Drug combination: pharmaceutical technologies applied to the manufacturing of combined dosage forms for oral administration

Lo scopo di questa ricerca di dottorato è stato lo studio di una forma di dosaggio flessibile e personalizzabile, indirizzata alle necessità individuali di ogni paziente, per il trattamento dell’iperplasia prostatica benigna. La terapia proposta prevede l’utilizzo di due farmaci, un alfa bloccante (farmaco A) e un inibitore delle 5- fosfodiesterasi (farmaco B) e, somministrati in una singola forma di dosaggio contenenti differenti dosi e combinazioni dei due farmaci. Lo sviluppo di un sistema di rilascio per la somministrazione orale di farmaco A e farmaco B è stato realizzato grazie alla tecnologia Dome Matrix. La tecnologia si basa sull’assemblaggio di moduli utilizzati come elementi di controllo del rilascio. L’assemblaggio dei moduli può essere ottenuto attraverso diverse configurazioni. Sono stati quindi realizzati sistemi assemblati in grado di galleggiare sul contenuto gastrico; la prolungata permanenza della forma farmaceutica nello stomaco favorisce la solubilizzazione dei due principi attivi che quindi potrebbero raggiungere il sito di assorbimento nel primo tratto intestinale già in dispersione molecolare, condizione ideale per essere assorbiti. La prima parte della ricerca è stata focalizzata sulla realizzazione di un sistema assemblato a rilascio modificato di farmaco A. Moduli contenenti diversi dosaggi di farmaco sono stati assemblati in varie configurazioni e dosi differenti per ottenere una forma di dosaggio flessibile, adattabile alle esigenze terapeutiche del paziente. La seconda parte del lavoro di tesi ha riguardato la realizzazione di un sistema assemblato, contenente entrambi i farmaci in associazione. L’ultima parte della ricerca è stata svolta presso la “University of Texas at Austin” sotto la supervisione del Professor Nicholas Peppas. Il lavoro svolto è stato focalizzato sullo studio delle caratteristiche di rigonfiamento dei singoli moduli di farmaco e dei loro sistemi assemblati; il comportamento di tali sistemi è stato investigato anche grazie all’utilizzo della tecnica di tomografia computerizzata a raggi X.

Downdraft gasification of biomass

The objectives of this research were to investigate the parameters affecting the gasification process within downdraft gasifiers using biomass feedstocks. In addition to investigations with an open-core gasifier, a novel open-topped throated gasifier was designed and used. A sampling system was designed and installed to determine the water, tar and particular content of the raw product gas. This permitted evaluation of the effects of process parameters and reactor design on tar and particular production, although a large variation was found for the particulate measurements due to the capture of large particles. For both gasifiers, the gasification process was studied in order to identify and compare the mechanisms controlling the position and shape of the reaction zones. The stability of the reaction zone was found to be governed by the superficial gas velocity within the reactor. A superficial gas velocity below 0.2 Nms-1 resulted in a rising reaction zone in both gasifiers. Turndown is achieved when the rate of char production by flaming pyrolysis equals the rate of char gasification over a range of throughputs. A turndown ratio of 2:1 was achieved for the hybrid-throated gasifier, compared to 1.3:1 for the open-core. It is hypothesized that pyrolysis is a surface area phenomenon, and that in the hybrid gasifier the pyrolysis front can expand to form a dome-shape. The rate of char gasification is believed to increase as the depth of the gasification zone increases. Vibration of the open-core reactor bed decreased the bed pressure drop, reduced the voidage, aided solids flow and gave a minor improvement in the product gas energy content. Insulation improved the performance of both reactors by reducing heat losses resulting in a reduced air to feed ratio requirement. The hybrid gasifier gave a higher energy conversion efficiency, a higher product gas heating value, and a lower tar content than the open-core gasifier due to efficient gas mixing in a high temperature tar cracking region below the throat and reduced heat losses.

Interactions between endothelin receptor B and transcription factors Sox10 and Pax3 in the melanocyte lineage

Genetic interactions that underlie developmental processes such as cell differentiation and pattern formation are complex and difficult to elucidate. Neural Crest (NC) cells and their derivatives offer an optimal system in which to probe for these complex interactions as they acquire different cell fates and constitute a variety of structures. The transcription factors Sox10 and Pax3 as well as the transmembrane receptor Endothelin receptor b (Ednrb) are temporally and spatially co-expressed early in NC cells and mutations in these genes lead to similar hypopigmentation phenotypes due to a reduced number of NC-derived melanocyte precursors, the melanoblasts. The goal of this study was to establish whether Sox10 and Ednrb or Pax3 and Ednrb interact to promote normal murine melanocyte development. Crosses of Sox10 or Pax3 with Ednrb heterozygous mutants showed that the double heterozygous hypopigmentation phenotype was significantly more pronounced than phenotypes of single heterozygotes, implying that a synergistic interaction exists between Sox10 and Ednrb and Pax3 and Ednrb. This interaction was further explored by the attempt to rescue the Sox10 and Pax3 hypopigmentation phenotypes by the transgenic addition of Ednrb to melanoblasts. Pigmentation was completely restored in the Sox10 and partially restored in the Pax3 mutant mice. The comparison of the number of melanoblasts in transgenic and non-transgenic Sox10 mutant embryos showed that the transgenic rescue occurred as early as E11.5, a critical time for melanoblast population expansion. Cell survival assays indicated that the rescue was not due to an effect of the transgene on melanoblast survival. A novel phenotype arose when studying the interaction between Ednrb and Pax3. Newborns appeared normal but by 3.5 weeks of age, the affected pups were smaller than normal littermates and developed a dome-shaped head; some also developed thoracic kyphosis. Affected pups were dead by 4 weeks of age: 80% were Pax3Sp/+ and 75% were female. When compared to normal littermates, affected mice had brains with enlarged 4th ventricles and more glia while skeletal staining showed kyphosis, wider rib cages and pelvic differences. An epistatic interaction resulting from the mixing of genetic backgrounds that is exacerbated in the presence of Pax3 heterozygosity is suspected.

Interactions between Endothelin Receptor B and Transcription Factors Sox10 and Pax3 in the Melanocyte Lineage

Genetic interactions that underlie developmental processes such as cell differentiation and pattern formation are complex and difficult to elucidate. Neural Crest (NC) cells and their derivatives offer an optimal system in which to probe for these complex interactions as they acquire different cell fates and constitute a variety of structures. The transcription factors Sox10 and Pax3 as well as the transmembrane receptor Endothelin receptor b (Ednrb) are temporally and spatially co-expressed early in NC cells and mutations in these genes lead to similar hypopigmentation phenotypes due to a reduced number of NC-derived melanocyte precursors, the melanoblasts. The goal of this study was to establish whether Sox10 and Ednrb or Pax3 and Ednrb interact to promote normal murine melanocyte development. Crosses of Sox10 or Pax3 with Ednrb heterozygous mutants showed that the double heterozygous hypopigmentation phenotype was significantly more pronounced than phenotypes of single heterozygotes, implying that a synergistic interaction exists between Sox10 and Ednrb and Pax3 and Ednrb. This interaction was further explored by the attempt to rescue the Sox10 and Pax3 hypopigmentation phenotypes by the transgenic addition of Ednrb to melanoblasts. Pigmentation was completely restored in the Sox10 and partially restored in the Pax3 mutant mice. The comparison of the number of melanoblasts in transgenic and non-transgenic Sox10 mutant embryos showed that the transgenic rescue occurred as early as E11.5, a critical time for melanoblast population expansion. Cell survival assays indicated that the rescue was not due to an effect of the transgene on melanoblast survival. A novel phenotype arose when studying the interaction between Ednrb and Pax3. Newborns appeared normal but by 3.5 weeks of age, the affected pups were smaller than normal littermates and developed a dome-shaped head; some also developed thoracic kyphosis. Affected pups were dead by 4 weeks of age: 80% were Pax3Sp/+ and 75% were female. When compared to normal littermates, affected mice had brains with enlarged 4th ventricles and more glia while skeletal staining showed kyphosis, wider rib cages and pelvic differences. An epistatic interaction resulting from the mixing of genetic backgrounds that is exacerbated in the presence of Pax3 heterozygosity is suspected.

Sedimentology of various cores from the West Antarctic continental margin

Three megascopic and disseminated tephra layers (which we refer to as layers A, B, and C) occur in late Quaternary glaciomarine sediments deposited on the West Antarctic continental margin. The stratigraphical positions of the distal tephra layers in 28 of the 32 studied sediment cores suggest their deposition during latest Marine Isotopic Stage (MIS) 6 and MIS 5. One prominent tephra layer (layer B), which was deposited subsequent to the penultimate deglaciation (Termination II), is present in almost all of the cores. Geochemical analyses carried out on the glass shards of the layers reveal a uniform trachytic composition and indicate Marie Byrd Land (MBL), West Antarctica, as the common volcanic source. The geochemical composition of the marine tephra is compared to that of ash layers of similar age described from Mount Moulton and Mount Takahe in MBL and from ice cores drilled at Dome Fuji, Vostok and EPICA Dome C in East Antarctica. The three tephra layers in the marine sediments are chemically indistinguishable. Also five englacial ash layers from Mt. Moulton, which originated from highly explosive Plinian eruptions of the Mt. Berlin volcano in MBL between 142 ka and 92 ka ago, are chemically very similar, as are two tephra layers erupted from Mt. Takahe at ca. 102 ka and ca. 93 ka. Statistical analysis of the chemical composition of the glass shards indicates that the youngest tephra (layer A) in the marine cores matches the ash layer erupted from Mt. Berlin at 92 ka, which was previously correlated with tephra layers in the EPICA Dome C and the Dome Fuji ice cores. A tephra erupted from Mt. Berlin at 136 ka seems to correspond to a tephra layer deposited at 1733 m in the EPICA Dome C ice core. Additionally, the oldest tephra (layer C) in the marine sediments resembles an ash layer deposited at Vostok around 142 ka, but statistical evidence for the validity of this correlation is inconclusive. Although our results underscore the potential of tephrostratigraphy for correlating terrestrial and marine palaeoclimate archives, our study also reveals limitations of this technique, which may result in the miscorrelation of tephra. Such pitfalls comprise failure to recognise the occurrence of various tephra layers in marine sediment cores, 'swamping' of records with chemically indistinguishable tephra from a single volcanic source, and exclusive use of 'geochemical fingerprinting' for correlating ash layers.

Last Interglacial synthesis of high-latitude temperature: temperature anomalies and associated errors for 4 time slices

The Last Interglacial (LIG, 129-116 thousand of years BP, ka) represents a test bed for climate model feedbacks in warmer-than-present high latitude regions. However, mainly because aligning different palaeoclimatic archives and from different parts of the world is not trivial, a spatio-temporal picture of LIG temperature changes is difficult to obtain. Here, we have selected 47 polar ice core and sub-polar marine sediment records and developed a strategy to align them onto the recent AICC2012 ice core chronology. We provide the first compilation of high-latitude temperature changes across the LIG associated with a coherent temporal framework built between ice core and marine sediment records. Our new data synthesis highlights non-synchronous maximum temperature changes between the two hemispheres with the Southern Ocean and Antarctica records showing an early warming compared to North Atlantic records. We also observe warmer than present-day conditions that occur for a longer time period in southern high latitudes than in northern high latitudes. Finally, the amplitude of temperature changes at high northern latitudes is larger compared to high southern latitude temperature changes recorded at the onset and the demise of the LIG. We have also compiled four data-based time slices with temperature anomalies (compared to present-day conditions) at 115 ka, 120 ka, 125 ka and 130 ka and quantitatively estimated temperature uncertainties that include relative dating errors. This provides an improved benchmark for performing more robust model-data comparison. The surface temperature simulated by two General Circulation Models (CCSM3 and HadCM3) for 130 ka and 125 ka is compared to the corresponding time slice data synthesis. This comparison shows that the models predict warmer than present conditions earlier than documented in the North Atlantic, while neither model is able to produce the reconstructed early Southern Ocean and Antarctic warming. Our results highlight the importance of producing a sequence of time slices rather than one single time slice averaging the LIG climate conditions.

Water temperature reconstructions based on paired Uk'37 and Tex86 records, and paired surface and subsurface Mg/Ca records

This dataset contains the collection of available published paired Uk'37 and Tex86 records spanning multi-millennial to multi-million year time scales, as well as a collection of Mg/Ca-derived temperatures measured in parallel on surface and subsurface dwelling foraminifera, both used in the analyses of Ho and Laepple, Nature Geoscience 2016. As the signal-to-noise ratios of proxy-derived Holocene temperatures are relatively low, we selected records that contain at least the last deglaciation (oldest sample >18kyr BP).

Geochemistry of Atlantis Massif crust

The Atlantis Massif (Mid-Atlantic Ridge, 30°N) is an oceanic core complex marked by distinct variations in crustal architecture, deformation and metamorphism over distances of at least 5 km. We report Sr and Nd isotope data and Rare Earth Element (REE) concentrations of gabbroic and ultramafic rocks drilled at the central dome (IODP Hole 1309D) and recovered by submersible from the southern ridge of the massif that underlie the peridotite-hosted Lost City Hydrothermal Field. Systematic variations between the two areas document variations in seawater penetration and degree of fluid-rock interaction during uplift and emplacement of the massif and hydrothermal activity associated with the formation of Lost City. Homogeneous Sr and Nd isotope compositions of the gabbroic rocks from the two areas (87Sr/86Sr: 0.70261-0.70429 and epsilon-Nd: +9.1 to +12.1) indicate an origin from a depleted mantle. At the central dome, serpentinized peridotites are rare and show elevated seawater-like Sr isotope compositions related to serpentinization at shallow crustal levels, whereas unaltered mantle isotopic compositions preserved in the gabbroic rocks attest to limited seawater interaction at depth. This portion of the massif remained relatively unaffected by Lost City hydrothermal activity. In contrast, pervasive alteration and seawater-like Sr and Nd isotope compositions of serpentinites at the southern wall (87Sr/86Sr: 0.70885-0.70918; epsilon-Nd: -4.7 to +11.3) indicate very high fluid-rock ratios (~20 and up to 10**6) and enhanced fluid fluxes during hydrothermal circulation. Our studies show that Nd isotopes are most sensitive to high fluid fluxes and are thus an important geochemical tracer for quantification of water-rock ratios in hydrothermal systems. Our results suggest that high fluxes and long-lived serpentinization processes may be critical to the formation of Lost City-type systems and that normal faulting and mass wasting in the south facilitate seawater penetration necessary to sustain hydrothermal activity.