PopED is a software developed by the Pharmacometrics Research Group at the Department of Pharmaceutical Biosiences, Uppsala University written mainly in MATLAB. It uses pharmacometric population models to describe the pharmacokinetics and pharmacodynamics of a drug and then estimates an optimal design of a trial for that drug. With optimization calculations in average taking a very long time, it was desirable to increase the calculation speed of the software by parallelizing the serial calculation script. The goal of this project was to investigate different methods of parallelization and implement the method which seemed the best for the circumstances.The parallelization was implemented in C/C++ by using Open MPI and tested on the UPPMAX Kalkyl High-Performance Computation Cluster. Some alterations were made in the original MATLAB script to adapt PopED to the new parallel code. The methods which where parallelized included the Random Search and the Line Search algorithms. The testing showed a significant performance increase, with effectiveness per active core rangingfrom 55% to 89% depending on model and number of evaluated designs.

The study felld into three sections. The first section that a liquid chromatography method with fluorescence detection was developed for simultaneous determination of 11 quinolones (QNs; marbofloxacin, norfloxacin, ciprofloxacin, lomefloxacin, danofloxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid, nalidixic acid and flumequine) in chicken, pork, fish and shrimp. The analytes were extracted with 0.3% metaphosphoric acid: acetonitrile (1:1, v/v), followed by a HLB cartridge clean-up procedure. The HPLC separation was carried out on a symmetry column C18 (250 mm x 4.5 mm i.d., 5 £gm) with linear gradient elution of 0.1% formic acid: acetonitrile as mobile phase and programmable fluorescence detection. The method was validated by spiking blank animals tissues at three different levels (25, 50 and 250 ng/g; except 6.25, 12.5 and 62.5 ng/g for DAN) and linearity, detection limit, quantification limit, precision and accuracy were checked. Mean recoveries of 11 QNs from edible animal tissues were 71.7-105.3%. The limits of quantification in different muscle tissues ranged from 5.0 to 28.0 ng/g. The results showed it was simple, rapid, sensitive and suitable for routine test. The second section that a LC-ESI-MS/MS method was developed for determining 18 (fluoro)quinolone (QNs) residues in milk, chicken, pork, fish and shrimp. This method is capable of screening and confirming the presence of 12 amphoteric QNs (marbofloxacin, norfloxacin, enrofloxacin, ciprofloxacin, desethylene ciprofloxacin, lomefloxacin, danofloxacin, sarfloxacin, difloxacin, ofloxacin, orbifloxacin and enoxacin) and 6 acidic QNs (oxolinic acid, nalidixic acid, flumequine, cinoxacin, piromidic acid and pipemidic acid). The drugs were extracted from matrix using acetonitrile with 1% formic acid, diluted in 10% acetonitrile and defatted by extraction with hexane. The LC separation was conducted on a XDB C8 (150 x 4.6 mm, 5£gm) column with gradient elution of 20 mM ammonium formate with 0.1% formic acid¡Vacetonitrile as the mobile phase. Mass spectral acquisition was completed in the positive ion mode by applying multiple reaction mode (MRM). The decision limit (CC£\) and detection capability (CC£]) stated in the Decision No. 2002/657/EC and the ISO standard No.11843, has been calculated in the case of the nonauthorized substance. The values of CC£\ ranged from 0.18 to 0.68 ng/g and CC£] ranged from 0.24 to 0.96 ng/g under specified conditions. The third section that the pharmacokinetics of ENR and its active metabolite (CIP and des-CIP) were estimated in tilapia after intravenous (i.v.) and oral (p.o.) administration of a single dose of 2.5 and 10 mg/kg body weigh, respectively. At prefixed time points, from 0.25 h to 7 days after administration, whole blood and main tissue (liver, kidney, bile and muscle) from 4 individuals in each were collected. The concentration of ENR and its active metabolites in the main tissue were simultaneously detected by LC/MS/MS method. Limited of quantitation (LOQ) of this method were 0.01£gg/g. Pharmacokinetic parameters from both routes were described to have a two- compartment open model with first-order elimination. After i.v. administration, the area under the drug concentration-time (AUC), elimination half-life (t1/2£]), maximum plasma concentration (Cmax ), total body clearance (Cltot) and apparent volume of distribution at steady-state (Vss) of ENR were 109.6 ¡Ó 31.33 £gg.h/mL, 55.17 ¡Ó 22.84 h, 4.70 ¡Ó 0.36 £gg/mL, 14.82 ¡Ó 4.24 L/h/kg, 1105 ¡Ó 223.40 L/kg ,respectively. After oral administration, the AUC , t1/2£], Tmax , Cmax of ENR were 599.42 ¡Ó 76.19£gg.h/mL , 75.95 ¡Ó 12.94 h, 0.601¡Ó0.06h, 9.75 ¡Ó 0.46£gg/mL, respectively. After p.o. administration, CIP could be detected in liver, kidney and bile. Regarding des-CIP, the main active metabolite of CIP, could be detected in 120¡ã168 h bile among tissue. ENR and CIP had significance enterohepatic cycle in Tilapia and easily accumulated in bile. It seems reasonable to explain the phenomenon of ENR and CIP maintenance of high concentration in blood and muscle during the test time.

Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections. Invasive fungal infection in the lungs in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. However, drug delivery of antifungal agents directly to the lungs could potentially result in high concentrations of drug in the lungs, a quicker onset of action, and reduction of systemic side effects. Voriconazole (VRC) is a second, generation triazole antifungal agent with increased potency, a broad spectrum of antifungal activity, and a fairly poor aqueous solubility. It is the recommended therapeutic agent for the treatment of Invasive Pulmonary Aspergillosis (IPA), and its use has improved therapeutic outcomes in immunocompromised patients with IPA. Still, systemic administration by oral or intravenous delivery is limited by high inter- and intra-patient pharmacokinetic variability, many potential drug interactions, and a narrow therapeutic index with many adverse effects, leading to clinical failures. Therefore, development of novel particulate formulations containing VRC for targeted drug delivery to the lungs is critical to improving therapeutic outcomes in patients with invasive fungal infections in the lungs. Within the framework of this dissertation, two particle engineering processes, thin film freezing (TFF) and advanced evaporative precipitation into aqueous solution (AEPAS), were investigated. The goal was to investigate microcrystalline VRC, nanocrystalline VRC, and nanostructured amorphous VRC formulations suitable for pulmonary delivery and to determine the effect of morphology on the in vivo deposition and distribution of inhaled particulate VRC formulations. TFF process parameters significantly affected the solid state properties and aerodynamic performance of the dry powder formulations containing VRC. Following dry powder insufflation into the lungs of mice, microstructured crystalline TFF-VRC achieved higher and more prolonged concentrations of VRC in the lungs with slightly lower systemic bioavailability than nanostructured amorphous TFF-VRC-PVP K25. AEPAS and TFF of template nanoemulsions did not lead to production of crystalline nanoparticles, as predicted. In particular, VRC proved to be a difficult molecule to stabilize in the nanocrystalline and nanostructured amorphous states. Ultimately, this body of work demonstrated that the particle engineering process, TFF, could be used to develop voriconazole formulations suitable for dry powder inhalation with more favorable pharmacokinetic parameters compared to inhaled voriconazole solution. / text

No description available.

Ο κλασματικός λογισμός είναι ο κλάδος της μαθηματικής ανάλυσης που μελετά παραγώγους και ολοκληρώματα κλασματικής τάξης, και επομένως επιτρέπει την διατύπωση κλασματικών διαφορικών εξισώσεων (FDEs). Aν και ο κλασματικός λογισμός εισήχθη για πρώτη φορά από τον Leibniz περισσότερα από 300 χρόνια πριν, εν τούτοις η εφαρμογή του σε προβλήματα της μαθηματικής φυσικής ξεκίνησε τις τελευταίες δεκαετίες. Συγκεκριμένα, η κλασματική ανάλυση ξεκίνησε βρίσκοντας εφαρμογή σε πολλούς τομείς των φυσικών επιστημών και της επιστήμης της μηχανικής, και μόλις το 2009 εισήχθη για πρώτη φορά στον τομέα της φαρμακοκινητικής. Η φαρμακοκινητική είναι η επιστήμη η οποία μελετά την κινητική της απορρόφησης, της κατανομής και της απομάκρυνσης των φαρμάκων, δηλαδή περιγράφει τη χρονική εξέλιξη του φαρμάκου στον ανθρώπινο οργανισμό και χρησιμοποιεί κυρίως διαμερισματικά μοντέλα. Έχει αποδειχθεί ότι συγκεκριμένα είδη φαρμάκων, μετά τη χορήγησή τους στο ανθρώπινο σώμα, ακολουθούν κινητική η οποία περιγράφεται καλύτερα με τη χρήση κλασματικών διαφορικών εξισώσεων. Ο κλασματικός λογισμός και οι εφαρμογές του είναι ένας αναπτυσσόμενος τομέας ενεργούς έρευνας. Σε ό,τι αφορά τη φαρμακοκινητική, πρόκειται για ένα πολλά υποσχόμενο εργαλείο και η αντίστοιχη βιβλιογραφία αυξάνεται ολοένα και περισσότερο. Στην παρούσα εργασία μελετάται η εφαρμογή του κλασματικού λογισμού στη φαρμακοκινητική. Συγκεκριμένα, δίνουμε αναλυτική λύση σε γραμμικά συστήματα κλασματικών διαφορικών εξισώσεων, τα οποία αντιπροσωπεύουν φαρμακοκινητικά μοντέλα που έχουν προκύψει από την έως τώρα βιβλιογραφία. Όλα τα φαρμακοκινητικά μοντέλα που έχουν μελετηθεί δίνουν μόνο αριθμητικές λύσεις. Aυτό που επιχειρείται για πρώτη φορά στην παρούσα εργασία, είναι να δοθούν οι αναλυτικές λύσεις των μοντέλων αυτών, έστω και αν η μορφή τους είναι πολύπλοκη. Αναλυτικότερα, το πρώτο κεφάλαιο της εργασίας περιέχει μια ανασκόπηση των βασικότερων στοιχείων της θεωρίας της κλασματικής ανάλυσης που θα χρησιμοποιήσουμε, όπως: συναρτήσεις Mittag-Leffler, βασικές ιδιότητες αυτών και υπολογισμός μετασχηματισμού Laplace συγκεκριμένων μορφών αυτών των συναρτήσεων, καθώς επίσης και ορισμός του κλασματικού ολοκληρώματος και της κλασματικής παραγώγου συναρτήσεων. Στο δεύτερο κεφάλαιο αναλύεται η σύνδεση της διαμερισματικής ανάλυσης με την φαρμακοκινητική. Στο τρίτο κεφάλαιο περιγράφεται η σύνδεση του κλασματικού λογισμού με τη φαρμακοκινητική, καθώς και οι λόγοι για τους οποίους υπερτερεί η προσέγγιση αυτή έναντι των προσεγγίσεων που χρησιμοποιούνταν έως και το 2009. Tο τέταρτο κεφάλαιο αφορά εφαρμογές του κλασματικού λογισμού, ενώ δίνονται οι αναλυτικές λύσεις των γραμμικών συστημάτων κλασματικών διαφορικών εξισώσεων που προκύπτουν. Ακόμη, στο Παράρτημα Α αναφέρονται κάποια στοιχεία που αφορούν στο ισοζύγιο μάζας, στο Παράρτημα Β δίνονται τα αποτελέσματα και οι γραφικές παραστάσεις των εφαρμογών που μελετήθηκαν στο τέταρτο κεφάλαιο, και, τέλος, στο Παράρτημα Γ δίνονται οι εντολές του Mathematica που χρησιμοποιήθηκαν για την απεικόνιση των αναλυτικών λύσεων. / Fractional calculus is the sector of mathematical analysis that deals with derivatives and fractional order integrals, resulting the derivation of Fractional Differential Equations (FDEs). Fractional calculus was first introduced by Leibniz more than 300 years ago. Nevertheless, its application on mathematical physics problems has just started the last few decades. In particular, fractional analysis started being applied on sciences of physics and mechanics . Furthermore, fractional analysis was introduced in the field of pharmacokinetics only a few years ago (2009). Pharmacokinetics is the science that deals with the kinetics of the absorption, the distribution and the excretion of drugs. In other words, it describes the time course of the drug inside the human body. Pharmacokinetics mostly uses compartmental models . It has been demonstrated that several types of drugs, follow a kinetic operation after entering in the human body, which is better described by Fractional Differential Equations. Fractional calculus and its applications is a developing sector of active research. Pharmacokinetics, in particular, is a promising tool and the corresponding literature is increasingly growing. The present thesis deals with the application of fractional calculus in pharmacokinetics. In particular, we provide an analytical solution in fractional differential equations linear systems, which represent pharmacokinetic models that have emerged of the existing literature. All the pharmacokinetic models that have been studied provide only arithmetical solutions. The new aspect of the present thesis is an attempt to provide the analytical solutions of these models, even if their form is complicated. In more detail, the first chapter of the study contains a review of the most fundamental fractional-analysis-theory elements that we will use, such as: Mittag-Leffler functions, their basic properties, calculation of Laplace transformation for specific forms of these functions, definition of the fractional integral and the fractional derivative of functions. In the second chapter the binding of compartmental analysis with pharmacokinetics is analyzed. In the third chapter the binding of fractional calculus with pharmacokinetics is described, as well as the reasons why this approach is superior to the previous approaches that were used until 2009. The fourth chapter contains applications of fractional calculus. The analytical solutions for the fractional differential equations linear systems that arise are also given. Furthermore, Appendix A includes some elements related to the mass balance, while Appendix B contains the results and graphs of the applications that were studied in the fourth chapter. Finally, Appendix C provides the Mathematica code that were used for the illustration of the analytical solutions.

The objectives of this study were to determine the cardiopulmonary effects and pharmacokinetics of fentanyl in dogs during isoflurane anesthesia and during anesthetic recovery with or without dexmedetomidine or acepromazine sedation. This was investigated in 7 healthy dogs using a randomized cross over study design. Dogs were given fentanyl as an initial IV loading dose (5 μg/kg) followed by an infusion (5 μg/kg/hr) for 120 minutes during isoflurane anesthesia and for 60 minutes following isoflurane discontinuation. Dogs received IV dexmedetomidine (2.5 μg/kg), acepromazine (0.05 mg/kg) or saline at the time of isoflurane discontinuation. Cardiopulmonary variables were measured and blood samples were obtained at multiple time points during the anesthetic maintenance and recovery phases. Plasma concentrations of fentanyl were measured using HPLC-MS, and subsequent population pharmacokinetic analysis was performed. During isoflurane anesthesia, fentanyl bolus administration resulted in significant changes in measured cardiopulmonary variables, however, many returned to baseline values during the maintenance of anesthesia. During anesthetic recovery, dexmedetomidine administration resulted in significant increases in PaCO2, and decreases in PvO2 and CI. Systemic arterial blood pressures were significantly lower in dogs receiving acepromazine, however CI and PvO2 were significantly higher compared to the other treatments. Analysis of fentanyl plasma concentrations showed that fentanyl pharmacokinetics best fit a 2-compartmental model, with average concentrations in the treatment groups ranging from 1.6 to 4.5 ng/mL during isoflurane anesthesia, and from 1.6 to 2.0 ng/mL during anesthetic recovery. Plasma concentrations of fentanyl were significantly higher with dexmedetomidine administration compared to the other treatments during the recovery period. Compared to the maintenance phase of anesthesia, anesthetic recovery with dexmedetomidine administration did not significantly change fentanyl pharmacokinetics, while acepromazine administration increased systemic and intercompartmental clearance, and recovery without sedation increased the central volume of distribution and systemic clearance. In conclusion, recovery from anesthesia with concurrent fentanyl administration, with or without sedation, caused clinically significant alterations in cardiopulmonary function that influenced fentanyl disposition in healthy dogs. / Ontario Veterinary College Pet Trust Fund

Despite its widespread use, little research has been undertaken on the use of progestogen-only injectable contraceptives by South African women. This thesis is comprised of two sections. Section 1 provides the first comprehensive description of injectable contraceptive use among rural South African women. It includes an analysis of the contraceptive method mix, prevalence of injectable contraceptive use, discontinuation patterns and reported side effects. A comparison of depot medroxyprogesterone acetate (DMPA) versus norethisterone oenanthate (NET-EN) focuses on utilization patterns and costs. The second section gives an account of the pharmacokinetics of DMPA including the first ever population analysis. A cross-sectional, community-based household survey was undertaken in the Hlabisa sub-district of KwaZulu-Natal, South Africa. Interviews were held during 1998 and 1999, with 848 randomly selected women (aged 15-49 years) and with 14 focus groups. There was a heavy reliance on injectable contraceptives which were used by 74% of women practising contraception. By contrast, the condom was the current method of only 4%. The injectable method was the most commonly used method among teenagers. However, in most cases, contraceptive use appeared to commence only after the first pregnancy. Slightly more NET-EN (54%) than DMPA (46%) was used, with younger women more likely to use NET-EN than DMPA (p=0.001). No significant differences in self-reported side effects were found between current users of the two injectables. Health workers played an important role in women's decisions to use the injectable, and in product selection, with NET-EN being recommended for younger women on the basis of concerns about method reversibility. While some women used injectables for long periods of time, discontinuation rates at two years were high, most commonly due to menstrual disturbances. Many side effects were reported by users of both DMPA and NET-EN, with amenorrhoea the most common, experienced by 63% of current injectable users. Heavy bleeding was most commonly reported by previous users (38%). Vaginal wetness was also common, mentioned by 18% and 29% of current and previous users respectively. Utilisation patterns of the two injectable products (DMPA and NET-EN) were analysed by means of a Pareto analysis of injectables issued from four South African provincial pharmaceutical depots over three financial years (1997/8, 1998/9 and 1999/2000). Injectables accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from two depots increased over the period of analysis, even though DMPA was the cheaper option. The pharmacokinetic analysis was undertaken amongst DMPA users routinely attending family planning services in three Durban clinics in 1996. Medroxyprogesterone acetate levels at the end of the dosing interval were analysed for 94 women. In addition a population pharmacokinetic analysis of 291 serum levels from 111 DMPA users was undertaken. This involved the use of Non Linear Mixed Effect Modelling (NONMEM) to fit the data and determine the pharmacokinetic parameters, apparent clearance (CLIP) and apparent volume of distribution (VIP), and to estimate the influence of covariates on CLIP and VIP (where P is the bioavailability). The final model estimates for CLIP and VIP were 1080 (95% confidence interval: 994, 1166) litres/day and 86200 litres (95% confidence interval: 68246, 104154) respectively. No significant relationships were found between the covariates tested and CLIP and VIP. Concerns raised in the literature about the influence of weight or ethnicity on the pharmacokinetics of DMPA were shown to be unfounded. In the context of South Africa's HIV epidemic, the heavy reliance on injectable contraceptives, which offer no protection against HIV, should be addressed by expanding the contraceptive method mix to include barrier methods such as the female condom. Health providers are influential in contraceptive decision-making and should be encouraged and supported to redress the dependence on the injectable method alone, taking into account the need of many for dual protection against HIV and unwanted pregnancy. Provider counseling should also focus on adherence to dosing regimens, improving continuation rates, and should provide appropriate advice for women complaining about vaginal wetness with injectable use. Promotion of one injectable product over another to younger women is not appropriate. Since DMPA is the cheaper product, provider training about the rational use of injectable contraceptives should include cost considerations. / Thesis (Ph.D.)-University of Natal, 2003.

No description available.

Sterically stabilized liposomes with saturated lipid as the major lipid component (DSPC:m-PEGDSPE were applied in DB-67 delivery. The drug retention in vitro and pharmacokinetic properties in vivo were investigated. Liposomal DB-67 was cleared faster from the circulation in the larger liposomes (~180 nm) than in the smaller ones (~120 nm), even though DB-67 was retained longer in smaller size liposomes in vitro. Liposomal DB-67 clearance was increased when cholesterol was present in the liposomal composition (40 mole %). It can be attributable to the faster drug release from cholesterol containing liposomes as compared to liposomes without cholesterol. Cholesterol free liposomes with smaller particle size (~120 nm) were chosen as the optimal formulation. In addition, high lipid doses led to the lower clearance of liposomal DB-67 because the liposomal carriers were retained in the circulation longer. Liposomes of larger particle size were taken up by the liver and spleen to a greater extent than the smaller ones. But cholesterol content and lipid dose did not alter the tissue uptake of liposomes. The area under the DB-67 plasma concentration-time curve (AUC) for liposomal DB-67 was 40-fold higher that for non-liposomal DB-67.

Chemical warfare agents including organophosphorus nerve agents (NA) continue to be a significant threat to both military and civilian populations. The current Canadian Armed Forces (CAF) treatment of NA poisoning includes administration of the oxime HI-6 (used to reactivate inhibited acetylcholinesterase) in combination with atropine contained in an autoinjector, with a benzodiazepine also being administered. Two salts of HI-6 are currently available: HI-6 2Cl (1-[[[4-(Aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyiminio)methyl] pyridinium dichloride (MW 376.22 g/mol) and HI-6 DMS (1-[[[4-(Aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyiminio)methyl] pyridinium dimethanesulfonate (MW 477.49 g/mol). Currently HI-6 is available to the Canadian Armed Forces under a special access program. In order to attain licensure of HI-6 numerous studies must be carried out in animal models to ensure its safety (tolerability and toxicity), efficacy and pharmacokinetics prior to human clinical trials. The present experiment aimed to determine and compare the pharmacokinetic parameters of HI-6 in two animal models under various conditions including: direct comparison of salts (HI-6 2Cl compared to HI-6 DMS), comparison of routes of administration (intramuscular compared to intravenous), comparison of effect of anaesthetic, comparison of different concentrations of HI-6, determination of the effect of atropine sulphate co-administration and evaluation of calculated pharmacokinetic parameters when infusing HI-6. Serial plasma samples were collected and HI-6 levels were quantified using a HPLC method. In all studies a significant difference was reported for absorption/distribution parameters when comparing salts. Additionally the absorption/distribution parameters when comparing routes of administration were significantly different however all other parameters were similar. Significant differences in calculated parameters were reported when examining the effect of anaesthetic on the pharmacokinetics of HI-6. Similar to previous ascending dose studies, differences were reported for the absorption/distribution kinetics. Co-administration of HI-6 with atropine sulphate did not have significant effect on the pharmacokinetics of HI-6. The determined pharmacokinetic values for both salts were accurate for the determination of an infusion rate to reach and maintain a target plasma concentration. Finally the calculated animal model pharmacokinetic data was compared to previously published human clinical trial data and the calculated pharmacokinetic values were found to be similar.