuAd5 highlights its potential for clinical development.
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Adenovirus de los Simios , Vectores Genéticos/normas , Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Infecciones por Adenovirus Humanos/epidemiología , Infecciones por Adenovirus Humanos/virología , Adenovirus de los Simios/genética , Adenovirus de los Simios/inmunología , Animales , Anticuerpos Antivirales/sangre , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos/genética , Vectores Genéticos/inmunología , Ghana/epidemiología , Gorilla gorilla , Humanos , Interferón gamma/sangre , Kenia/epidemiología , Malaria/epidemiología , Vacunas contra la Malaria/normas , Ratones , Ratones Endogámicos BALB C , Plásmidos , Plasmodium yoelii/inmunología , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Estudios Seroepidemiológicos , Bazo/citología , Bazo/inmunología , Linfocitos T/inmunología , Transgenes/inmunología , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE:To study the pharmacokinetic characteristics of Recombinant hirudin enteric-coated capsule by single and multiple administration in Beagle dogs. METHODS:12 Beagle dogs were divided into single ig group and single iv group by random control method,6 in each group. Recombinant hirudin 0.2 mg/kg was intragastrically administrated or intravenously inject-ed,blood sample was collected;after 2 weeks of cleaning,12 dogs were intragastrically administrated recombinant hirudin 0.2 mg/kg,for 7 d. Sample blood was collected,referred to multiple ig group. Recombinant hirudin concentration in plasma was deter-mined by enzyme-linked immunosorbent assay,and pharmacokinetic parameters were calculated by DAS 2.0 software. RESULTS:The results showed that pharmacokinetics by ig and iv recombinant hirudin in Beagle dogs fitted to two-compartment model,abso-lute bioavailability of ig Recombinant hirudin enteric-coated capsule was(14.908±1.868)%;the pharmacokinetic parameters in sin-gle ig group and multiple ig group were tpeak of(2.105±0.243),(3.000±0.000)h,t1/2β of(8.660±2.965),(14.870±2.710)h, cmax of(10.700±0.872),(12.05±1.587)ng/mL,AUC0-1440 min of(55.250±4.386),(58.978±6.002)ng·h/mL,without statistical significances in two groups(P>0.05). CONCLUSIONS:The ig Recombinant hirudin enteric-coated capsule can be absorbed into the blood to a certain extent. There is no accumulation for ig Recombinant hirudin enteric-coated capsule for several days,and it dose not change the pharmacokinetic characteristics.
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Objective To study the time-toxicity and dose-toxicity relationship of hepatotoxicity induced by Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning Capsules (CQC) with single dose in mice.Methods In the Time-Toxicity relationship study,Kunming mice were randomly divided into control,PT,CPAH,CDH,and CQC group,and mice of.each drug administration group were randomly divided into nine subgroups according to the time (1,2,4,8,12,24,48,72 and 96 h after administration) of blood collection.The acetaminophen contents in PT,CPAH,and CDH groups were 425.98 mg/kg,and the dose of CQC group was 3 680.50 mg/kg.In the Dosage-Time relationship study,mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium and low dose group.The acetaminophen contents of high,medium,and low dose were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH group,and the dose of CQC group was 1437.70,2300.31,and 3680.50 mg/kg,10 mice in each group,sex in half.Blood was collected 12 h after administration.Animal behavior was observed every day,blood and organs were collected at the corresponding time points,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),and alkaline phosphatase (ALP) level were detected,and the organs index of spleen and thymus,liver were calculated.Results There were no significant changes of ALT,AST,ALP,and organs index after once ig administration of CQC at dosage of 1437.70 mg/kg to 3680.50 mg/kg in mice.The study on time-toxicity relationship indicated that,after once administration of PT,CPAH,and CDH at 425.98 mg/kg,mice showed toxic symptom such as hypokinesia,dry hair and so on,12 h was the most obvious,24 ～ 72 h disappeared.The level of ALT,AST,and ALP in serum increased and reached to the peak at 12 h and then restored near normality after 72,24,and 24 h in PT,CPAH,and CDH group.Their organ index of liver,spleen and thymus all had no significant changes.The study on the dosage-toxicity relationship indicated that,there were no significant changes of animal behavior,ALT,AST,ALP,and organs index after once ig administration of PT,CPAH,and CDH at 266.24 mg/kg.Obvious liver injury can be induced by the three drugs with dosage of 425.98 to 681.57 mg/kg and the level of ALT,AST,and ALP increased significantly with the increase of dosage.Their liver index increased significantly with dosage of 681.57 mg/kg,but the organs index of spleen,thymus had no significant changes.Conclusion There was no hepatotoxicity after once ig administration of CQC with dosage of 3680.50 mg/kg in mice.Mice were once ig administration ofPT,CPAH,and CDH with a large dose,may induce acute liver injury and show obvious time-toxicity and dose-toxicity relationships.
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Many pathogens enter the host through mucosal surfaces and spread rapidly via the circulation. The most effective way to prevent disease is to establish mucosal and systemic immunity against the pathogen. However, current vaccination programs in poultry industry require repeated administrations of live-attenuated virus or large amounts (10 to 100µg) of antigen together with adjuvant to induce specific secretory IgA immune responses at the mucosal effector sites. In the present study, we show that a single administration of 0.4µg of oligopeptide complexed with an agonistic anti-chicken CD40 (chCD40) monoclonal antibody (Mab) effectively targets antigen-presenting cells of the bird's mucosa-associated lymphoid tissue in vivo, and induces peptide-specific secretory IgA (sIgA) in the trachea 7days post administration. Anti-chCD40 Mab-peptide complex was administered once to four-week old male Leghorns via various mucosal routes (orally, via cloacal drinking, or oculo-nasally) or via subcutaneous (s.c.) immunization. Immunization through any of the three mucosal induction routes induced significant peptide-specific mucosal sIgA responses 7 and 14days after immunization. Interestingly, s.c. injection of the complex also induced mucosal sIgA. Our data suggest in vivo targeting of CD40 as a potential adjuvant platform, particularly for the purpose of enhancing and speeding up mucosal vaccine responses in chickens, and potentially other food animals. This is the first study able to elicit specific sIgA immune responses in remote mucosal sites with a single administration of only 0.4µg of antigen.
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Proteínas Aviares/metabolismo , Antígenos CD40/inmunología , Pollos/inmunología , Inmunoglobulina A Secretora/metabolismo , Enfermedades de las Aves de Corral/prevención & control , Vacunación/veterinaria , Adyuvantes Inmunológicos/administración & dosificación , Administración Intranasal/veterinaria , Administración Oral , Animales , Antígenos CD40/administración & dosificación , Inyecciones Subcutáneas/veterinaria , Masculino , Membrana Mucosa/inmunologíaRESUMEN
PURPOSE: Tedizolid phosphate is a new antibacterial agent under investigation for the treatment of Gram-positive infections in China. This study was conducted to assess the pharmacokinetic (PK) properties, oral bioavailability, and safety of once daily tedizolid phosphate 200 mg in Chinese subjects to support its further clinical development in China. METHODS: This Phase I single-center study, conducted in 16 healthy Chinese male subjects, consisted of a single-dose administration, 1:1 randomized, two-way, intravenous (IV)/oral (PO) crossover of tedizolid phosphate 200 mg (Part 1) and, after a 7-day washout, a nonrandomized, multiple-dose, 7-day tedizolid phosphate 200 mg once daily administration (IV for 3 days, PO for 4 days; Part 2). Blood samples were collected for up to 72 hours after single dosing and for up to 2 hours on Day 3 and 72 hours on Day 7 of multiple dosing to determine PK parameters. Adverse events (AEs) were recorded throughout the entire study. FINDINGS: The Cmax and AUC of tedizolid (the active moiety of tedizolid phosphate) were 3.02 µg/mL and 30.50 µg ⢠h/mL after single IV dosing of tedizolid phosphate, and 2.25 µg/mL and 26.10 µg ⢠h/mL after single PO dosing, respectively, and the mean half-life was 10.1 hours for both administration routes. The oral bioavailability of tedizolid was 85.5%. PK parameters of tedizolid were similar after single and multiple dosing of tedizolid phosphate, indicating no time dependency. Only minor accumulation of tedizolid was observed after multiple dosing (expressed as accumulation ratios RAAUC: 1.18 for PO dosing, and RACmax: 1.16 and 1.05 for IV and PO dosing, respectively). Steady state of tedizolid was reached after about 3 days, and trough concentrations remained constant when switching from IV to PO dosing. Tedizolid phosphate was well tolerated with 6 subjects (37.5%) in Part 1 and 5 subjects (31.3%) in Part 2 experiencing an AE; all AEs but one were related to the study drug assessed by the investigator. All AEs were of mild intensity and had recovered or resolved by the end of the study. No serious AEs were observed, and no subjects prematurely discontinued the study due to an AE. IMPLICATIONS: The results of this Phase I study conducted in Chinese male subjects indicate that no dosage adjustment of tedizolid phosphate 200 mg would be required when switching administration routes in this population. Tedizolid phosphate was well tolerated in healthy Chinese subjects. China Food and Drug Administration clinical trial permission numbers 2014L00360 and 2014L00361.
Asunto(s)
Antibacterianos/administración & dosificación , Organofosfatos/administración & dosificación , Oxazoles/administración & dosificación , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Pueblo Asiatico , Disponibilidad Biológica , China , Estudios Cruzados , Semivida , Humanos , Masculino , Persona de Mediana Edad , Organofosfatos/efectos adversos , Organofosfatos/farmacocinética , Oxazoles/efectos adversos , Oxazoles/farmacocinética , Adulto JovenRESUMEN
Vaccines are a critical clinical tool in preventing illness and death due to infectious diseases and are regularly administered to children and adults across the globe. In order to obtain full protection from many vaccines, an individual needs to receive multiple doses over the course of months. However, vaccine administration in developing countries is limited by the difficulty in consistently delivering a second or third dose, and some vaccines, including the inactivated polio vaccine (IPV), must be injected more than once for efficacy. In addition, IPV does not remain stable over time at elevated temperatures, such as those it would encounter over time in the body if it were to be injected as a single-administration vaccine. In this manuscript, we describe microspheres composed of poly(lactic-co-glycolic acid) (PLGA) that can encapsulate IPV along with stabilizing excipients and release immunogenic IPV over the course of several weeks. Additionally, pH-sensitive, cationic dopants such as Eudragit E polymer caused clinically relevant amounts of stable IPV release upon degradation of the PLGA matrix. Specifically, IPV was released in two separate bursts, mimicking the delivery of two boluses approximately one month apart. In one of our top formulations, 1.4, 1.1, and 1.2 doses of the IPV serotype 1, 2, and 3, respectively, were released within the first few days from 50mg of particles. During the delayed, second burst, 0.5, 0.8, and 0.6 doses of each serotype, respectively, were released; thus, 50mg of these particles released approximately two clinical doses spaced a month apart. Immunization of rats with the leading microsphere formulation showed more robust and long-lasting humoral immune response compared to a single bolus injection and was statistically non-inferior from two bolus injections spaced 1 month apart. By minimizing the number of administrations of a vaccine, such as IPV, this technology can serve as a tool to aid in the eradication of polio and other infectious diseases for the improvement of global health.