RESUMO
OBJECTIVE: The focus of this study was to investigate the possibility of producing ibuprofen-nicotinamide (IBU-NIC) and ibuprofen-isonicotinamide (IBU-INA) cocrystal-containing granules, using a one-step fluidized bed dryer granulation manufacturing process, and evaluate their mechanical properties. SIGNIFICANCE: Pharmaceutical cocrystals represent a suitable strategy to improve properties of active pharmaceutical ingredients (APIs), such as solubility and processability. Ibuprofen (IBU) is a small molecule API which can form cocrystals with different coformers, including NIC and INA. An improvement in mechanical properties for IBU-NIC cocrystals relative to IBU was previously reported but, to date, the formulation of IBU cocrystals in a solid dosage form has not been investigated. METHODS: In situ cocrystallization and granulation were achieved concurrently by processing in a lab-scale fluidized bed granulator following a design of experiment (DoE) approach using a two-level factorial design with both process and formulation variables. Solid-state, micrometric, dissolution, and mechanical (tabletability) characteristics of granules were assessed post-processing. RESULTS: Granules containing cocrystals were successfully prepared for 11 of 16 DoE runs. Parameters with a significant effect on granule drug loading, flow function, porosity, and size could be identified from the DoE model. Process yield was increased by using a high inlet temperature at high solution feed rate. To avoid the formation of sticky particles, caking and over-wetting of the powder during the process, the utilization of high inlet temperature, low API + coformer:filler ratio, low API concentration in solution and low solution feed rate were suggested by the model. CONCLUSION: The multivariable model developed enables accurate optimization of the granulation process for IBU cocrystals.
Assuntos
Excipientes , Ibuprofeno , Porosidade , Pós , SolubilidadeRESUMO
The incidence of fungal pulmonary infections is known to be on the increase, and yet there is an alarming gap in terms of marketed antifungal therapies that are available for pulmonary administration. Amphotericin B (AmB) is a highly efficient broad-spectrum antifungal only marketed as an intravenous formulation. Based on the lack of effective antifungal and antiparasitic pulmonary treatments, the aim of this study was to develop a carbohydrate-based AmB dry powder inhaler (DPI) formulation, prepared by spray drying. Amorphous AmB microparticles were developed by combining 39.7 % AmB with 39.7 % γ-cyclodextrin, 8.1 % mannose and 12.5 % leucine. An increase in the mannose concentration from 8.1 to 29.8 %, led to partial drug crystallisation. Both formulations showed good in vitro lung deposition characteristics (80 % FPF < 5 µm and MMAD < 3 µm) at different air flow rates (60 and 30 L/min) when used with a DPI, but also during nebulisation upon reconstitution in water.
Assuntos
Anfotericina B , Pneumonia , Humanos , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Inaladores de Pó Seco , Manose , Pulmão , Macrófagos Alveolares , Administração por Inalação , Tamanho da Partícula , Pós/farmacologia , Aerossóis e Gotículas RespiratóriosRESUMO
The present study evaluates the effect of L-leucine concentration and operating parameters of a laboratory spray dryer on characteristics of trehalose dry powders, with the goal of optimizing production of these powders for inhaled drug delivery. Trehalose/L-leucine mixtures were spray dried from aqueous solution using a laboratory spray dryer. A factorial design of experiment (DoE) was undertaken and process parameters adjusted were: inlet temperature, gas flow rate, feed solution flow rate (pump setting), aspiration setting and L-leucine concentration. Resulting powders were characterised in terms of particle size, yield, residual moisture content, and glass transition temperature. Particle size was mainly influenced by gas flow rate, whereas product yield and residual moisture content were found to be primarily affected by inlet temperature and spray solution feed rate respectively. Interactions between a number of different process parameters were elucidated, as were relationships between different responses. The leucine mass ratio influenced the physical stability of powders against environmental humidity, and a high leucine concentration (30% w/w) protected amorphous trehalose from moisture induced crystallization. High weight ratio of leucine in the formulation, however, negatively impacted the aerosol performance. Thus, in terms of L-leucine inclusion in a formulation designed for pulmonary delivery, a balance needs to be found between physical stability and deposition characteristics.
Assuntos
Composição de Medicamentos/métodos , Leucina/química , Trealose/química , Administração por Inalação , Aerossóis , Dessecação , Desenho de FármacosRESUMO
Currently in the pharmaceutical industry, continuous manufacturing is an area of significant interest. In particular, hot-melt extrusion (HME) offers many advantages and has been shown to significantly reduce the number of processing steps relative to a conventional product manufacturing line. To control product quality during HME without process interruption, integration of inline analytical technology is critical. Vibrational spectroscopy (Raman, NIR and FT-IR) is often employed and used for real-time measurements because of the non-destructive and rapid nature of these analytical techniques. However, the establishment of reliable Process Analytical Technology (PAT) tools for HME of thermolabile drugs is challenging. Indeed, the Raman effect is inherently weak and might be subject to interference. Moreover, during HME, heating and photodecomposition can occur and disrupt spectra acquisition. The aim of this research article was to explore the use of inline Raman spectroscopy to characterise a thermolabile drug, ramipril (RMP), during continuous HME processing. Offline measurements by HPLC, LC-MS and Raman spectroscopy were used to characterise RMP and its main degradation product, ramipril-diketopiperazine (RMP-DKP, impurity K). A set of HME experiments together with inline Raman spectroscopic analyses were performed. The feasibility of implementing inline Raman spectroscopic analysis to quantify the level of RMP and RMP-DKP in the extrudate was addressed. Two regions in the Raman spectrum were selected to differentiate RMP and RMP-DKP. When regions were combined, a principle component analysis (PCA) model defined by these two main components (PC 1â¯=â¯50.1% and PC 2â¯=â¯45%) was established. Using HPLC analyses, we were able to confirm that the PC 1 score was attributed to the level of RMP-DKP, and the PC 2 score was related to the RMP drug content. Investigation of the PCA scatterplot indicated that HME processing temperature was not the only factor causing RMP degradation. Additionally, the plasticiser content, feeding speed and screw rotating speed contributed to RMP degradation during HME processing.
Assuntos
Tecnologia de Extrusão por Fusão a Quente , Controle de Qualidade , Análise Espectral Raman/métodos , Cromatografia Líquida de Alta Pressão , Citratos/química , Combinação de Medicamentos , Plastificantes/química , Ácidos Polimetacrílicos/química , Ramipril/químicaRESUMO
The purpose of this study was to prepare excipient-free porous microparticles of bendroflumethiazide by spray drying and to characterise the physicochemical properties of the particles produced. Solutions of bendroflumethiazide in ethanol/water, ethanol/water/ammonium carbonate or methanol/water/ammonium carbonate were spray dried using a laboratory spray dryer. Spray dried products were characterised by scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, FTIR, laser diffraction particle sizing and density measurement. Nanoporous microparticles (NPMPs) were prepared from the alcoholic solutions containing ammonium carbonate. NPMPs were amorphous in nature, had median particles sizes less than 3 microm and densities that were significantly reduced compared to non-porous spray dried bendroflumethiazide powder. The novel process may be used to produce excipient-free amorphous microparticles with desirable physical properties such as amorphous solid state, porosity and low bulk density. This new engineering technology has applications in the design of other therapeutic agents such as those used in pulmonary delivery.
Assuntos
Anti-Hipertensivos/química , Bendroflumetiazida/química , Nanopartículas , Anti-Hipertensivos/administração & dosagem , Bendroflumetiazida/administração & dosagem , Dessecação , Microscopia Eletrônica de Varredura , Nebulizadores e Vaporizadores , Tamanho da Partícula , Pós , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos , Difração de Raios XRESUMO
The purpose of this work was to investigate the application of different advanced continuous processing techniques (hot melt extrusion and spray drying) to the production of fixed-dose combination (FDC) monolithic systems comprising of hydrochlorothiazide and ramipril for the treatment of hypertension. Identical FDC formulations were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Drug dissolution rates were investigated using a Wood's apparatus, while physical stability was assessed on storage under controlled temperature and humidity conditions. Interestingly both drugs were transformed into their amorphous forms when spray dried, however, hydrochlorothiazide was determined, by PXRD, to be partially crystalline when hot melt extruded with either polymer carrier (Kollidon® VA 64 or Soluplus®). Hot melt extrusion was found to result in significant degradation of ramipril, however, this could be mitigated by the inclusion of the plasticizer, polyethylene glycol 3350, in the formulation and appropriate adjustment of processing temperature. The results of intrinsic dissolution rate studies showed that hot-melt extruded samples were found to release both drugs faster than identical formulations produced via spray drying. However, the differences were attributable to the surface roughness of the compressed discs in the Wood's apparatus, rather than solid state differences between samples. After a 60-day stability study spray dried samples exhibited a greater physical stability than the equivalent hot melt extruded samples.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Diuréticos/química , Temperatura Alta , Hidroclorotiazida/química , Ramipril/química , Tecnologia Farmacêutica/métodos , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Portadores de Fármacos , Combinação de Medicamentos , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Cinética , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Plastificantes/química , Polietilenoglicóis/química , Polivinil/química , Difração de Pó , Pirrolidinas/química , Solubilidade , Propriedades de Superfície , Compostos de Vinila/químicaRESUMO
Adherence to a substratum is a characteristic feature of monocyte-macrophages which may be required for several effector functions. Human peripheral blood monocytes selected by adherence were found to readhere preferentially at 1 h to fibronectin or to a biological matrix. There was then a progressive decrease in the number of adherent cells, and by 48 h only 8-20% of monocytes remained adherent. This loss of adherence occurred while monocytes remained viable by criteria such as exclusion of trypan blue or release of lactate dehydrogenase. 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) maintained the adherence of cultured monocytes to tissue culture plastic as well as to the biological matrix. This effect was concentration- and time-dependent, and suppressed by inhibitors of protein synthesis. Cellular proteins were labeled after incubation with [35S]methionine. Analysis by two-dimensional gel electrophoresis revealed increased labeling of several distinct proteins in 1,25-(OH)2D3-treated monocytes compared with control monocytes. The increased loss of adherence and decreased overall protein synthesis observed in monocytes incubated at 45 degrees C was partially prevented by preincubation of the cells with 1,25-(OH)2D3. We further evaluated the effects of thermal stress and 1,25-(OH)2D3 on protein synthesis by monocytes, and found that 1,25-(OH)2D3 increased the synthesis of heat shock proteins, protected normal protein synthesis, and increased the rate of recovery of normal protein synthesis after the thermal stress. These observations suggest that 1,25-(OH)2D3 influences monocytes by preserving the synthesis of proteins, including those critical for the maintenance of cell adherence.
Assuntos
Calcitriol/farmacologia , Temperatura Alta , Monócitos/citologia , Adesão Celular/efeitos dos fármacos , Cicloeximida/farmacologia , Eletroforese em Gel de Poliacrilamida , Proteínas de Choque Térmico/biossíntese , Humanos , Técnicas In Vitro , Interferon gama/farmacologia , Peso Molecular , Monócitos/efeitos dos fármacosRESUMO
Interactions of cells with components of the extracellular matrix can modulate cellular functions. We measured binding of a major matrix protein to U937 cells, a human promonocytic line. Radioiodinated type I or type III human collagen was bound only to U937 cells differentiated to a more mature phenotype with 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). Binding was observed at 4 degrees C and was saturable; Scatchard analysis of the binding to 1,25-(OH)2D3-pretreated U937 cells indicated a single class of high-affinity binding sites. Preincubation of U937 cells with interferon gamma did not induce collagen binding. Collagen binding did not appear to be dependent on fibronectin binding. Surface proteins of U937 cells were 125I labeled and cell membrane proteins resolved by affinity chromatography on collagen-Sepharose. Major specifically labeled bands of 180, 155, and 125 kD were identified in membrane fractions from 1,25-(OH)2D3-pretreated U937 cells only. 1,25-(OH)2D3 appears to specifically regulate collagen binding to monocyte precursors.
Assuntos
Calcitriol/farmacologia , Colágeno/metabolismo , Monócitos/metabolismo , Adesão Celular/efeitos dos fármacos , Diferenciação Celular , Fibronectinas/metabolismo , Humanos , Interferon gama/farmacologia , Cinética , Proteínas de Membrana/análise , Peso Molecular , Monócitos/efeitos dos fármacos , Receptores de Calcitriol , Receptores de Esteroides/metabolismo , Fatores de TempoRESUMO
The activity of the coagulation system is regulated, in part, by the interaction of thrombin with the endothelial cell receptor thrombomodulin with subsequent generation of activated protein C and suppression of thrombin production. Our previous investigation demonstrated that ablation of the thrombomodulin gene in mice causes embryonic lethality before the assembly of a functional cardiovascular system, indicating a critical role for the receptor in early development. In the current study, we show that a single amino acid substitution in thrombomodulin dissociates the developmental function of the receptor from its role as a regulator of blood coagulation. Homozygous mutant mice with severely reduced capacity to generate activated protein C or inhibit thrombin develop to term, and possess normal reproductive performance. The above animals exhibit increased fibrin deposition in selected organs, which implies tissue specific regulation of the coagulation system that is supported by further evidence from the examination of mice with defects in fibrinolysis. The thrombomodulin-deficient animals provide a murine model to examine known or identify unknown genetic and environmental factors that lead to the development of thrombosis.
Assuntos
Coagulação Sanguínea/fisiologia , Mutação Puntual , Trombomodulina/genética , Trombose/etiologia , Animais , Desenvolvimento Embrionário e Fetal , Ativação Enzimática , Feminino , Fertilidade , Fibrina/metabolismo , Fibrinólise/fisiologia , Homozigoto , Camundongos , Camundongos Mutantes , Mutagênese Sítio-Dirigida , Placenta/metabolismo , Gravidez , Proteína C/metabolismo , Trombomodulina/deficiência , Trombose/genética , Distribuição TecidualRESUMO
A series of BAL 31 deletions were constructed in the upstream region of the Saccharomyces cerevisiae CYC7 gene to determine sequences required for transcriptional initiation. These deletions identified the TATA box as an alternating A-T sequence at -160 and the initiation sequences as well as the spatial relationship between them. The TATA box was necessary for wild-type levels of expression of the CYC7 gene. Decreasing the distance between the TATA sequence and the initiation site did not alter gene expression, but the site of transcription was shifted 3'-ward. In most cases, transcription initiated at a number of sites, the 5'-most of which was the first suitable site greater than 45 base pairs 3' of the TATA sequence, suggesting a spatial relationship between these sequences. Consensus sequences previously proposed for initiation sites were evaluated with respect to the start sites identified in this study as well as the start sites of other yeast genes.
Assuntos
Ciclo Celular , Genes Fúngicos , Regiões Promotoras Genéticas , Saccharomyces cerevisiae/genética , Sequência de Bases , Clonagem Molecular , Análise Mutacional de DNA , Regulação da Expressão Gênica , Dados de Sequência Molecular , RNA Fúngico/genética , RNA Mensageiro/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/fisiologia , Transcrição GênicaRESUMO
Microscopic screening of a collection of cold-sensitive mutants of Saccharomyces cerevisiae led to the identification of a new gene, CDC55, which appears to be involved in the morphogenetic events of the cell cycle. CDC55 maps between CDC43 and CHC1 on the left arm of chromosome VII. At restrictive temperature, the original cdc55 mutant produces abnormally elongated buds and displays a delay or partial block of septation and/or cell separation. A cdc55 deletion mutant displays a cold-sensitive phenotype like that of the original isolate. Sequencing of CDC55 revealed that it encodes a protein of about 60 kDa, as confirmed by Western immunoblots using Cdc55p-specific antibodies. This protein has greater than 50% sequence identity to the B subunits of rabbit skeletal muscle type 2A protein phosphatase; the latter sequences were obtained by analysis of peptides derived from the purified protein, a polymerase chain reaction product, and cDNA clones. An extragenic suppressor of the cdc55 mutation lies in BEM2, a gene previously identified on the basis of an apparent role in bud emergence.
Assuntos
Proteínas de Ciclo Celular , Proteínas Fúngicas/genética , Genes Fúngicos , Fosfoproteínas Fosfatases/genética , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Fúngicos , Biblioteca Gênica , Genes Supressores , Genótipo , Substâncias Macromoleculares , Dados de Sequência Molecular , Morfogênese/genética , Músculos/enzimologia , Oligonucleotídeos , Fenótipo , Proteína Fosfatase 2 , Coelhos , Mapeamento por Restrição , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Homologia de Sequência do Ácido NucleicoRESUMO
This study compared concentrations of amyloid A in bovine milk with the cell-based indicators of intramammary inflammation, somatic cell count and California Mastitis Test. Mammary quarter data pertaining to 180 cows were categorised according to concentrations of serum amyloid A in the cow of origin. Ranked correlation, ranked regression and receiver operator characteristics all demonstrated acceptable agreement between milk amyloid A concentrations and cell-based indices. There were some indications of reduction in this agreement, in cows with raised concentrations of serum amyloid A. However, there were also indications that serum amyloid A did not significantly influence milk amyloid A. The results of the current study indicate that milk amyloid A exhibits good correlation with established cell-based indicators of intramammary inflammation.
Assuntos
Glândulas Mamárias Animais/patologia , Mastite Bovina/sangue , Mastite Bovina/patologia , Leite/química , Proteína Amiloide A Sérica/análise , Animais , Biomarcadores/análise , Biomarcadores/sangue , Bovinos , Feminino , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/patologia , Mastite Bovina/diagnóstico , Sensibilidade e EspecificidadeRESUMO
The aim of this work was to investigate the dissolution rate from both the curved and planar surfaces of cylindrical compacts of benzoic acid, which were placed centrally and non-centrally at the base of the vessel of the paddle dissolution apparatus. The effect of fixing the compacts to a particular position on the variability of dissolution results was also examined. In addition, computational fluid dynamics (CFD) was used to simulate fluid flow around compacts in the different positions in the vessel, and the relationship between the local hydrodynamics in the region of the compacts and the dissolution rate determined. The dissolution rate was found to increase from the centre position to the off-centre positions for each surface examined. There was a corresponding increase in maximum fluid velocities calculated from the CFD fluid flow simulations at a fixed distance from the compact. There was less variability in dissolution from compacts fixed to any of the positions compared with those that were not fixed. Fluid flow around compacts in different positions could be successfully modelled, and hydrodynamic variability examined, using CFD. The effect of asymmetric fluid flow was evident visually from the change in shape of the eroded compacts.
Assuntos
Simulação por Computador , Comprimidos/química , Tecnologia Farmacêutica/métodos , Ácido Benzoico/química , Ácido Benzoico/farmacocinética , Desenho de Equipamento , Reologia/métodos , Solubilidade , Comprimidos/farmacocinética , Tecnologia Farmacêutica/instrumentaçãoRESUMO
Recent evidence indicates that basic fibroblast growth factor (bFGF), which lacks a conventional signal recognition sequence, is a component of the subendothelial matrix. However, the molecular mechanisms regulating its cellular release and subsequent matrix deposition remain equivocal. To examine the cellular and subcellular mechanisms regulating bFGF release and subendothelial sequestration, we generated polyclonal antibodies against a chemically cross-linked bFGF. We then used anti-bFGF IgG in conjunction with 3T3 cell [3H]thymidine incorporation assays, enzyme immunoassays and immunofluorescence to learn whether bFGF accumulation in the subendothelial matrix is dependent upon endothelial cell (EC)-cell contact, which coincides with growth arrest. In contrast to subconfluent cultures, which lacked any detectable extracellular matrix bFGF localization, bovine aortic and microvascular EC plated at confluent densities displayed a punctate extracellular staining pattern that was abolished when EC were pretreated with 10 micrograms/ml cycloheximide. Additionally, when EC were treated with either 1 mM beta-D xyloside, an inhibitor of proteoglycan assembly, or 100 micrograms/ml heparin, there was a 40% reduction in matrix-associated bFGF (quantified by image analysis of antibody stained cultures). 3T3 [3H]thymidine incorporation assays indicated that the beta-D xyloside-induced reduction of matrix-associated bFGF coincided with a significant increase in bFGF activity in the conditioned media. Neither sparsely-plated nor confluent EC cultures possessed specific bFGF localization of the nuclear compartment when cells were fixed using cold methanol; however, when EC were fixed in formaldehyde and lysed in isotonic buffers containing 0.1% Triton X-100 or absolute acetone, there was a marked decrease in anti-bFGF staining of the postconfluent extracellular matrix and a concomitant increase in nuclear fluorescence. Because bFGF-stimulated vascular cell growth has been implicated in controlling neointimal cell proliferation, we screened normal and atherosclerotic coronary blood vessels for bFGF, but we were unable to detect it either in lesioned or normal intima. In contrast, significant bFGF levels were observed in association with the EC and mesangial cells of the renal corpuscle, where heparan sulfate accumulates within the glomerular basement membrane. Our in vitro results suggest that bFGF accumulates within the proteoglycan-containing subendothelial matrix concomitant with the formation of cell-cell contacts. In situ, the composition of the microvascular matrix and the cellular phenotype may facilitate the selective accumulation of bFGF that we observed. This, in turn, may influence vascular morphogenesis and remodeling during angiogenesis.
Assuntos
Endotélio Vascular/metabolismo , Matriz Extracelular/química , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células 3T3/metabolismo , Animais , Bovinos , Contagem de Células , Células Cultivadas/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/análise , Glicosídeos/farmacologia , Heparina/farmacologia , Glomérulos Renais/química , CamundongosRESUMO
Leukotrienes are lipid messenger molecules that are secreted by leukocytes to orchestrate a rapid and prolonged immune response. The enzyme 5-lipoxygenase catalyzes the rate-limiting first two steps in the synthesis of leukotrienes from arachidonic acid. Although it has long been known that 5-lipoxygenase moves from the cytoplasm to a membrane following activation, it has only recently been recognized that the enzyme may shuttle into and out of the nucleus before activation. The regulation of this movement of soluble 5-lipoxygenase between the cytoplasm and the nucleoplasm, as well as its impact on 5-lipoxygenase action, leukotriene synthesis and cell function, is only now being elucidated. This review details the state of our understanding of the nuclear import of 5-lipoxygenase and its potential importance in immunity.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Núcleo Celular/enzimologia , Animais , Araquidonato 5-Lipoxigenase/imunologia , Transporte Biológico Ativo , Citoplasma/enzimologia , Ativação Enzimática , Humanos , Leucócitos/enzimologia , Leucócitos/imunologia , Leucotrienos/biossíntese , Leucotrienos/imunologia , Leucotrienos/metabolismoRESUMO
Heat shock (HS) proteins (HSP) are a family of molecular chaperones induced by environmental stresses such as oxidative injury, and contribute to protection from and adaptation to cellular stress. We investigated in human monocytes the expression and subcellular distribution of hsp70 and hsc70 after HS and inflammation-related stresses leading to generation of reactive oxygen species by these cells, such as the phorbol ester PMA and erythrophagocytosis (E phi). By combining immunofluorescent staining and Western blot on subcellular fractions, we found that all three stress factors resulted in an increased hsp70 expression, however the subcellular distribution pattern was different depending on the type of stress. While HS induced a rapid translocation of hsp70 into the nucleus, no nuclear translocation of hsp70 was observed after PMA or E phi. Neither of the examined stresses induced membrane expression of hsp70. The observed differences in subcellular distribution pattern might relate to distinct regulation and specific functions of hsp70 in inflammation.
Assuntos
Proteínas de Choque Térmico/metabolismo , Monócitos/metabolismo , Transporte Biológico , Compartimento Celular , Células Cultivadas , Transtornos de Estresse por Calor , Proteínas de Choque Térmico/análise , Humanos , Inflamação , Monócitos/citologia , Espécies Reativas de OxigênioRESUMO
The aim of the present study was to determine the apparent diffusion boundary layer and dissolution rate constant for various surfaces of compacts and at various locations in the USP paddle dissolution apparatus. Benzoic acid compacts were coated with paraffin wax leaving only the surface under investigation free for dissolution. The dissolution rates for various surfaces at varying locations in the paddle dissolution vessel were determined from the slope of the dissolution profile (amount dissolved (mg) versus time (min)). The apparent diffusion boundary layer and dissolution rate constant were calculated and were found to vary depending on the surface of the compact from which dissolution took place and also on the location and size of the compact. It may be concluded that, in developing models to describe the dissolution from solid dosage forms, it is not accurate to assume constant hydrodynamics and mass transfer rates at all surfaces of the system, or in different locations within the test device. A more exact description of the hydrodynamics would be necessary in order to precisely model drug dissolution in the paddle dissolution apparatus.
Assuntos
Tecnologia Farmacêutica/instrumentação , Antifúngicos , Ácido Benzoico , Desenho de Equipamento , Sensibilidade e EspecificidadeRESUMO
Fourteen cases of cervico-thoracic (C-T) vertebral osteomyelitis in calves were investigated over a 6 year period. The onset of clinical signs was between 2 and 9 weeks of age. There was no breed or sex predisposition. The clinical history prior to referral extended from 5 days to 8 weeks (mean 20 days). The most common clinical presentation was difficulty in rising with a tendency to knuckle or kneel on the forelimbs which displayed hypotonia and hyporeflexia. In over half the cases pain could be elicited on manipulation of the neck. The lesion in all cases involved one or more of the vertebrae from C6 to T1. The diagnosis was confirmed by radiology and/or at post mortem. Four animals were discharged after treatment, 10 animals were humanely destroyed. Salmonella dublin was isolated from the vertebral lesion in eight of the 10 calves at post mortem.
Assuntos
Doenças dos Bovinos/patologia , Vértebras Cervicais/patologia , Osteomielite/veterinária , Vértebras Torácicas/patologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Bovinos , Doenças dos Bovinos/diagnóstico por imagem , Doenças dos Bovinos/tratamento farmacológico , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/microbiologia , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Quimioterapia Combinada , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Osteomielite/tratamento farmacológico , Osteomielite/patologia , Radiografia , Salmonella/isolamento & purificação , Salmonelose Animal/tratamento farmacológico , Salmonelose Animal/patologia , Sulfadoxina/administração & dosagem , Sulfadoxina/uso terapêutico , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/microbiologia , Trimetoprima/administração & dosagem , Trimetoprima/uso terapêuticoRESUMO
Thirty of 52 pedigree Suffolk lambs (58 per cent) were born with arthrogryposis characterised by bilateral flexion rigidity of the metacarpophalangeal and carpal joints. The recent introduction of a breeding ram was identified as the only significant risk factor in the flock, and embryo transfer was used to test the hypothesis that the arthrogryposis was an inherited disorder associated with the introduction of this ram. Two adult ewes that had previously produced lambs with arthrogryposis by the ram and four of its affected daughters were available as donors, and 20 crossbred ewes were used as recipients. Ten Suffolk-crossed ewes that had no known familial relationship with the ram were also mated by the ram as controls and they produced 10 normal lambs. Following embryo transfer, 19 lambs were born, of which seven were stillborn; arthrogryposis was evident in 10 of the 12 live lambs. Analysis of the data suggested that in the population under study, arthrogryposis was inherited as an autosomal recessive condition.
Assuntos
Artrogripose/veterinária , Carpo Animal/anormalidades , Doenças dos Ovinos/congênito , Doenças dos Ovinos/genética , Animais , Artrogripose/genética , Transferência Embrionária/veterinária , Extremidades/patologia , Feminino , Masculino , Linhagem , Ovinos , Doenças dos Ovinos/patologiaRESUMO
Using the Interactive Autism Network Research Database, the Autistic Spectrum Disorder concordance rates for twins and non-twin siblings were calculated. For males, females and both genders together, the concordance rate for dizygotic twins is approximately twice that of non-twin siblings. We also determined that the concordance rate for non-twin siblings decreases as the interval between pregnancies increases. Our results appear to indicate that the uterine environment may contribute to autism concordance rates.