Strategic development and physicochemical analysis of oral preparations for unstable drugs

Oral liquid formulations are ideal dosage forms for paediatric, geriatric and patient with dysphagia. Dysphagia is prominent among patients suffering from stroke, motor neurone disease, advanced Alzheimer’s and Parkinson’s disease. However oral liquid preparations are particularly difficult to formulate for hydrophobic and unstable drugs. Therefore current methods employed in solving this issue include the use of ‘specials’ or extemporaneous preparations. In order to challenge this, the government has encouraged research into the field of oral liquid formulations, with the EMEA and MHRA publishing list of drugs of interest. The current work investigates strategic formulation development and characterisation of select API’s (captopril, gliclazide, melatonin, L-arginine and lansoprazole), each with unique obstacles to overcome during solubilisation, stabilisation and when developing a palatable dosage from. By preparing a validated calibration protocol for each of the drug candidates, the oral liquid formulations were assessed for stability, according to the ICH guidelines along with thorough physiochemical characterisation. The results showed that pH and polarity of the solvent had the greatest influence on the extent of drug solubilisation, with inclusion of antioxidants and molecular steric hindrance influencing the extent of drug stability. Captopril, a hydrophilic ACE inhibitor (160 mg.mL-1), undergoes dimerisation with another captopril molecule. It was found that with the addition of EDTA and HP-β-CD, the drug molecule was stabilised and prevented from initiating a thiol induced first order free radical oxidation. The cyclodextrin provided further steric hindrance (1:1 molar ratio) resulting in complete reduction of the intensity of sulphur like smell associated with captopril. Palatability is a crucial factor in patient compliance, particularly when developing a dosage form targeted towards paediatrics. L-arginine is extremely bitter in solution (148.7 g.L-1). The addition of tartaric acid into the 100 mg.mL-1 formulation was sufficient to mask the bitterness associated with its guanidium ions. The hydrophobicity of gliclazide (55 mg.L-1) was strategically challenged using a binary system of a co-solvent and surfactant to reduce the polarity of the medium and ultimately increase the solubility of the drug. A second simpler method was developed using pH modification with L-arginine. Melatonin has two major obstacles in formulation: solubility (100 μg.mL-1) and photosensitivity, which were both overcome by lowering the dielectric constant of the medium and by reversibly binding the drug within the cyclodextrin cup (1:1 ratio). The cyclodextrin acts by preventing UV rays from reaching the drug molecule and initiated the degradation pathway. Lansoprazole is an acid labile drug that could only be delivered orally via a delivery vehicle. In oral liquid preparations this involved nanoparticulate vesicles. The extent of drug loading was found to be influenced by the type of polymer, concentration of polymer, and the molecular weight. All of the formulations achieved relatively long shelf-lives with good preservative efficacy.

The Economic Case for Electric Mining Equipment and Technical Considerations Relating to their Implementation

Underground hardrock mining can be very energy intensive and in large part this can be attributed to the power consumption of underground ventilation systems. In general, the power consumed by a mine’s ventilation system and its overall scale are closely related to the amount of diesel power in operation. This is because diesel exhaust is a major source of underground air pollution, including diesel particulate matter (DPM), NO2 and heat, and because regulations tie air volumes to diesel engines. Furthermore, assuming the size of airways remains constant, the power consumption of the main system increases exponentially with the volume of air supplied to the mine. Therefore large diesel fleets lead to increased energy consumption and can also necessitate large capital expenditures on ventilation infrastructure in order to manage power requirements. Meeting ventilation requirements for equipment in a heading can result in a similar scenario with the biggest pieces leading to higher energy consumption and potentially necessitating larger ventilation tubing and taller drifts. Depending on the climate where the mine is located, large volumes of air can have a third impact on ventilation costs if heating or cooling the air is necessary. Annual heating and cooling costs, as well as the cost of the associated infrastructure, are directly related to the volume of air sent underground. This thesis considers electric mining equipment as a means for reducing the intensity and cost of energy consumption at underground, hardrock mines. Potentially, electric equipment could greatly reduce the volume of air needed to ventilate an entire mine as well as individual headings because they do not emit many of the contaminants found in diesel exhaust and because regulations do not connect air volumes to electric motors. Because of the exponential relationship between power consumption and air volumes, this could greatly reduce the amount of power required for mine ventilation as well as the capital cost of ventilation infrastructure. As heating and cooling costs are also directly linked to air volumes, the cost and energy intensity of heating and cooling the air would also be significantly reduced. A further incentive is that powering equipment from the grid is substantially cheaper than fuelling them with diesel and can also produce far fewer GHGs. Therefore, by eliminating diesel from the underground workers will enjoy safer working conditions and operators and society at large will gain from a smaller impact on the environment. Despite their significant potential, in order to produce a credible economic assessment of electric mining equipment their impact on underground systems must be understood and considered in their evaluation. Accordingly, a good deal of this thesis reviews technical considerations related to the use of electric mining equipment, especially ones that impact the economics of their implementation. The goal of this thesis will then be to present the economic potential of implementing the equipment, as well as to outline the key inputs which are necessary to support an evaluation and to provide a model and an approach which can be used by others if the relevant information is available and acceptable assumptions can be made.

INVESTIGATIVE COMPARISON OF TANK AND RECOVERED ASPHALT SAMPLES THROUGH PHYSICAL PERFORMANCE TESTING AND CHEMICAL ANALYSIS

Despite the development of improved performance test protocols by renowned researchers, there are still road networks which experience premature cracking and failure. One area of major concern in asphalt science and technology, especially in cold regions in Canada is thermal (low temperature) cracking. Usually right after winter periods, severe cracks are seen on poorly designed road networks. Quality assurance tests based on improved asphalt performance protocols have been implemented by government agencies to ensure that roads being constructed are at the required standard but asphalt binders that pass these quality assurance tests still crack prematurely. While it would be easy to question the competence of the quality assurance test protocols, it should be noted that performance tests which are being used and were repeated in this study, namely the extended bending beam rheometer (EBBR) test, double edge-notched tension test (DENT), dynamic shear rheometer (DSR) test and X-ray fluorescence (XRF) analysis have all been verified and proven to successfully predict asphalt pavement behaviour in the field. Hence this study looked to probe and test the quality and authenticity of the asphalt binders being used for road paving. This study covered thermal cracking and physical hardening phenomenon by comparing results from testing asphalt binder samples obtained from the storage ‘tank’ prior to paving (tank samples) and recovered samples for the same contracts with aim of explaining why asphalt binders that have passed quality assurance tests are still prone to fail prematurely. The study also attempted to find out if the short testing time and automated procedure of torsion bar experiments can replace the established but tedious procedure of the EBBR. In the end, it was discovered that significant differences in performance and composition exist between tank and recovered samples for the same contracts. Torsion bar experimental data also indicated some promise in predicting physical hardening.

Colic surgery in the equine patient: novel biomarkers, postoperative management, microbiotal influence and epidemiological analysis on the italian territory

The aim of this work was to investigate novel diagnostic and prognostic tools, postoperative treatments and epidemiologic factors impacting the outcome of surgical cases of colic. To make a more accurate diagnosis and establish a prognosis, several biomarkers have been investigated in colic patients. In this study we evaluated peritoneal PCT and blood ADMA and SDMA in SIRS positive and negative colic patients to be used as prognostic biomarkers. Our results highlighted the limits of these biomarkers in detection and the lack of specificity. In fact PCT was not detectable and even if ADMA and SDMA significantly increased in colic horses, they are not diagnostic nor prognostic markers for SIRS. Fluid therapy has been described to be crucial for the outcome of colic patients, nevertheless no guidelines have been established. Overhydration was the common practice in post surgical management. We compared cases with an extended fluid therapy protocol and cases with a restricted protocol. Results showed that survival rate and postoperative complications were similar between the groups, despite costs being significantly lower in the restricted group. The possible correlation between intestinal microbiota and colics has gained interest. In this study, cecal and colonic content from horses undergoing laparotomy were collected, and the microbiota analized. Results showed some differences in microbiota between discharged and non discharged patients, and between strangulating and non strangulating types of colic, that might suggest some influence of hind gut microbiota on the disease. A multicentric study involving three veterinary teaching hospitals on the italian territory was conducted investigating factors affecting postoperative survival and complications in colics. Results showed that the influence of age, PCV, TPP, blood lactate, reflux, type of disease, type of lesion, presence of anastomosis, duration of surgery and surgeons, were in line with literature. Amount of crystalloids used could affected the outcome.

Geochemistry Of Acid Mine Drainage From A Coal Mining Area And Processes Controlling Metal Attenuation In Stream Waters, Southern Brazil.

Acid drainage influence on the water and sediment quality was investigated in a coal mining area (southern Brazil). Mine drainage showed pH between 3.2 and 4.6 and elevated concentrations of sulfate, As and metals, of which, Fe, Mn and Zn exceeded the limits for the emission of effluents stated in the Brazilian legislation. Arsenic also exceeded the limit, but only slightly. Groundwater monitoring wells from active mines and tailings piles showed pH interval and chemical concentrations similar to those of mine drainage. However, the river and ground water samples of municipal public water supplies revealed a pH range from 7.2 to 7.5 and low chemical concentrations, although Cd concentration slightly exceeded the limit adopted by Brazilian legislation for groundwater. In general, surface waters showed large pH range (6 to 10.8), and changes caused by acid drainage in the chemical composition of these waters were not very significant. Locally, acid drainage seemed to have dissolved carbonate rocks present in the local stratigraphic sequence, attenuating the dispersion of metals and As. Stream sediments presented anomalies of these elements, which were strongly dependent on the proximity of tailings piles and abandoned mines. We found that precipitation processes in sediments and the dilution of dissolved phases were responsible for the attenuation of the concentrations of the metals and As in the acid drainage and river water mixing zone. In general, a larger influence of mining activities on the chemical composition of the surface waters and sediments was observed when enrichment factors in relation to regional background levels were used.

De Novo Assembly And Transcriptome Analysis Of The Rubber Tree (hevea Brasiliensis) And Snp Markers Development For Rubber Biosynthesis Pathways.

Hevea brasiliensis (Willd. Ex Adr. Juss.) Muell.-Arg. is the primary source of natural rubber that is native to the Amazon rainforest. The singular properties of natural rubber make it superior to and competitive with synthetic rubber for use in several applications. Here, we performed RNA sequencing (RNA-seq) of H. brasiliensis bark on the Illumina GAIIx platform, which generated 179,326,804 raw reads on the Illumina GAIIx platform. A total of 50,384 contigs that were over 400 bp in size were obtained and subjected to further analyses. A similarity search against the non-redundant (nr) protein database returned 32,018 (63%) positive BLASTx hits. The transcriptome analysis was annotated using the clusters of orthologous groups (COG), gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Pfam databases. A search for putative molecular marker was performed to identify simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs). In total, 17,927 SSRs and 404,114 SNPs were detected. Finally, we selected sequences that were identified as belonging to the mevalonate (MVA) and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways, which are involved in rubber biosynthesis, to validate the SNP markers. A total of 78 SNPs were validated in 36 genotypes of H. brasiliensis. This new dataset represents a powerful information source for rubber tree bark genes and will be an important tool for the development of microsatellites and SNP markers for use in future genetic analyses such as genetic linkage mapping, quantitative trait loci identification, investigations of linkage disequilibrium and marker-assisted selection.

Chronic Telogen Effluvium And Female Pattern Hair Loss Are Separate And Distinct Forms Of Alopecia: A Histomorphometric And Immunohistochemical Analysis.

Chronic telogen effluvium (CTE), a poorly understood condition, can be confused with or may be a prodrome to female pattern hair loss (FPHL). The pathogenesis of both is related to follicle cycle shortening and possibly to blood supply changes. To analyze a number of histomorphometric and immunohistochemical findings through vascular endothelial growth factor (VEGF), Ki-67, and CD31 immunostaining in scalp biopsies of 20 patients with CTE, 17 patients with mild FPHL and 9 controls. Ki-67 index and VEGF optical density were analyzed at the follicular outer sheath using ImageJ software. CD31 microvessel density was assessed by a Chalkley grid. Significant follicle miniaturization and higher density of nonanagen follicles were found in FPHL, compared with patients with CTE and controls. Ki-67+ index correlated positively with FPHL histological features. The FPHL group showed the highest VEGF optical density, followed by the CTE and control groups. No differences were found in CD31 microvessel density between the three groups. Histomorphometric results establish CTE as a distinct disorder, separate from FPHL from its outset. Its pathogenic mechanisms are also distinct. These findings support the proposed mechanism of 'immediate telogen release' for CTE, leading to cycle synchronization. For FPHL, accelerated anagen follicular mitotic rates and, thus, higher Ki-67 and VEGF values, would leave less time for differentiation, resulting in hair miniaturization.

Corrosion Kinetics And Topography Analysis Of Ti-6al-4v Alloy Subjected To Different Mouthwash Solutions.

This study evaluated the corrosion kinetics and surface topography of Ti-6Al-4V alloy exposed to mouthwash solutions (0.12% chlorhexidine digluconate, 0.053% cetylpyridinium chloride and 3% hydrogen peroxide) compared to artificial saliva (pH6.5) (control). Twenty Ti-6Al-4V alloy disks were used and divided into 4 groups (n=5). For the electrochemical assay, standard tests as open circuit potential and electrochemical impedance spectroscopy (EIS) were applied at baseline, 7 and 14days after immersion in the solutions. Scanning electron microscopy, atomic force microscopy and profilometry (average roughness - Ra) were used for surface characterization. Total weight loss of disks was calculated. Data were analyzed by ANOVA and Bonferroni's test (α=0.05). Hydrogen peroxide generated the lowest polarization resistance (Rp) values for all periods (P<0.05). For the capacitance (Cdl), similar results were observed among groups at baseline (P=0.098). For the 7 and 14-day periods, hydrogen peroxide promoted the highest Cdl values (P<0.0001). Hydrogen peroxide promoted expressive superficial changes and greater Ra values than the others (P<0.0001). It could be concluded that solutions containing cetylpyridinium chloride and chlorhexidine digluconate might be the mouthwashes of choice during the post-operatory period of dental implants. However, hydrogen peroxide is counter-indicated in these situations. Further studies evaluating the dynamics of these solutions (tribocorrosion) and immersing the disks in daily cycles (two or three times a day) to mimic a clinical situation closest to the application of mouthwashes in the oral cavity are warranted to prove our results.

Comparison Between Automated And Microscopic Analysis In Body Fluids Cytology.

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Mechanical And Photoelastic Analysis Of Four Different Fixation Methods For Mandibular Body Fractures.

The aim of the present study was to compare four methods of fixation in mandibular body fractures. Mechanical and photoelastic tests were performed using polyurethane and photoelastic resin mandibles, respectively. The study groups contained the following: (I), two miniplates of 2.0 mm; (II) one 2.0 mm plate and an Erich arch bar; (III) one 2.4 mm plate and an Erich arch bar, and (IV) one 2.0 mm plate and one 2.4 mm plate. The differences between the mean values were analyzed using Tukey's test, the Mann-Whitney test and the Bonferroni correction. Group II recorded the lowest resistance, followed by groups I, IV and III. The photoelastic test confirmed the increase of tension in group II. The 2.4 mm system board in linear mandibular body fractures provided more resistance and the use of only one 2.0 mm plate in the central area of the mandible created higher tension.

Association Between Unilateral Tonsillar Enlargement And Lymphoma In Children: A Systematic Review And Meta-analysis.

Lymphoma is the most common head and neck malignancy in children, and palatine tonsils asymmetry is the most frequent clinical manifestation of tonsillar lymphoma. However, several studies with children with tonsillar asymmetry found no case of lymphoma, showing that the relationship of tonsillar asymmetry with lymphoma is unclear. In this review, we aimed to identify the association between tonsillar asymmetry and tonsillar lymphoma in children by conducting systematic reviews of the literature on children with palatine tonsil lymphoma and tonsillar asymmetry. Articles comprising the paediatric age group (up to 18 years) with information concerning clinical manifestations of tonsillar lymphoma or the diagnosis of the tonsillar asymmetry were included. The main cause of asymmetry of palatine tonsils was lymphoid hyperplasia, followed by lymphoma and nonspecific benign changes. The asymmetry of tonsils was present in 73.2% of cases of lymphoma. There was an association between asymmetric palatine tonsils and lymphoma, with a likelihood ratio of 43.5 for children with asymmetry of palatine tonsils and 8938.4 for children with asymmetry of tonsils and other signs of suspicion for malignancy. We also provide recommendations on the management of suspicious cases of palatine tonsil lymphoma.

Escala de autoaceitação para pessoas com cegueira congênita ou precoce : desenvolvimento e investigação psicométrica = Self-acceptance acale for people with congenital or early blindness : development and psychometric analysis

Universidade Estadual de Campinas . Faculdade de Educação Física

Adhesion of an endodontic sealer to dentin and gutta-percha: shear and push-out bond strength measurements and SEM analysis

The use of an adequate method for evaluation of the adhesion of root canal filling materials provides more reliable results to allow comparison of the materials and substantiate their clinical choice. The aims of this study were to compare the shear bond strength (SBS) test and push-out test for evaluation of the adhesion of an epoxy-based endodontic sealer (AH Plus) to dentin and gutta-percha, and to assess the failure modes on the debonded surfaces by means of scanning electron microscopy (SEM). Three groups were established (n=7): in group 1, root cylinders obtained from human canines were embedded in acrylic resin and had their canals prepared and filled with sealer; in group 2, longitudinal sections of dentin cylinders were embedded in resin with the canal surface smoothed and turned upwards; in group 3, gutta-percha cylinders were embedded in resin. Polyethylene tubes filled with sealer were positioned on the polished surface of the specimens (groups 2 and 3). The push-out test (group 1) and the SBS test (groups 2 and 3) were performed in an Instron universal testing machine running at crosshead speed of 1 mm/min. Means (±SD) in MPa were: G1 (8.8±1.13), G2 (5.9±1.05) and G3 (3.8±0.55). Statistical analysis by ANOVA and Student's t-test (a=0.05) revealed statistically significant differences (p<0.01) among the groups. SEM analysis showed a predominance of adhesive and mixed failures of AH Plus sealer. The tested surface affected significantly the results with the sealer reaching higher bond strength to dentin than to gutta-percha with the SBS test. The comparison of the employed methodologies showed that the SBS test produced significantly lower bond strength values than the push-out test, was skilful in determining the adhesion of AH Plus sealer to dentin and gutta-percha, and required specimens that could be easily prepared for SEM, presenting as a viable alternative for further experiments.

Systematic review and cladistic analysis of the Hernandariinae (Opiliones: Gonyleptidae)

The harvestmen subfamily Hernandariinae is reviewed and a new classification is proposed based on cladistic analysis using 67 morphological characters. The subfamily is composed of six genera and 23 species and occurs in south-southeastern Brazil, Paraguay, and northeastern Argentina. Fourteen new combinations are proposed: Hernandaria armatifrons (Roewer, 1917); H. una (Mello-Leitão, 1927); Acrogonyleptes granulatus (H. Soares, 1966); A. pectinifemur (Soares & Soares, 1947); Acanthogonyleptes alticola (Mello-Leitão, 1922); A. editus (Roewer, 1943); A. fallax (Mello-Leitão, 1932); A. fulvigranulatus (Mello-Leitão, 1922); A. marmoratus (Mello-Leitão, 1940); A. pictus (Piza, 1942); A. singularis (Mello-Leitão, 1935); A. soaresi (Mello-Leitão, 1944); A. variolosus (Mello-Leitão, 1944). Seven synonymies are proposed: Proweyhia Mello-Leitão, 1927 and Metaxundarava Mello-Leitão, 1927 = Hernandaria Sørensen, 1884; Apembolephaenus calcaratus Soares & Soares, 1945 = H. armatifrons (Roewer, 1917); Sphaerobunus Rower, 1917 and Paraproweyhia Soares & Soares, 1947 = Acrogonyleptes Roewer, 1917; Paraproweyhia curitibae Soares & Soares, 1947 = Acrogonyleptes exochus (Mello-Leitão, 1931); and Melloleitaniana curitibae B. Soares, 1943 = Acrogonyleptes spinifrons Roewer, 1917. Three species are revalidated: Acrogonyleptes granulatus (H. Soares, 1966), A. pectinifemur (Soares & Soares, 1947), and A. spinifrons Roewer, 1917. Seven new species are described: Hernandaria sundermannorum sp. nov. (São Paulo State, Brazil), Hernandaria anitagaribaldiae sp. nov. (Santa Catarina State, Brazil), Hernandaria zumbii sp. nov. (Santa Catarina State, Brazil), Hernandaria chicomendesi sp. nov. (Santa Catarina State, Brazil), Acrogonyleptes cheguevarai sp. nov. (Rio Grande do Sul State, Brazil), Pseudotrogulus pagu sp. nov. (São Paulo State, Brazil), Pseudotrogulus trotskyi sp. nov. (Paraná State, Brazil).

Tensile bond strength and SEM analysis of enamel etched with Er:YAG laser and phosphoric acid: a comparative study In vitro

Er:YAG laser has been studied as a potential tool for restorative dentistry due to its ability to selectively remove oral hard tissue with minimal or no thermal damage to the surrounding tissues. The purpose of this study was to evaluate in vitro the tensile bond strength (TBS) of an adhesive/composite resin system to human enamel surfaces treated with 37% phosphoric acid, Er:YAG laser (lambda=2.94 mum) with a total energy of 16 J (80 mJ/pulse, 2Hz, 200 pulses, 250 ms pulse width), and Er:YAG laser followed by phosphoric acid etching. Analysis of the treated surfaces was performed by scanning electron microscopy (SEM) to assess morphological differences among the groups. TBS means (in MPa) were as follows: Er:YAG laser + acid (11.7 MPa) > acid (8.2 MPa) > Er:YAG laser (6.1 MPa), with the group treated with laser+acid being significantly from the other groups (p=0.0006 and p= 0.00019, respectively). The groups treated with acid alone and laser alone were significantly different from each other (p=0.0003). The SEM analysis revealed morphological changes that corroborate the TBS results, suggesting that the differences in TBS means among the groups are related to the different etching patterns produced by each type of surface treatment. The findings of this study indicate that the association between Er:YAG laser and phosphoric acid can be used as a valuable resource to increase bond strength to laser-prepared enamel.