Thesis (Ph. D.)--University of Wisconsin--Madison, 1941. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--Syracuse University, 2003. / "Publication number AAT 3081627."

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / Many pediatric patients require medications that are not available in age appropriate formulations, especially those with cardiovascular diseases. Furosemide and Captopril generally are produced in solid dosage forms for adults, and need to be fractionated and transformed in suspensions for use in children. The use of a suitable vehicle is critical to the preparation of a homogeneous, stable and palatable extemporaneous formulation that can guarantee the expected effect. In this work was evaluated the acceptability of a vehicle, named Gute, developed by a research group from Universidade Federal do CearÃ, considering that palatability is essential to treatment adherence in children. We analyzed the vehicle in different flavors with respect to the ability to mask the bitter taste of Captopril and Furosemide, the acceptance and preference without actives by healthy children and their parents, and the acceptance of extemporaneous formulations of the mentioned drugs administered to pediatric patients as prescribed. In the laboratory, eight panelists evaluated the masking ability of the vehicle flavored in mint, cherry, strawberry and neutral using a linear scale. ANOVA scores for bitterness intensity for captopril and furosemide showed that the flavored samples had significantly greater capacity of masking the bitter taste than the vehicle without flavor (neutral), however, there was no different between the flavors. 62 children 4-12 years and 21 guardians participated in the evaluation of the vehicle without actives flavored in mint, strawberry and cherry, using a facial-verbal hedonic scale with seven degrees. The three flavors were accepted and equally preferred by children and guardians. In hospitalized patients who received suspensions of Captopril (34) and furosemide (36), the flavors mint, strawberry and neutral acceptance was evaluated through the guardians with the hedonic scale and compared with the observation of the researcher .Suspensions in neutral and strawberry flavors were considered acceptable for both drugs. The correlation between the results from the two methods was moderate for Captopril, and absent Furosemide. The results for the neutral flavor showed that the addition of flavoring agents did not influenced in the acceptance and can be avoided in this case, an advantage in terms of safety for infants and neonates. / Muitos medicamentos necessÃrios a pacientes pediÃtricos nÃo sÃo disponÃveis em formulaÃÃes apropriadas à idade, principalmente aqueles que tratam doenÃas cardiovasculares. Captopril e Furosemida, de modo geral, sÃo produzidos na forma sÃlida em doses para adultos, e necessitam ser fracionados e transformados em suspensÃes para uso em crianÃas. O uso de um veÃculo adequado à crÃtico para o preparo de formulaÃÃes extemporÃneas homogÃneas, palatÃveis e estÃveis, que possam garantir o efeito esperado. Neste trabalho foi avaliada a aceitabilidade de um veÃculo com nome fantasia Gute, desenvolvido por um grupo de pesquisa da Universidade Federal do CearÃ, tendo em vista que a palatabilidade à essencial para a adesÃo ao tratamento em crianÃas. Analisou-se o veÃculo em diferentes sabores em relaÃÃo à capacidade de mascarar o gosto amargo de Captopril e Furosemida, sua aceitaÃÃo e preferÃncia sem ativos por crianÃas sadias e seus responsÃveis, bem como a aceitaÃÃo de formulaÃÃes extemporÃneas dos medicamentos citados, administradas a pacientes pediÃtricos, conforme prescriÃÃo. Em laboratÃrio, oito provadores avaliaram a capacidade de mascaramento do veÃculo flavorizado nos sabores menta, cereja, morango e neutro, utilizando uma escala linear. A anova dos valores de intensidade do sabor amargo, para Captopril e Furosemida, mostrou que a capacidade dos sabores flavorizados de mascarar o sabor amargo foi significativamente maior do que a do veÃculo sem sabor, contudo, os sabores nÃo diferiram entre si. Participaram da avaliaÃÃo do veÃculo sem ativos, nos sabores menta, morango e cereja, 62 crianÃas de 4 a 12 anos e 21 responsÃveis, usando uma escala hedÃnica facial-verbal de sete graus. Os trÃs sabores foram aceitos e igualmente preferidos pelas crianÃas e pelos responsÃveis. Com os pacientes internados que receberam suspensÃes de Captopril (34) e Furosemida (36), nos sabores menta, neutro e morango, a aceitaÃÃo foi avaliada atravÃs dos responsÃveis com uso da escala hedÃnica e comparada com a observaÃÃo da pesquisadora. As suspensÃes nos sabores neutro e morango foram consideradas aceitas para ambos os medicamentos. A correlaÃÃo entre os resultados provenientes dos dois mÃtodos de avaliaÃÃo da aceitaÃÃo foi moderada para Captopril, e para Furosemida, nÃo houve correlaÃÃo. Os resultados relativos ao sabor neutro mostraram que a adiÃÃo de flavorizantes nÃo influenciou na aceitaÃÃo das suspensÃes, podendo ser evitada nesses casos, uma vantagem em termos de seguranÃa para bebÃs e neonatos.

University of Macau / Institute of Chinese Medical Sciences

This study involves using methyllithium to synthesize Fischer carbene complexes as precursors for metal templated α,β-unsaturated complexes with potential as acceptors in the Baylis Hillman reaction as well as in Dötz benzannulation. Fischer carbene complexes contain low oxidation state metal centers, are electrophilic in nature and are stabilized by π-donating substituents such as alkoxy and amino groups. The increased electron withdrawing nature of the metal carbonyl moiety was expected to improve the rates of reaction compared to organic carbonyls. Four Fischer carbenes were synthesized via nucleophilic addition of MeLi to chromium and tungsten hexacarbonyl at low temperatures followed by alkylation using either a Meerwein salt (Me₃OBF₄) to give the desired Fischer metal methyl methoxy carbenes or Et₄NBr/alkylhalide to make the corresponding ethoxy and allyloxy carbenes. Characterization was by means of ¹³C NMR, ¹H NMR, and IR. In silico studies were carried out looking at the effect of substituents on the carbene bond. Synthesis of α,β-unsaturated complexes was effected via the aldol condensation route and found to be unfavorable using enolizable aldehydes, although the use of two aryl aldehydes resulted in successful preparation of two α,β-unsaturated complexes. Difficulty in the purification of these complexes hindered their full characterization. Computational studies looked at the effect of substituents on the system as well as variation of the metal from Cr to Mo and W. Synthesis of Baylis Hillman adducts using α,β-unsaturated complexes as acceptors was unsuccessful due to the ease of product oxidization. One potential product was obtained in its crude form although purification was not possible due to oxidation. Computational studies suggested that the oxygen on the ligand negatively impacts the stability of these Fischer carbene derived Baylis Hillman adducts promoting intramolecular oxidation of the metal. The α,β-unsaturated complexes and Baylis Hillman adducts were considered to be candidates to undergo Dötz benzannulation methodology. The use of the α,β-unsaturated complexes in this reaction was generally unsuccessful, both in the microwave and in conventional reflux conditions. Computational studies of these compounds were carried out to facilitate understanding of their stability and configuration.

Introduction: Process analytical technologies are systems for the analysis and control of manufacturing processes to assure acceptable end-product quality. This is achieved by timely measurements of critical parameters and performance attributes of raw material and in-process material and processes. The introduction of process analytical technology using near infrared analysis was investigated in three areas, namely incoming raw material analysis, blend uniformity analysis and moisture determination in the fluid bed dryer. Methodology: Incoming raw material identification - The FOSS XDS rapid content analyzer was used for the development of a NIR method for the identification and material qualification of starch maize and lactose monohydrate. Blend uniformity analysis – The SP15 Laboratory Blender fitted with near infrared probe was utilized for the study. Two types of blend experiments were designed to monitor the distribution of magnesium stearate (lubricant) in the blend, namely, a powder blend utilizing lactose monohydrate and a granule blend utilizing Ridaq® granule. Software methods were developed to monitor the standard deviation of the absorbance at the wavelengths that were specific for lactose monohydrate, Ridaq® granule and magnesium stearate. To confirm the prediction of end-point using near infrared, results were verified using an atomic absorption method for magnesium stearate. The blends were sampled at the selected time intervals corresponding to three states of the blend, namely, before end-point, at end-point and after end-point using a sampling plan. An additional six blends were conducted for the granule blend and sampled when the standard deviation had reached a value below 3 x 10-6 at the magnesium stearate wavelength at four consecutive data points (standard deviation value extrapolated from blends carried out to predetermined time intervals). Moisture determination in the fluid bed dryer – Moisture values for two products (Product A and Product B) were retrospectively collected from past production batches. A process capability study was conducted on the moisture values to determine if the current process was in a state of control. Results and Discussion: Incoming raw material identification – The algorithms used for the spectral library were able to distinguish between the raw materials selected. The spectral library positively identified the starch maize and lactose monohydrate samples that were not present in the library. The negative challenge with pregelatinised starch and tablettose demonstrated that the spectral library was able to differentiate between closely related compounds. Blend uniformity analysis – Blends sampled at the predetermined time intervals demonstrated a homogeneous state when the standard deviation of the absorbance was low and a non-homogeneous state when the standard deviation of the absorbance was high, thus near infrared prediction on the state of the blend was confirmed by the standard analytical methods. The series of Ridaq® granule and magnesium stearate blends sampled when the standard deviation was below 3 x 10-6 were homogeneous with the exception of one blend that was marginally out of specification. Blend durations were significantly lower than the standard blend durations used in the facility and ranged from 112 to 198 seconds. Moisture determination in the fluid bed dryer – From the process capability study of the two products it was noted that Product A is stable but can still be optimized while Product B is at a desirable state. The statistical evaluation of the moisture values for Product A and Product B demonstrated that the use of the product temperature to monitor the moisture gave consistent results. The current process is stable and capable of producing repeatable results although near infrared provides a means for continuously monitoring the product moisture and allows one to take action to prevent over-drying or under-drying. Conclusion: From the investigations conducted, it can be seen that there is definitely a niche for process analytical technology at this pharmaceutical company. The implementation is a gradual process of change, which may take time, probably several years (Heinze & Hansen 2005).

No description available.

Alzheimer's disease (AD) is commonly characterized by a loss of cognitive function due to the deterioration of neuronal synapses from the presence of senile amyloid beta-42 (Aß42) plaques. Evaluating cognitive deficits caused by Aß42 using human cortical neurons poses a challenge due to sourcing difficulties, and the use of animal models to assess drug efficacy creates biological hurdles from lack of species translatability. Recent advances in induced-pluripotent stem cell technology have enabled the development of mature, human-based cortical neuron models. The development of an hiPSC-cortical neuron differentiation protocol facilitates the exploration of disease onset and functional analysis from a patient-derived cell source, and further investigation of potential therapeutic treatments, while eliminating biological efficacy concerns. Long-term potentiation (LTP) was utilized as an in vitro correlate for memory and learning to quantify cognitive deficits in sporadic AD (SAD) and familial AD (FAD) systems and assess drug treatments for the prevention of Aß42-induced neurotoxicity. Synaptic connectivity and LTP induction through high-frequency stimulation was simulated through cortical neurons cultured on microelectrode arrays (MEAs), such that the functional activity of the neuronal population could be assessed overtime. AD therapeutic treatments were shown to block the Aß42-induced neurotoxic loss of synaptic plasticity and maintain persistent LTP in a model for SAD. Subsequently, FAD was assessed through the differentiation of patient-derived AD iPSCs, where LTP proficiency could be evaluated to relate to clinical cognitive evaluations. This study established a serum-free, in vitro human-derived iPSC-cortical neuron protocol that could be adapted to validate disease mechanisms and drug efficacy in patient-derived neural networks as a potential platform for precision medicine.

A series of 3-aminotetralins were synthesized as potential opioid antagonists. Each proposed target compound was based on a 3-(mono- or dialkylamino )-7 -(hydroxy or methoxy)-2, 2-dimethyl-1-tetralone parent structure. Three synthetic schemes were developed utilizing the common intermediate, ethyl3-benzylamino-2, 2-dimethyl-4-(4- methoxyphenyl)butyrate 3. In Scheme I, compound 3 was modified through a series of six steps to obtain 3-(N-methyl-N-cyclopropanecarboxamido )-7 -methoxy-2, 2-dimethyl- 1-hydroxy-1-phenyltetralin (9). To carry out further synthetic steps on the intermediate 9 required the reduction of the amide function, which proved to be problematic in terms of product isolation. Scheme II was a four-step procedure, which utilized the intermediate ethyl 3- amino-2, 2 dimethyl-4-(4-methoxyphenyl)butyrate (4), also utilized in Scheme I. Ester hydrolysis of the amino ester 4 produced the amino acid 12. Internal cyclization of 12 yielded the key intermediate, 3-amino-7 -methoxy-2, 2-dimethyl-1-tetralone (13). TheNalkylation step was carried out on 13 and this yielded the target compounds, 3-[N- ( cyclopropylmethyl)amino ]- and 3-[N, N-( dicyclopropylmethyl)amino ]-7 -methoxy-2, 2- dimethyl-1-tetralone (14, 15). Subsequently, compounds 14 and 15 were 0-demethylated to obtain the respective target compounds, 3-[N-(cyclopropylmethyl)amino]- and 3-[N, N-(dicyclopropylmethyl)amino ]-7-hydroxy-2, 2-dimethyl-1-tetralone (16, 17). Scheme III was an alternate synthetic route to obtain the target compounds 3-[Nmethyl- N-( cyclopropylmethyl)amino ]-2, 2-dimethyl-7-(hydroxy or methoxy)-1-hydroxy- 1-phenyltetralin (10, 11) without the amide reduction step required in Scheme I. The intermediate 3 was N-methylated to form the 3-N-methyl-N-benzylamino ester 18 by the Eschweiler-Clarke procedure. Compound 18 was converted through a series of four steps to obtain 3-[ N-methyl-N-( cyclopropylmethyl)amino ]-7 -methoxy-2, 2-dimethyl-1- tetralone (22), a target compound which was 0-demethylated to obtain compound 23, the 7-0H analog. The mono- and dialkylated 3-aminotetralins were synthesized and confirmed for purity and correct molecular formula by utilizing 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The target compounds 14, 15, 16, 17,22 and 23 were converted to their salts and are being analyzed for opioid-related activity in receptor binding assays.

Salt formation provides a means of altering the physicochemical and resultant biological characteristics of a drug entity without modifying its molecular structure. Many published reviews have indicated the importance of the selection of the most appropriate salt form. This work is an investigation into the salt formation of two heterocyclic drugs. This is done by the physicochemical and the crystallographic studies of 19 high resolution single crystal diffraction studies. The particular targets of the work are the selection of the most appropriate salt forms, investigations into the tautomerism and polymorphism (or pseudopolymorphism) and an understanding of the interactions most likely between these heterocyclic drugs and their specific receptor sites. Section 1 describes the effect of protonation on the absorption of drugs, the rationale for using various salt forms and the resultant effect this has on a number of physicochemical properties of the parent compound. Section 2 is a description of the experimental techniques used in the physicochemical investigations and in crystal structure determination. In Sections 3 and 7, the preparation and characterisation of the salts and modifications of the two heterocyclic drugs, GU and IM is described. In Sections 4 and 8, the physicochemical investigations into the hygroscopicity and solid-state stabilities of the salts of GU and IM is described. Van't Hoff solubility studies are used to determine the enthalpies of solution and where appropriate the relative thermodynamic stabilities of the various phases produced. The structures of 19 of the salts or modifications of GU and IM, together with their packing and hydrogen bonding interactions is described in Sections 5 and 9. Sections 6 and 10 describe the ionisation properties of these molecules. Both the guanidine and imidazole moieties of GU and IM, respectively, are tautomeric, the particular form(s) found in these investigations and the effect of protonation is discussed. The conformations of these structures are discussed and the effect of protonation, especially on the puckering of the piperazine ring, is described.