Thesis (Ph. D.)--University of Wisconsin--Madison, 1943. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Bibliographies: leaves 60-89, 126-135.

Theophylline is one of the few preparations available for the treatment of apnoea of prematurity. Currently little data is available on the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationships of theophylline for premature neonates during the first few days of life, a time when neonates undergo profound physiological changes and when the drug is most often used. Furthermore, the influence of theophylline on hypoxaemic episodes has not yet been quantified. The study aimed to investigate optimal theophylline dosing in this group by establishing pharmacokinetic parameters, assessing the effectiveness of the drug in abolishing apnoea and hypoxaemic episodes and investigating the concentration/effect relationship. The project was conducted in the neonatal wards of King Edward VIII Hospital, Durban, South Africa. The study group comprised a total of 105 Black, apnoeic, premature neonates, with respiratory distress syndrome, who were receiving intravenous theophylline. Serum samples (263), collected from patients during routine care, were analysed for theophylline. Forty-six patients were monitored before and after theophylline therapy with a neonatal capnograph linked to a data acquisition. Apnoea incidents were classified into total (all apnoea <_5 seconds) and pathologic (all apnoea >_20 seconds) and a hypoxaemic episode was defined as a >_10% fall for >10 seconds in peripheral oxygen saturation. Within each of these groups patients were assessed as responders (>_50% reduction in the clinical effect from baseline to the last recording) and non-responders. Patient characteristics were identified as possible markers of non-response to theophylline therapy. The Nonlinear Mixed Effects Model (NONMEM) was used to derive population pharmacokinetic models and parameters for theophylline as well as to assess the concentration-effect relationship. The pharmacokinetic analysis estimated a low clearance and volume of distribution, with oxygen support enhancing clearance. Relatively high inter-individual and residual variability values were obtained prompting testing for inter-occasion variability. This resulted in a decrease of inter-individual variability for clearance and volume of distribution as well as in residual variability. In the theophylline doses used, a significant reduction in total and pathologic apnoea but not in hypoxaemic episodes occurred over the first three days after birth. The most positive improvement was seen on the first day of treatment after the loading dose. A statistically significant increase in the average pulse rate and a decrease in episodes of bradycardia from baseline to all three days of monitoring were recorded. Most patients responded at serum theophylline concentrations of 3 to 9 mg/L. Most serum theophylline concentration measurements were also in this range and it was not possible to clearly define a concentration-effect relationship. The cumulative percentage of non-responders was relatively high for total apnoea (48%) and hypoxaemic episodes (45%), but low for pathological apnoea (13%). Being one of a set of twins was identified as a marker of poor response for both total apnoea and hypoxaemic episodes. Other possible markers for poor response, in terms of total hypoxaemic episodes, were being born by caesarean section and having more than the 75th percentile pathologic apnoea per hour at baseline. It was interesting to note that, with regard to total apnoea, there were some features that seemed to predict a favourable response to theophylline. These were birth weight and 5 minute Apgar score below the 25th percentile, and patients with baseline total apnoea counts above the 75th percentile. The cumulative graphs of the responders and non-responders resembled the fixed effect model, which is the simplest model to explain drug-effect relationships. More sophisticated analysis of the concentration-effect relationship, using NONMEM and the count model proved difficult. None of the models tested were found to be satisfactory, but that which included the influence of a hypothetical respiratory depressant factor gave the most realistic value of EC50. It is suggested that further even more complex modelling may be required to accurately define the concentration-effect relationship (and hence the therapeutic range) for theophylline in neonatal apnoea. / Thesis (Ph.D.)-University of Natal, Durban, 2000.

Pharmacokinetic parameters for theophylline and dyphylline were evaluated in horse cerebrospinal fluid (csf) and plasma. Pharmacokinetic parameters did not differ significantly (p > 0.05) at the same dose for either drug when administered alone or concomitantly. Theophylline and dyphylline penetrate horse csf to produce approximately 1/2 the concentrations found in plasma. Doubling the theophylline dose from 10 mg/Kg to 20 mg/Kg doubled both csf and plasma theophylline concentrations. However, doubling the dyphylline dose from 20 mg/Kg to 40 mg/Kg tripled both csf and plasma dyphylline concentrations. Simultaneous fitting between plasma and csf drug concentrations indicates that plasma is a good indicator for predicting csf concentrations for both theophylline and dyphylline. The influence of ibuprofen input rate on antipyresis was studied in rats with yeast induced fever. In addition, a data analysis comparison was made between rat data collected from this present study and literature data from fevered children. Counterclockwise hysteresis curves (ibuprofen plasma concentration versus temperature decrement) were observed following ibuprofen oral suspension when administered to rats and children. When the collapsed hysteresis curves were plotted (mean predicted total ibuprofen effect compartment concentration versus mean predicted temperature decrement effect) the rat and children's curves were not superimposable. However, the collapsed hysteresis curves of mean predicted ibuprofen unbound effect concentration versus mean predicted temperature decrement effect were superimposable for data from the rats and children. Based on mean unbound ibuprofen effect compartment concentration versus mean predicted temperature decrement effect, the antipyretic response to ibuprofen appears to be comparable between rats and children. The apparent qualitative trend in temperature decrement, although not statistically significant, perhaps due to variability, appears to be different among ibuprofen input regimens in rats. Maximum temperature decrement appears to relate not just to the concentration of ibuprofen obtained at steady-state, but the rate at which it is obtained. / Graduation date: 1993

The theophylline clearance was evaluated in patients with liver dysfunction and/or congestive heart failure. One hundred and twenty two patients were categorized into four groups; Group I: Liver dysfunction (n=20), Group II: Congestive heart failure (CHF, n=22), Group III: Both liver dysfunction and CHF (n=12), and Group IV: Control group (n=68). The severity of liver dysfunction and CHF were evaluated using Child-Turcotte- Pugh index (CTP) and a Cardiac Function index, respectively. Theophylline clearance was significantly decreased in Groups I, II, and III when compared to the control group; but, no significant difference was found among these three groups (mean values were 0.515, 0.479, 0.417, and 0.682 mllmin/kg, respectively). Moreover, patients with compensated cirrhosis or moderate to severe CHF had the lowest theophylline clearance values (mean values 0.344, and 0.335 ml/min/kg, respectively). There was a significant correlation between Cardiac Function index and theophylline clearance (r=-0.621) in Group II. Smokers had larger theophylline clearance values than those of nonsmokers in Groups I, II, and IV. Impairment of theophylline clearance did not correlate well with any of the indices of liver function or the CTP index. A model for prediction of the clearance in CHF was developed, which consisted of a Cardiac Function index and smoking habit. This model accounts for approximately 60% of the variation of theophylline clearance. However, models describing theophylline clearance in liver dysfunction and in congestive heart failure with liver dysfun ction did not appear to be useful. Thus, routine laboratory data and indices of liver function were not helpful in evaluating the impaired hepatic theophylline elimination. The Cardiac Function index appeared to be useful in estimation of theophylline clearance in CHF; however, the association between the theophylline clearance and severe CHF needs to be evaluated further.

No / Spherical crystallization involves crystallization and simultaneous agglomeration of a crystalline particle using an immiscible phase, which has preferential affinity for the crystal surface. Here, we report application of a spherical crystallization technique to the field of co-crystallization. Carbamazepine/saccharin (CBZ/SAC) co-crystals were generated using reverse antisolvent addition and agglomerated using different bridging liquids. Two crystal forms of CBZ/SAC co-crystals were formed, depending on the levels of supersaturation achieved during processing. The selective agglomeration of co-crystal occurred during the agglomeration stage, depending on the relative interaction between bridging liquid and the crystal surfaces. The computational investigation of isosteric heats of adsorption of the bridging liquids at the prominent crystal surfaces proved to be a useful tool in understanding the surface interactions. The spherical crystallization technique shows opportunity to generate co-crystals and its purification through selective agglomeration.

O objetivo deste trabalho foi desenvolver formulações de pellets contendo teofilina, utilizando a goma gelana como aglutinante. Inicialmente, o uso desse polímero foi avaliado em comparação com o PVP. Por meio de delineamento experimental 32 foram analisadas as variáveis aglutinante e diluente. Os pellets obtidos apresentaram resultados satisfatórios na friabilidade e esfericidade. Verificou-se que o diluente exerceu influência significativa na granulometria, de modo que formulações com manitol apresentaram maior formação de pó após a produção. Com relação ao aglutinante sua maior influência foi na dissolução, pois formulações com gelana apresentaram eficiência de dissolução, em média, menor que as formulações com PVP. A seguir, foi avaliada a influência do polímero, sua quantidade, e seu modo de incorporação nas formulações. Para isso foi realizado um delineamento experimental 23, tendo a gelana, a quantidade, e a incorporação como variáveis. Verificou-se que a característica que sofreu maior influência das variáveis foi a granumoletria, pois as condições empregadas influenciaram significativamente o rendimento de pellets. Com relação à friabilidade, esfericidade e dissolução, não foram observadas diferenças significativas entre os resultados, ainda que algumas tendências puderam ser identificadas. / Aim of this work was to develop pellet formulations containing theophylline, using gellan gum as a binding agent. Inicially, application of the polymer was compared with PVP. By a 32 experimental design, variables binder and diluent were analyzed. Pellets presented satisfactory results in friability and sphericity. It was found that the diluent exerted significant influence on granulometry, so formulations with mannitol showed higher dust formation after production. Regarding binder variable, its higher influence was in the dissolution, since formulations with gellan presented smaller dissolution efficiency than formulations with PVP. Next, the influence of polymer, amount, and incorporation were evaluated. In this part, a 23 experimental design was carried out, with gellan, quantity, and incorporation as variables. It was found that granulometry was the most influenced by variables. So conditions employed influenced significantly the yield of pellets. Regarding friability, sphericity and dissolution, no significant differences were observed, although some trends could be identified.

Crystal engineering study using spray dryer was performed for scale-up and rapid, continuous crystallisation of co-crystals from solution. The study emphasise on developing co-crystals of two structurally similar compounds, caffeine (CAF) and theophylline (THEO) with various di-carboxylic acids. The incongruently soluble pair of CAF and THEO with di-carboxylic acids acquires large solubility difference which is important to consider for its utility in product development. Based on previous assumption that maleic acid (MAL) elevates CAF’s solubility; solubility of the two similar compounds was tested in various dicarboxylic acids. Other solubility enhancement strategies such as introduction of surfactant and binary solvents were also scrutinised. A kinetically similar bench-scale technique, rotary evaporator (rotavap) was investigated as a pre-screening tool for the production of co-crystals via spray drying. Furthermore, various process parameters within the spray dryer were optimised to control the kinetic conditions which influence co-crystallisation and quality of the product. Another polymorphic co-crystal pair, CBZ (carbamazepine) and SAC (saccharin) was examined in various solvents and its degradation was evaluated over a period of few months. In this study, a two-step conversion of CBZ into its degradate was hypothesised. Rotavap delivered a true reflection of co-crystal favoured via spray drying apart from co-crystal pairs depicting polymorphism. Spray dryer offered a unique environment favouring metastable forms of co-crystals irrespective of the starting component stoichiometry; generating CAF:MAL 2:1. However, due to process limitation and solubility constraint, the impurity of CAF in CAF:MAL 2:1 co-crystals could not be abolished.

Carbon tetrachloride (CCl4) is a hepatotoxicant known to elevate alanine aminotransferase (ALT) and other liver enzyme levels, and cause lipid peroxidation, as well as centrilobular necrosis. A number of poly ADP-ribose polymerase (PARP) inhibitors were administered via intraperitoneal (i.p.) injections to male ICR mice as cotreatments at various time intervals relative to the CCl4. Aminophylline, a water soluble complex consisting of two molecules of theophylline bridged by ethylene diamine, was administered one-half hour, one hour and two hours after CCl4. The levels of ALT in the serum, as well as malondialdehyde and its equivalent markers of oxidative damage in the liver, were significantly reduced by aminophylline, relative to those in mice receiving only CCl4. The hepatoprotective effects of aminophylline were confirmed via the examination of histopathologic samples from the livers of mice receiving aminophylline in conjunction with CCl4 as opposed to those administered CCl4 alone. The potential benefit to society as a result of this research is that aminophylline, which has already been approved by the Food and Drug Administration (FDA), could potentially be administered in the event of an overexposure to CCl4 or similar halocarbons to minimize the free radical-mediated hepatotoxicity resulting from overexposure.

In asthma therapy, the use of theophylline to prevent bronchial spasm and glucocorticoids to decrease inflammation is widely indicated. Apart from the acute asthma attack oral theophylline is treated for chronic therapy in order to minimize inflammation and to enhance the efficiency of corticosteroids and recover steroids’ anti-inflammatory actions in COPD treatment. The preferred application route for respiratory disease treatment is by inhalation, such as dry powder inhalers (DPI) being the delivery systems of first choice. As shown recently, there is an advantageous effect if the drugs are given simultaneously which is caused by a synergistic effect at the same target cell in the lung epithelia. Therefore, it seems rational to combine both substances in one particle. This type of particle has the advantage over a combination product containing both drugs in a physical mixture which occurs rather randomly deposition leading to API segregation and non-dose-uniformity. Dry powder inhalers (DPIs) is a type of therapeutic pharmaceutical formulations usually present in the solid form. Due to the nature of the solid-state, an understanding of chemical and physical properties must be established for acquiring optimum performance of the active pharmaceutical ingredients (APIs). In recent year, generation of DPIs is a destructive procedure to meet the micron size. Such processes are inefficient and difficult to control. Moreover, according to current researches on combination APIs formulation, this type of DPIs performed a greater variability in does delivery of each active, leading to poor bioavailability and limit clinical efficient. This result suggest that combination formulations require advanced quality and functionality of particles with suitable physicochemical properties. Hence, in order to production of binary and combination DPIs products, the aim of this study was to develop the spray drying and ultrasonic process for engineering of combination drug particles that will be delivered more efficiently and independently of dose variations to the lung. Microparticles were produced by spray drying or/and ultrasonic technique. The processing parameters and addition of excipients (polymers) were optimized using a full factorial design such that microparticles were produced in a narrow size range suitable for inhalation. Employing excipients resulted in high saturation environment leading to minimized sphere particles when compared to conventional solvent. Solid state characterization of microparticles using powder x-ray diffraction and differential scanning calorimetry indicated that the particles contained crystalline but no cocrystal. The combination particles comparable to or better than micronized drug when formulated as a powder blended with lactose. It was concluded that the use of HPMC enhanced crystallinity suitable for inhalation; and combination particles improved uniform distribution on the stage of NGI.

O objetivo deste trabalho foi desenvolver formulações de pellets contendo teofilina, utilizando a goma gelana como aglutinante. Inicialmente, o uso desse polímero foi avaliado em comparação com o PVP. Por meio de delineamento experimental 32 foram analisadas as variáveis aglutinante e diluente. Os pellets obtidos apresentaram resultados satisfatórios na friabilidade e esfericidade. Verificou-se que o diluente exerceu influência significativa na granulometria, de modo que formulações com manitol apresentaram maior formação de pó após a produção. Com relação ao aglutinante sua maior influência foi na dissolução, pois formulações com gelana apresentaram eficiência de dissolução, em média, menor que as formulações com PVP. A seguir, foi avaliada a influência do polímero, sua quantidade, e seu modo de incorporação nas formulações. Para isso foi realizado um delineamento experimental 23, tendo a gelana, a quantidade, e a incorporação como variáveis. Verificou-se que a característica que sofreu maior influência das variáveis foi a granumoletria, pois as condições empregadas influenciaram significativamente o rendimento de pellets. Com relação à friabilidade, esfericidade e dissolução, não foram observadas diferenças significativas entre os resultados, ainda que algumas tendências puderam ser identificadas. / Aim of this work was to develop pellet formulations containing theophylline, using gellan gum as a binding agent. Inicially, application of the polymer was compared with PVP. By a 32 experimental design, variables binder and diluent were analyzed. Pellets presented satisfactory results in friability and sphericity. It was found that the diluent exerted significant influence on granulometry, so formulations with mannitol showed higher dust formation after production. Regarding binder variable, its higher influence was in the dissolution, since formulations with gellan presented smaller dissolution efficiency than formulations with PVP. Next, the influence of polymer, amount, and incorporation were evaluated. In this part, a 23 experimental design was carried out, with gellan, quantity, and incorporation as variables. It was found that granulometry was the most influenced by variables. So conditions employed influenced significantly the yield of pellets. Regarding friability, sphericity and dissolution, no significant differences were observed, although some trends could be identified.