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Chittchang, Montakarn Johnston Thomas P. "Effect of secondary structure on paracellular transport of polypeptides." Diss., UMK access, 2004.
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Thesis (Ph. D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2004."A dissertation in pharmaceutical sciences and chemistry." Advisor: Thomas P. Johnston. Typescript. Vita. Description based on contents viewed Feb. 23, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 202-223). Online version of the print edition.
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Dalal, Suntanu. "Amphetamine drugs potentiate morphine analgesia in the formalin test." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55488.
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There has been a great deal of research investigating drug combinations which can increase analgesia. A number of studies have been conducted with one particular combination--opioids combined with the amphetamine drugs. Despite the existing literature, this combination is rarely used in clinical practice. One purpose of this thesis is to review the literature pertaining to the opioid-amphetamine combination. Another purpose of this thesis is to investigate whether dextroamphetamine sulfate ($ circler$Dexedrine) can potentiate morphine sulfate analgesia in rats in the formalin test (Experiment 1). To investigate whether these results can be generalized to another psychostimulant, methylphenidate hydrochloride ($ circler$Ritalin) is used in Experiment 2. Methylphenidate has been chosen instead of another amphetamine drug because it is currently being used in clinical studies without supporting evidence from animal studies. The results of the two experiments indicate that low doses of d-amphetamine and methylphenidate can potentiate the analgesic effects of morphine.
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Church, Donna Lea. "Depot medroxyprogesterone acetate discontinuation after weight gain in 17-19 year old adolescent girls." CSUSB ScholarWorks, 2002. https://scholarworks.lib.csusb.edu/etd-project/2047.
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Depot medroxyprogesterone acetate (DMPA) is a long acting progesterone only contraceptive agent. Side effects such as irregular bleeding patterns and weight gain are attributed to discontinuation. The purpose of this study was to describe depot medroxyprogesterone acetate discontinuation after weight gain in 17 to 19 year-old adolescent girls.
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Heiberg, Ludvig. "An electrophoretic study of fetal mouse brain proteins after in vivo exposure to phenytoin and disulfiram." Master's thesis, University of Cape Town, 1990. http://hdl.handle.net/11427/27187.
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Although there have been two-dimensional electrophoretic studies on fetal brain tissue (for instance, Yoshida and Takahashi, 1980), the emphasis in most of this work has been on developmental changes in protein expression, and not on the effects that drugs have on fetal brain protein complement. Klose and co-workers (1977) did an early study using two-dimensional gel electrophoresis to determine the effects of various teratogens on whole embryos. No protein changes were found and that line of research was not continued. In this study two-dimensional gel electrophoresis is extensively used, in the belief that the usefulness of this technique to experimental teratology has not been fully evaluated. It is reasonable to suppose that a central nervous system teratogen administered during critical periods of susceptibility will led to perturbations of orderly brain development, and that these perturbations will be reflected as changes to the protein complement. The total brain protein complement of mice that have been exposed to drugs in utero will therefore be analysed, in the hope that any inductions or deletions of proteins as a result of drug exposure may provide a clue to the molecular events underlying drug injury to the fetus.
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Goble, David. "The impact of low to moderate alcohol consumption on different types of human performance." Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1006042.
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Despite extensive research into the effects of alcohol consumption, there is no clear understanding into the mechanisms underlying human information processing impairment. The acute consumption of alcohol was investigated to determine the implications for human information processing capabilities, and to identify the extent to which these implications were stage-specific. Further aims included the investigation and quantification of caffeine-induced antagonism of alcohol impairment. Moreover, the aforementioned relationships were investigated in morning versus evening conditions. A test battery of six resource-specific tasks was utilised to measure visual perceptual, cognitive and sensory-motor performance, fashioned to return both simple and complex measures of each task. The tasks implemented were: visual perceptual performance (accommodation, visual detection, visual pattern recognition); cognition (memory recall- digit span); and motor output (modified Fitts‟ and a driving simulated line-tracking). Performance measures were recorded by the respective computer based tasks. Physiological variables measured included heart rate frequency, heart rate variability (RMSSD, High and Low Frequency Power) and body temperature. Saccade speed, saccade amplitude, pupil size and fixation duration were the oculomotor parameters measured. Three groups of participants (alcohol, caffeine+alcohol and control) n=36 were studied, split evenly between sexes in a mixed repeated/non-repeated measures design. The control group performed all test batteries under no influence. The alcohol group performed test batteries one and two sober, and three and four under the influence of a 0.4 g/kg dose of alcohol. Group caffeine+alcohol conducted test battery one sober, two under the effect of caffeine only (4 mg/kg), and three and four under the influence of both caffeine and alcohol (0.4 g/kg). The third test battery demonstrated the effects of alcohol during the inclining phase of the blood alcohol curve, and the fourth represented the declining phase. Morning experimentation occurred between 10:00 - 12: 45 and 10:30 -13:15 with evening experimentation between 19:00 - 21:30 and 19:30 - 22:00. Acute alcohol consumption at a dose of approximately 0.4 g/kg body weight effected an average peak breath alcohol concentration of 0.062 % and 0.059 % for the alcohol and caffeine+alcohol groups respectively. Task-related visual perceptual performance demonstrated significant decrements for simple reaction time, choice reaction time and error rate. Cognitive performance demonstrated no significant performance decrements, while motor performance indicated significant decrements in target accuracy only. Physiological parameters in response to alcohol consumption showed significantly decreased heart rate variability (RMSSD) in the modified Fitts‟ task only. A significant decrease in saccade amplitude in the memory task was the only change in oculomotor parameters. Prior caffeine consumption demonstrated limited antagonism to task-related alcohol impairment, significantly improving performance only in reduced error rate while reading. Caffeine consumption showed stimulating effects on physiological parameters, significantly increasing heart rate and heart rate variability when compared to alcohol alone. The design of the tasks allows for comparison between complex and simple task performance, indicating resource utilisation and depletion. Complex tasks demonstrated higher resource utilisation, however with no statistical performance differences to simple tasks. Physiological parameters showed greater change in response to alcohol consumption, than did the performance measures. Alcohol consumption imposed significant changes in physiological and oculomotor parameters for cognitive tasks only, significantly increasing heart rate frequency and decreasing heart rate variability, skin temperature and saccade amplitude. Caffeine consumption showed no antagonism of alcohol-induced performance measures. Physiological measures showed that caffeine consumption imposed stimulating effects in only the neural reflex and memory tasks, significantly increasing heart rate frequency and heart rate variability. Prior caffeine consumption significantly decreased fixation duration in the memory task only. The time of day at which alcohol was consumed demonstrated significant performance and physiological implications. Results indicated that morning consumption of alcohol imposes greater decrements in performance and larger fluctuations in physiological parameters than the decrements in evening experimental sessions. It can be concluded that alcohol consumption at a dose of 0.4 g/kg affects all stages in the information processing chain. Task performance indicates that alcohol has a greater severity on the early stages of information processing. Conversely, under the influence of alcohol an increased task complexity induces greater effects on central stage information processing. In addition, caffeine consumption at a dose of 4 mg/kg prior to alcohol does not antagonise the alcohol-induced performance decrements.
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Bhatnagar, Barkha. "An examination of the effects of ivermectin on Brugia malayi adult worms /." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100768.
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Brugia malayi is one of the causative agents of the disabling and disfiguring disease known as Lymphatic Filariasis (LF). This infection is a well-established ailment in tropical and subtropical countries and recently the drug ivermectin has been introduced for the LF control programs. Ivermectin (IVM) is an excellent microfilaricide, but is not markedly macrofilaricidal. However, it causes a long-lasting reduction in the production of new larvae by female worms, suggesting that adult stages are affected. However, the mechanism by which IVM produces such effect in the adult worm is not well understood. One major reason is our incomplete understanding about the biological effect of IVM on adult stages. The present study was carried out to examine the in vitro effects of IVM on B. malayi adult worms using Brugia-gerbil animal model. And also to have some leads in understanding the drug-uptake and location of probable targets in the worm body by using fluorescent labeled IVM and confocal microscopy.The antifilarial effects of IVM were examined using three parameters: mf release by female worms, and motility, and viability in both male and female worms. The results reported in this study demonstrate that although IVM did not kill the adult worm, but showed significant antifilarial effects on B. malayi adult stages when examined in an in vitro system. Confocal microscopy images of the worms incubated in bodipy FITC-IVM showed strong specific localization signal in the anterior cephalic region of both male and female worms. These observations suggest the early/initial interactions of the drug with its probable receptors that could be located specifically in the head region.
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Kim, Chang Kwon. "The role of the drug-effect contingency in the development of cross tolerence to anticonvulsant drug effects." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/28249.
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It was recently demonstrated that tolerance develops to the anticonvulsant effect of ethanol on kindled convulsions elicited in rats by electrical stimulation of the amygdala, following each of a series of ethanol injections delivered on a bidaily schedule (once every 48 hr). The tolerance developed only when the convulsive stimulation was administered during the periods of ethanol exposure: subjects that received ethanol 1.5 hr before each convulsive stimulation demonstrated tolerance after just five ethanol injections; whereas, no tolerance was evident in subjects that received ethanol 1.5 hr after each stimulation. Such tolerance, which is not the inevitable product of drug exposure but is contingent upon the expression of the drug effect--the anticonvulsant effect in this case--has been termed contingent tolerance.
In Experiment 1A, tolerance developed to the anticonvulsant effects of bidaily IP injections of phenobarbital (30 mg/kg), trimethadione (270 mg/kg) and clonazepam (0.40 or 0.35 mg/kg) delivered 1 hr before each convulsive stimulation. In Experiment IB, the rats tolerant to the anticonvulsant effects of phenobarbital, trimethadione, or clonazepam received bidaily injections of carbamazepine (35 mg/kg, IP), administered 1 hr before each stimulation. There was a statistically significant transfer of tolerance from phenobarbital to carbamazepine, but not from either trimethadione or clonazepam to carbamazepine. Thus, cross tolerance appears to be greatest between anticonvulsant drugs that are effective against a similar profile of clinical and experimental seizures and that have similar mechanisms of action.
In Experiment 2A, tolerance developed to the anticonvulsant effect of bidaily pentobarbital (15 mg/kg, IP) injections only in those rats that received the drug 1 hr before the convulsive stimulation, but not in those rats that had received the drug 1 hr after each stimulation. Furthermore, those rats that had received the convulsive stimulations while under the influence of pentobarbital subsequently displayed a greater degree of cross tolerance to the anticonvulsant effect of ethanol (1.5 g/kg, IP) than those that had received the drug after each stimulation (contingent cross tolerance). Experiment 2B was the converse of Experiment 2A: contingent tolerance was demonstrated to ethanol and contingent cross tolerance to pentobarbital. This study provided the first unambiguous and bidirectional demonstration that the drug-effect contingency plays an important role in the development of cross tolerance.
In Experiment 3, tolerance to the anticonvulsant effect of ethanol dissipated when bidaily pentobarbital (15 mg/kg, IP) injections were delivered 1 hr after each convulsive stimulation (contingent cross-dissipation of tolerance), but did not dissipate when it was delivered 1 hr before each stimulation. Thus, the drug-effect contingency was shown to be important in the dissipation of tolerance to one drug following the administration of another drug. In Experiment 4, different groups of rats received different doses of pentobarbital (10-50 mg/kg, IP) on a bidaily schedule 1 hr before the convulsive stimulation. Greater tolerance was found to the anticonvulsant effect of pentobarbital in rats that had received successively larger doses of the drug, none of which were large enough to suppress the convulsions, than those rats that were maintained on a high dose of the drug that completely suppressed the convulsions. The greater tolerance in the group that received successively greater doses was attributed to the fact that the convulsions were experienced in the drugged state. This study challenged the generally accepted view that tolerance develops more rapidly and to a greater extent with larger drug doses .
This thesis provides the first unambiguous and systematic evidence of the role of the drug-effect contingency in the transfer of tolerance from one drug to another, and in the dissipation of tolerance to one drug following the administration of another. On the basis of the present experiments, several elaborations were proposed to the drug-effect theory of drug tolerance, which claims that tolerance develops to drug effects and not to drug exposure per se.Arts, Faculty of
Psychology, Department of
Graduate
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Chawla, Monica Kapoor 1950. "THE ROLE OF SEVERAL DRUGS AND COSOLVENTS ON INFUSION RELATED PHLEBITIS (THERMOGRAPHY)." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/276915.
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Weise-Kelly, Lorraine Ann. "Drug-induced ataxia : effect of the self-administration contingency /." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0030/NQ66245.pdf.
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Gabriel, Kara Irene. "Effects of prenatal ethanol exposure and postnatal handling on cognition/behavior and hypothalamic-pituitary-adrenal stress responsiveness in Sprague-Dawley rats." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ56547.pdf.
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Michaelsen, Maria Høtoft. "The effect of digestion and drug load on absorption of poorly water soluble drugs from self-nanoemulsifying drug delivery systems (SNEDDS)." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59178.
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Cook, Andrew T. "The effect of accelerated aging on peelable medical products seals /." Online version of thesis, 1994. http://hdl.handle.net/1850/11980.
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Davis, Christopher John. "Neuropharmacological investigations into the mechanisms of emesis caused by cytotoxic drugs and radiation." Thesis, University of Oxford, 1988. https://ora.ox.ac.uk/objects/uuid:b9afefde-a43e-415e-8754-ed2a8eaac620.
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Gouws, Stephanus Andries. "The impact of hospital surveillance programmes on the incidence of adverse drug reaction reporting in a South African teaching hospital." Master's thesis, University of Cape Town, 1989. http://hdl.handle.net/11427/27186.
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Post-marketing surveillance refers to any non-experimental or observational study, method, or monitoring strategy that is applied to obtain information on drug experience (primarily adverse) after a drug has been approved for clinical use. One of the major problems in post-marketing surveillance studies is the lack or under-reporting of drug experiences by health care professionals. This study was developed to describe the impact of three different prescription event monitoring programmes on the reporting of adverse drug reactions (ADR's) in the hospital situation. The intensive ADR monitoring programme and two voluntary ADR monitoring programmes which followed were conducted in the medical wards of an urban teaching and referral hospital. All patients admitted to the designated wards were monitored by a dedicated pharmacist in the intensive programme, ward pharmacists in the first voluntary programme and by medical and nursing staff in the second voluntary programme. The pharmacist monitored a cohort of patients prospectively in two medical wards for a period of three months. The patient's record was linked with any suspected ADR. All details, i.e. patient drug orders, characteristics and ADR description, were recorded and then reported. From 228 patients monitored, 25 cases have been reported. The impact of the intensive ADR monitoring programme was a reporting rate of 11 percent. Reports were received on ADR's of a particularly mild, common and pharmacologically predictable (type A) nature. The first voluntary ADR monitoring programme comprised the reporting of suspected AD R's and the recording of drug orders for the patients and the patient characteristics. The ward pharmacists monitored for suspected AD R's in all patients during their regular ward rounds. Six cases were reported in a population of 1506 patients monitored during the three months. The reports were mainly on moderate to severe suspected AD R's of pharmacologically unpredictable (type B) nature. The rate of reports received by the surveillance unit in this study was 4 reports per ward pharmacist per annum. The second voluntary ADR monitoring programme comprised the prospective monitoring of 1555 patients by medical and nursing staff during their stay at the designated medical wards during the three month period. Patients were monitored for any ADR and when an ADR was suspected, the patient characteristics and drug orders were recorded and reported to the surveillance unit. Ten cases were reported represented by six reports from doctors and four by sisters. The reporting rate was 2 reports per doctor in four years and 3 reports for each member of the nursing team in 5 years. Reports were mainly received on moderate to severe suspected ADR's of a pharmacologically unpredictable (type B) nature.
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Winter, Lara. "Characterisation of the neurosteroid analgesic alphadolone." Monash University, Dept. of Anaesthesia, 2004. http://arrow.monash.edu.au/hdl/1959.1/9669.
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Chehresa, Azita. "Benzimidazole-resistance and associated changes in life history traits of Heligmosomoides polygyrus (Nematoda) in mice." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42002.
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Association between albendazole anthelmintic resistance and a panel of life history traits in Heligmosomoides polygyrus was investigated both prior to and during drug-selection. Associations prior to anthelmintic application were studied in ten independent lines isolated without drug treatment from a susceptible stock population by random genetic drift. Variation among lines was detected in several life history traits (i.e., establishment, development and survival), and, despite lack of previous exposure to albendazole, lines also varied in their tolerance to the drug. No significant correlations were detected between drug-tolerance and any of the life history traits after 11 generations of isolation. The apparent lack of fitness differential between lesser and more drug-tolerant individuals of the susceptible population is not in accordance with the assumption that the low frequency of drug tolerant individuals in the susceptible population is explained by their lower fitness, but is consistent with the neutral theory. Associations between life history traits and drug resistance were also studied using two lines selected for albendazole resistance from the stock population, and two control lines exposed to the same monthly passage procedure but not to the drug. After 10 generations of selection, drug resistance increased from an LC50 of 0.48 $ mu$M to 2.03 $ mu$M. In a primary infection, the higher establishment and higher worm numbers one-month post-infection in the resistant parasites compared to the stock parasites occurred only in the drug-selected lines. Changes in these traits were attributed to the drug selection regime. In contrast, both drug-selected lines and passaged lines showed a faster rate of development and higher early egg production compared with the stock parasites; these changes were attributed to the passage procedure that presumably acted as a selective force on early life history traits. In immunized hosts, changes in several traits that o
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Wa, Kasongo Kasongo. "Development and in vitro evaluation of a clobetasol 17-propionate topical cream formulation." Thesis, Rhodes University, 2007. http://hdl.handle.net/10962/d1003277.
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One of the primary contributing factors to the escalating costs of health care is the high cost of innovator pharmaceutical products. As a consequence, health authorities in various countries and in particular in the developing world have identified generic prescribing and generic substitution as possible strategies to contain the escalating costs of health care provision. There is therefore a need for formulation scientists in developing countries to invest more time in the research and development of generic formulations. Clobetasol 17-propionate (CP) generic cream formulations containing 0.05% w/w of the drug were manufactured and characterized using in vitro testing. Formulation development studies were preceded by the development and validation of an RP-HPLC with UV detection for the quantitation and characterization of CP in innovator and generic cream formulations during formulation development and assessment studies. Furthermore the in vitro release ates of CP release from innovator and generic cream formulations were monitored using a validated in vitro release test method developed in these studies. The formulation of CP cream products was accomplished using a variety of commercially available mixed primary emulsifiers, such as Estol® 1474, Ritapro® 200, Emulcire® 61 WL and Gelot® 64. Successful formulations were selected based on their ability to remain physically stable immediately after manufacture and for 24 hours after storage at room temperature (22°C). Estol® 1474 was found to produce an unstable cream and was therefore not investigated further. The other three emulgents produced stable creams, but only the in vitro release profile of CP from a cream manufactured to contain Gelot® 64 was found to be statistically similar to that of the innovator formulation. Therefore the cream containing Gelot® 64 was selected as the most appropriate prototype generic cream formulation and was characterized in vitro in terms of CP content, viscosity, pH and in vitro release rate. Data generated from these studies were compared to those of the innovator product, Dermovate® cream, using statistical methods. The CP content, pH and in vitro release rate data of the CP formulation were similar to those of the innovator product, however the intrinsic viscosity of Dermovate® cream was almost three (3) times greater than the intrinsic viscosity of the test formulation developed using Gelot® 64. The CP cream formulation developed in these studies was stored for 4 weeks at 40 ± 2°C and 25 ± 5% RH in an incubator and the formulation was found to be stable. A formulation has been developed and assessed and found to be suitable for use as a topical semi-solid dosage form for CP.
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Solomon, Matthew D. "The effect of cost-sharing on the utilization of prescription drugs for chronically ill patients." Santa Monica, Calif. : Rand, 2005. http://www.loc.gov/catdir/toc/fy0612/2006279614.html.
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Chu, Yu-Hsuan. "Custom Fluorophores for Investigating the Cellular Uptake Mechanisms and Side-Effects of Pharmaceuticals." PDXScholar, 2015. http://pdxscholar.library.pdx.edu/open_access_etds/2343.
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There is a significant current need to elucidate the molecular mechanisms of the side-effects caused by widely-used pharmaceuticals. Examples include the acute nephrotoxicity and irreversible ototoxicity promoted by the cationic drugs gentamicin and cisplatin. Gentamicin is an aminoglycoside antibiotic used for the prevention and treatment of life-threatening gram-negative bacterial infections, such as tuberculosis and meningitis. Cisplatin is used to treat a broad spectrum of cancers including head and neck, ovarian, cervical, stomach, bladder, sarcoma, lymphoma, testicular cancer and others.
The objective of this study is to design and synthesize rhodamine derivatives that can be used for the construction of geometrically well-defined cationic drug conjugates. The long-term goal is to use the conjugates as tools to aid in elucidating the properties and identities of ion channels involved in the uptake of cationic pharmaceuticals into kidney and cochlear hair cells. This will shed light on the origin and potential prevention of unwanted side effects such as nephrotoxicity and ototoxicity associated with specific cationic drugs.
A series of extended rhodamine analogs with reactive groups for biomolecule conjugation has been synthesized. These fluorophores show similar spectral properties to their prototype, Texas Red succinimidyl ester (TR-SE). However, they contain rigid linkers between the fluorophore and amine-reactive moiety. The resultant gentamicin conjugates of these materials are rigidified enabling one to assess channel pore dimensions without the confounding issue of conjugate folding. Preliminary cell studies are promising, as one observes reduced gentamicin uptake in both kidney and sensory hair cell upon systematically increasing the dimension of the fluorophore. This work has enabled us to tentatively assign the maximum dilated MET channel pore size as between 1.44 nm to 1.56 nm. However, this preliminary finding, though encouraging, needs further validation via ongoing studies with larger diameter fluorophore conjugates,
A cisplatin-Texas Red conjugate has also been synthesized to enable studies of cellular uptake mechanisms. This conjugate preserves not only the spectral properties of Texas Red after conjugation, but also the cytotoxicity of cisplatin. This has been validated in zebrafish. The series of rhodamine probes that have been conjugated to gentamicin should be similarly useful for cisplatin studies. These studies are planned. Additional future work includes the synthesis of semi-flexible (glycol) and flexible (alkyl) linkers to evaluate structure-activity relationships.
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Bai, Shuang. "Effect of immunosuppressive agents on drug metabolism in rats." Thesis, Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008270.
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Brophy, Conor Jane. "The effect of theophylline on the respiratory and quadriceps femoris muscles in man /." Title page, contents and abstract only, 1992. http://web4.library.adelaide.edu.au/theses/09MD/09mdb873.pdf.
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Hammann, Felix. "Prediction of transport, pharmacokinetics, and effect of drugs /." Basel : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8905.
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De, Young Paul. "Effect of Medicaid prior authorization on drug utilization." CONNECT TO ELECTRONIC THESIS, 2007. http://dspace.wrlc.org/handle/1961/4249.
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Whalley, P. M. "The effect of propofol on hepatic drug metabolism." Thesis, University of Sheffield, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242307.
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Dwaikat, Mai Al. "The Effect of Ultrasound on Transdermal Drug Delivery." Thesis, Coventry University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492372.
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Maune, Jerene Mary 1953. "THE EFFECT OF CAFFEINE ON HEART RATE, RHYTHM AND BLOOD PRESSURE." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/276372.
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Cheng, Hiu-wan Keens. "The effect of polydrug abuse on neuropsychological functions." Click to view E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37100981.
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Ryan, Heather E. "Marijuana use and its cognitive effects." Virtual Press, 2006. http://liblink.bsu.edu/uhtbin/catkey/1337204.
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The present study compared three commonly used cognitive screeners: the Test of Cognitive Skills – Second Edition (TCS-2), the Kaufman Brief Intelligence Test (K-BIT), the Wide Range Achievement Test – Third editions (WRAT3) and the impact of marijuana use on these screeners in a population of juvenile delinquents. One hundred records (67 males and 33 females) were selected from archival data at the Allen County Juvenile Center. Results from this study found, that as predicted, individuals who tested positive for marijuana performed significantly worse on all subtests of the TCS-2, on the Verbal and Composite Score of the K-BIT, and the Spelling subtest of the WRAT3 than individuals who tested negative for marijuana use. The results of this study support the notion that marijuana can impair cognitive abilities in a group of adolescents.Department of Psychological Science
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Gregg, Amy B. "The immunological effects of antibiotic treatment and probiotic populations on oral tolerance in ova fed mice." Virtual Press, 2007. http://liblink.bsu.edu/uhtbin/catkey/1371839.
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Probiotics are a live microbial supplement that reside within the intestinal tract and are considered normal flora. The Balb/c mouse model was used to determine if the elimination of probiotics, general LAB species, by antibiotics plays a role in the breakdown of oral tolerance leading to the generation of an immune response to oral antigens. A mouse model was developed for in vivo research regarding probiotic populations and the effect on the induction of oral tolerance. The Balb/c mouse was used to determine if the mouse model had a colonized intestinal tract with probiotics followed by a reduction of probiotics that was done with orally administered antibiotics. After the reduction of probiotics, mice were fed oral antigen, ovalbumin, to determine that an immune response was not shown with oral antigen alone. After the mouse model was set up, mice were then fed oral antigen and then stimulated with immunizations to study the induction of oral tolerance and the possible effect of the absence of probiotics. The results indicated that mice with reduced probiotics and fed with oral antigen alone do not show an immune response. In contrast, mice fed with oral antigen followed by immunization indicate a higher OVA-specific serum IgG. This is evidence that correlates with clinical findings in disease states such as Crohn's Disease and Irritable Bowel Syndrome (IBD).Department of Biology
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Hoa, Nguyen Khanh. "Assessment of anti-diabetic effect of Vietnamese herbal drugs /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-585-2/.
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Elliott-Pearce, Ruth Ann. "The effect of drugs on isolated detrusor muscle contraction." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/34339.
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Detrusor instability is the commonest type of urinary incontinence in the elderly and is present in up to 50% of patients attending continence clinics. Treatment of this condition, aimed at reducing uncontrollable detrusor contractions, is at present unsatisfactory. For example, calcium antagonists are cliniclly disappointing and studies were carried out to investigate why they are ineffective. Rats were treated with nimodipine for 8 days or with a single dose. Treatment for 8 days had no effect on isolated detrasor contraction but a single dose reduced detrasor contractile response. It is propossed that chronic treatment with nimodipine caused an up-regulation of calcium channels as a compensatory mechanism. Oestrogens have been shown to have an inhibitory effect on detrusor muscle contraction after in vitro and in vivo treatment. In post-menopausal women with a uterus unopposed oestrogens should not be given, but progesterone has anti-oestrogenic actions. When rats were treated with oestrogen and progesterone for 8 days, there was no effect on rat detrasor contractile response. An anti-oestrogenic effect of progesterone has therefore been demonstrated in rat detrusor smooth muscle. Caffeine has been shown to increase detrasor pressme on bladder filling in patients with detrusor instability. The effect of low concentrations of caffeine on the contractile response of isolated human and rat detrusor muscle was therefore determined. Caffeine was found to have only a slight potentiating effect on isolated human and rat detruosr muscle contraction. The results in this thesis have important clinical imphcations for the treatment of detrusor instability. It may be more effective to administer calcium antagonists in an intermittent manner. Oestrogens are better given alone or with the lowest possible dose of progestogens. Caffeine would not be contraindicated in patients with detrusor instability.
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Dodd, Stanley Anthony. "The effect of the drug price intervention on retail pharmacies in South Africa / S.A. Dodd." Thesis, North-West University, 2007. http://hdl.handle.net/10394/4297.
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In May 2004 there was a shake-up in the private pharmaceutical industry in South Africa. The National Department of Health (DOH) introduced a form of price control which for the first time attempted to regulate prices at every level of the pharmaceutical distribution chain. The price controls was immediately challenged and was not properly implemented until partially upheld by the Constitutional Court at the end of 2005. Throughout 2006 the DOH (through the Pricing Committee) reconsidered parts of the price controls, dealing with an appropriate dispensing fee for retailers, which were struck down by the Constitutional Court. In late 2006, a new dispensing fee was published and then immediately challenged. The DOH claims they had to do this to make sure that medicines remain affordable, and pharmacists at the end of the day get a reasonable income from each price band. The United South African Pharmacies (USAP) and the Pharmacy Stakeholders1 Forum (PSF) claim that implementation of the price controls would have pharmacies not being able to cover their expenses. The objectives of the study are to ascertain whether the price controls forced upon the healthcare industry by the DOH of South Africa is viable in small retail pharmacies and what the impact will be on small retail pharmacies and their communities. The actual annual income statements for 2006 of three typical pharmacies were obtained. The next step was to determine the effect that the price controls would have had on the total sales and key financial factors in the income statement if the price controls was already in force in 2006. A revised experimental income statement was then created for the pharmacies. The experimental statements were then compared to the actual statements to determine the effects of the price controls. The comparison showed that all the pharmacies were following the same trend and had a decrease in net profit. Two of the pharmacies would have had a net loss for the year while the third will continue to show a net profit although much lower. This net profit decreased from 7% to 3% following a decrease in gross profit (GP) from 33% to 30%. The GP of the front sales shop remained unchanged, while the GP percentage for the dispensary decreased by 5% from 30% to 25%. The DuPont model showed that the Return on Equity (ROE) decreased from 83% to 33%. Drug price regulations could force many pharmacies into bankruptcy and ensure that the distribution of drugs to rural and remote areas will be financially impracticable. Once in place, the drug price regulations are likely to become ever more complex and onerous to comply with. The price regulations may end up reducing price competition among manufacturers, and in the long run, will harm the consumer by fixing prices above what would otherwise have been achieved in an open competitive market. The drug price regulations distort the normal market clearing process and effectively increase demand for medicine without providing the economic incentives that serve to match demand with supply.Thesis (M.B.A.)--North-West University, Potchefstroom Campus, 2008.
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Howell, Leonard L. "An experimental analysis of rate constancy." Diss., Georgia Institute of Technology, 1985. http://hdl.handle.net/1853/29865.
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Au, May-lan Alma. "The effects of subcortical lesions on memory." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1987. http://hub.hku.hk/bib/B29648270.
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Balaños, Guzman Carlos Alberto. "The effects of the kappa agonist U-50,488 on morphine-induced place preference conditioning and Fos immunoreactivity in the preweanling and periadolescent rat." CSUSB ScholarWorks, 1995. https://scholarworks.lib.csusb.edu/etd-project/1074.
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The effects of the kappa opioid agonist U-50,488 on morphine-induced condtioned place preference (CPP), locomotor activity and Fos immunoreactivity and assessed in 10-, 17- and 35-day old rats. It was predicted that kappa agonist treatment would block the unconditioned and conditioned behaviors produced by morhine (a mu opioid receptor agonist).
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Zajakowki, Susan M. "The effect of consumption pattern on tolerance to caffeine." Virtual Press, 1995. http://liblink.bsu.edu/uhtbin/catkey/941355.
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The effect of caffeine consumption on blood pressure has been widely studied. Robertson et al. (J Clin Invest 67: 1111-1117, 1981) cited findings of tolerance to humoral and hemodynamic effects from caffeine within four days when caffeine is consumed with each meal. These findings of tolerance have not been verified. The purpose of this study was to determine the effect of caffeine intake pattern on the development of tolerance to hemodynamic effects of caffeine. Fourteen volunteers were randomly assigned to two groups of seven. One group received 250 mg of caffeine in the morning only (MO), the other group received 250 mg of caffeine in the morning, afternoon, and evening (All Day-AD). Subjects underwent a seven day trial during which blood pressure (BP) and heart rate (HR) were assessed; morning beverage (250 mg of caffeine) was ingested and BP and HR assessments were obtained every 10 minutes for 50 minutes at rest, and after 10 minutes of cycling at 100 Watts. Afternoon and evening beverages were consumed which contained 250 mg caffeine each or placebo. No significant change in SBP, DBP, or HR from rest to 40 minutes post-caffeine absorption or between caffeine dosing pattern across trial days was found. A main effect was found for SBP post caffeine consumption (MO=5.4 vs. AD= 1.3). Mean values for DBP were stable across days 3-7 (M0=3.14-4.7 mmHg) but decreased from (3.86-.14 mmHg) from days 3 to 7 (AD). SBP revealed a significant interaction during exercise and across trial days. SBP and HR for the morning only group was higher than the all day caffeine consumption group across days. However DBP was lower across days for the morning only vs. the all day intake pattern. Therefore, caffeine dosing pattern does not appear to have an effect on tolerance to the hemodynamic effects of caffeine at rest or during exercise.School of Physical Education
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Silberstein, D. J. "The effect of renal failure on the elimination of drugs by the liver." Thesis, University of Leeds, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379649.
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Tolle, Michelle D. "In vivo Dilantin treatment alters expression levels and nuclear localization of cyclins A and B1 during mouse preimplantation embryo development." Muncie, IN : Ball State University, 2009. http://cardinalscholar.bsu.edu/677.
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Schwab, Anne Elisabeth. "The genetics of potential albendazole and ivermectin resistance in lymphatic filariae /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103006.
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A current initiative to eliminate lymphatic filariasis (LF), headed by the World Health Organization, aims to interrupt transmission of the disease through yearly community-wide treatment with the broad spectrum anthelmintic albendazole (ABZ), in combination with ivermectin (IVM) or diethylcarbamazine (DEC). Over the years, the use of both ABZ and IVM in the treatment of veterinary parasites has led to widespread anthelmintic resistance against these drugs. In this study, we genotyped microfilaria of Wuchereria bancrofti, a causative agent of LF, in order to detect the presence of mutations which confer ABZ resistance in other parasites, and we identified such mutations in worms obtained from untreated patients in Ghana and Burkina Faso, West Africa. Microfilaria from patients who had been treated with ABZ + IVM, had a significantly higher frequency of the resistant genotype, and this frequency was even higher in worms from patients that had received two rounds of treatment. In addition, the untreated population of microfilaria had an excess of homozygotes in the population. This excess homozygosity was equivalent to a Wright's Inbreeding Statistic of FIT= 0.44, and we found that the population was significantly subdivided between patients. In order to better understand the mechanisms and factors involved in the potential spread of ABZ resistance, caused by such mutations, through a population of Culex-transmitted W. bancrofti, we developed a deterministic model that incorporates genotype structure into the epidemiological model EPIFIL. This model predicts that the combination of ABZ + DEC leads to stronger selection for the resistant genotype than ABZ + IVM, and that drug efficacy assumptions are an important factor affecting the spread of drug resistance. Treatment coverage, non-random mating, initial allele frequency and number of treatments also had substantial impact on the speed and magnitude of the spread of ABZ resistance. When we expanded this model to include potential IVM-resistance alleles we found that, under ABZ + IVM treatment, selection for resistance to either drug is enhanced by the presence of resistance against the second drug. Similarly, excess homozygosity caused by parasite non-random mating may increase selection for a dominant IVM resistance allele through enhancing the spread of a recessive ABZ resistance allele. Resistence developed more slowly when it was inherited as a polygenic trait. Results from this study suggest that resistance monitoring is crucial, as resistance may not be apparent until treatment is stopped, recrudescence occurs and treatment is reapplied.
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Floresco, Stanley Bogdan. "Limbic-striatal interactions and their modulation by dopamine : electrophysiological, neurochemical and behavioral analyses." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ48635.pdf.
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Colthrust, Melissa B. "The effect of oral contraceptives on musculo-tendinous stiffness of the knee flexors." Virtual Press, 2005. http://liblink.bsu.edu/uhtbin/catkey/1319218.
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The purpose of this study is to investigate the relationship between oral contraceptive use and the musculo-tendinous stiffness of the knee flexors. Twenty-three female participants and ten male participants (control group) ranging in age from 20 - 30 years. A uniaxial accelerometer was used to assess stiffness based on the exponential decay of the damped oscillation. Female groups had estradiol and 17 a-OH progesterone levels tested. At 30% of MVC, the Ortho-Tri Cyclen group, the Other OC group and women not using OC's had a mean stiffness of 249.3+94.5, 274.1+79.1 and 216.0+43.3 Nm/rad respectively and at 50% of MVC values of 290.2+70.7, 326.7+78.9 and 267.9+52.6 Nm/rad respectively. No significant difference in stiffness was found. Also no correlation was found between estradiol and stiffness. These results indicate that there was no significance between knee stiffness and oral contraceptives within the female groups.School of Physical Education, Sport, and Exercise Science
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Cheng, Hiu-wan Keens, and 鄭曉韻. "The effect of polydrug abuse on neuropsychological functions." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37100981.
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Cox, Sander. "Modeling of drug effect in general closed-loop anesthesia." Thesis, Uppsala universitet, Institutionen för informationsteknologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-322249.
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In medicine, anesthesia is achieved by administering two interacting drugs. Nowadays,the Depth of Anesthesia can be expressed by the Bispectral Index Scale, which ismeasured by an EEG. In order to make automatic closed-loop anesthesia possiblewith the benefits of 1) relieving the anesthesiologist from the hard task of administering optimal drug doses, 2) achieving more consistent drug effects by meansof individualization, and 3) reducing side effects because of the achieved reduced overall drug administration, estimating accurate models of the effect of drug doses onthe Depth of Anesthesia is essential.The model used was a minimally parametrized PharmacoKinetic-Pharmaco Dynamic Wiener model. The parameters of the model were estimated using an Extended Kalman Filter, whose parameters were tuned manually. The model and filter were tested on new data from both the University of Porto and the University of Brescia.The unit of the reference data set from Porto was unknown, so in order to use the scale-dependent model an educated guess was made to convert the other data sets to a reasonable scale. Furthermore, the data from Brescia was incomplete, which could only partly be remediated. Similar tracking performances were obtained when using the new data sets compared to the reference data, however, either relatively constant estimates, or different parameter estimates for similar conditions, were typically obtained. This questions the validity of the model used and if the parameters foundcan be trusted. Therefore, the replication of the procedure on other complete data,and the comparison with the application of other models on the studied data, is subject for future research.
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Kohutek, Jodi Lynn. "Long-term effects of 3,4- Methylenedioxymethamphetamine (MDMA) on serotonergic and dopaminergic functioning." CSUSB ScholarWorks, 2003. https://scholarworks.lib.csusb.edu/etd-project/2305.
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Methylenedioxymethamphetamine (MDMA) popularly known as "Ecstasy" continues to gain popularity as a recreational drug that has been shown to increase serotonin and dopamine levels. The present study has demonstrated that repeated exposure to MDMA produces long-term damage to serotonergic and dopaminergic neurons in various regions of the rat brain.
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Lange, Jeremy David. "The effect of anti-malarial drugs on the pituitary gland." Thesis, University of Leeds, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238726.
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Ngamratanapaiboon, Surachai. "Metabolomics investigations of the effect of drugs on mammalian cells." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/41178/.
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Cell-based metabolomics using LC-MS systemizes the study of the uniqueness of small-molecule metabolite (metabolomes) profiles in cellular processes. Cell-based metabolomics can potentially be used in many applications for the study of biological perturbation from stimulants in cellular pathways. The advantages of cell-based metabolomics include ease of control and interpretation when compared to the study of human subjects and animal models. Furthermore, this method can decrease some highly challenging problems that occur in genomics, transcriptomics and proteomics. Nowadays, cell culture in metabolomics studies has been used in many applications. These include cell culture and bioreactor optimisation, phenotype classification, stimulant testing effect, target and toxicity analysis, metabolic networks determination and modelling, and biomarker and drug target discovery. In this study, the reverse phase-liquid chromatography-mass spectrometry and hydrophilic interaction chromatography-mass spectrometry for comprehensive metabolic profiling well suited to the untargeted analysis of non-polar and polar metabolites in mammalian cells were developed, optimized and validated. These methods can separate and detect most of hydrophobic and polar metabolites that are normally found in mammalian cell lines. After that the LC-MS methods were applied to assess the effects of drugs with known and unknown cellular metabolic effects on three mammalian cell lines, namely HMVECs for antipsychotics experiment, MCF-7 cells for cordycepin experiment and MIN6 cells for fluoxetine experiment by using untargeted metabolic profiling. The global effects of antipsychotics at high therapeutic dosage in HMVECs were investigated. The results support for the toxicity hypothesis with measurements that confirm previous findings and reveal the exact biological pathways of antipsychotic-altered BBB functions. It was found that antipsychotics may affect the bioenergetics pathway due to mitochondrial dysfunction resulted in ketoacidosis and inducing oxide stress by reactive oxygen species generation. In the MCF- cell experiment, the results of the untargeted metabolite profiling demonstrated the clear anti-breast cancer effects of cordycepin and pentostatin. By investigating the metabolite profiles, clear synergistic effects of cordycepin and pentostatin combined in comparison to cordycepin activity alone in MCF-7 cells was observed. Furthermore, the pathway analysis indicated that anti-breast cancer activity was mainly responsible for alterations in purine and pyrimidine metabolism and bioenergetics. Additionally, cordycepin may be involved in the inhibition of cell proliferation and differentiation, and the activation of cell apoptosis. The last experiment on MIN6 cells, the developed and optimized HILIC-MS approach in order to determine the biological pathways which are impaired by fluoxetine on glucose-stimulated insulin secretion on MIN6 cell lines was performed. It is found that fluoxetine may impair glycolysis, TCA and fatty acid metabolism on MIN6 cell lines. Moreover, it is also reveal that the alteration of biological pathways on MIN6 cells by known ETC inhibitors (rotenone (Complex I inhibitor) antimycin (Complex III inhibitor)) and azide (a complex IV inhibitor). From comparison with these ETC inhibitors, it is found that fluoxetine may have the same effect pattern with azide.
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Figueiredo, João Daniel Amaral. "The effect of anticancer drugs prodiginines in PP1 in melanoma." Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/6861.
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Mestrado em Biomedicina MolecularUm dos principais mecanismos reguladores da função celular é a fosforilação de proteínas. É de focar que a fosforilação anormal de proteínas-chave pode estar associada a várias patologias, incluindo o cancro. Embora já existam muitos estudos sobre cinases no cancro, o conhecimento sobre as fosfatases que antagonizam a acção das cinases é muito menos. A PP1, uma das principais proteínas fosfatase de serina/treonina expressa em todas as células eucarióticas, está envolvida em vários processos celulares incluindo apoptosis e ciclo celular. Na realidade, diversos estudos demonstram que a PP1 regula variadas proteínas que são elementos-chave no processo de tumorigenesis. A AKT, uma cinase serina/treonina que se encontra desregulada em vários tipos de cancro, é um factor crucial na progressão e sobrevivência de melanoma. Prodigiosina, um membro da família de metabolitos secundários tripirrolicos pigmentados de vermelho, as prodigininas, demonstra propriedades anticancerigenas em vários tipos de cancro. Na verdade alguns estudos verificaram que a AKT é desfosforilada pela prodigiosina embora ainda seja desconhecido o mecanismo pelo qual tal acontece. Dada a importância da AKT na progressão e sobrevivência do melanoma e a capacidade da PP1 em desfosforilar a AKT é possível que a PP1 esteja envolvida em tal mecanismo. Os resultados preliminares demonstraram que a PP1 liga-se a um membro da família das prodigininas provando a interacção entre estas moléculas. Por outro lado, ensaios em linhas celulares de melanoma usando tratamentos com prodigiosina e cantaridina, um inibidor da PP1, demonstraram que a prodigiosina afecta isoformas da PP1 diferencialmente. Estes resultados sugerem que a prodigiosina actua em duas vias de sinalização distintas em melanoma, a via da AKT e a da MAPK, uma vez que alteração nos níveis de PP1α, uma das isoformas da PP1, se correlaciona com a variação dos níveis de fosforilação da AKT e as mudanças nos níveis da PP1γ com a variação dos níveis de fosforilação da MAPK. Com estes resultados propomos um modelo de como a prodigiosina desfosforila a AKT e como este processo contribui para a indução da morte celular em células de melanoma. Esperamos que este modelo ajude na compreensão do mecanismo de acção da prodigiosina bem como no reconhecimento das fosfatases como novos alvos terapêuticos no tratamento de cancro.
Protein phosphorylation is a major regulatory mechanism for cell function. It is noteworthy that several pathologies, including cancer to be associated with abnormal phosphorylation of key proteins. Although many studies have addressed the kinases that are misregulated in cancer, much less is known about the phosphatases that counteract their actions. PP1, a major serine/threonine protein phosphatase that is ubiquitously expressed in all eukaryotic cells, is involved in many cellular processes including apoptosis and cell cycle. In fact, several studies demonstrate that PP1 regulates several proteins that are key elements in the tumorogenesis process. AKT, a serine/threonine kinase that is disregulated in several types of cancer is a crucial factor in melanoma progression and survival. Prodigiosin, a family member of the natural red pigmented tripyrrolic secondary metabolites, prodiginines, show anticancer properties in numerous types of cancer. In fact, some prodigiosin studies demonstrate that AKT is dephosphorylated by prodigiosin by an unknown mechanism. Given the importance of AKT in melanoma progression and survival and the capacity of PP1 to dephosphorylate AKT it is possible that PP1 is involved in this mechanism. Our preliminary results showed that PP1 binds to one member of prodiginine family proving the interaction between these molecules. On the other hand, experiments with melanoma cell lines, using prodigiosin and cantharidin, a PP1 inhibitor, treatments, demonstrate that prodigiosin affect differently PP1 isoforms. These results suggest that prodigiosin acts in a different way in two altered pathways in melanoma, AKT and MAPK, since the alterations in PP1α levels, one of PP1 isoforms, are correlated with the conversion in AKT dephosphorylation and the variations in PP1γ levels with the changes in MAPK dephosphorylation. Given these results we propose a model of how prodigiosin dephosphorylates AKT and how this process contributes to induce cell death in melanoma cells. We expect that this model helps to understand prodigiosin action mechanism as well as acknowledge phosphatases as a therapy target in cancer treatment.
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Zeitz, Christopher John. "Acute drug effects on the heart-haemodynamic, pharmacologic and metabolic correlations." Title page, contents and abstract only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phz48.pdf.
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Addenda and corrigenda inserted on verso of back end paper. Includes: Publications and communications to learned societies (p. 4-5). Bibliography: leaves 272-286. Examines the acute myocardial uptake of drugs, particularly perindoprilat and enalaprilat in humans. The uptake of these agents is examined, together with the haemodynamic, metabolic and biochemical effects. In particular, the impact of these agents on angiotensin and bradykinin peptides both within the heart and peripherally is described. The acute effects of a range of cardioactive drugs upon the left ventricular force-interval relationship is examined.
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Somasundaram, Balaji. "A surface plasmon resonance assay to determine the effect of influenza neuraminidase mutations on its affinity with antiviral drugs." Thesis, University of Canterbury. Chemical and Process Engineering, 2013. http://hdl.handle.net/10092/9183.
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The outbreak of pandemic influenza and its ability to spread rapidly makes it a severe threat to public health. Antiviral drugs such as oseltamivir (Roche’s Tamiflu™) and zanamivir (GlaxoSmithKline’s Relenza™) are neuraminidase (NA) inhibitors (NI), which bind more tightly to NA than its natural substrate, sialic acid. However, the virus can acquire resistance to antiviral drugs by developing single point mutations (such as H274Y) in the target protein. Thus in some cases the drugs may not be as effective as expected. The high level of inconsistency exhibited by fluorometric assays and the short half-life of the chemiluminescent assay for monitoring drug resistance lead to the need for a simple, label-free, reliable assay. To address this problem, this work focused on three main objectives: 1) to determine the binding affinities of two common anti-viral drugs (oseltamivir and zanamivir) against the influenza NA wild type and drug resistant mutants using bioinformatics software Schrodinger Suite™ 2010. 2) To develop a reliable label-free, real-time, surface plasmon resonance (SPR) assay to measure the binding affinity between influenza viral coat protein neuraminidase (wild type and mutant) and anti-viral drugs. 3) To develop an SPR inhibition assay to quantitatively compare the interactions of sialic acid, zanamivir and oseltamivir with the viral coat protein neuraminidase (wild type and mutant).
The entire docking process was carried out using Schrödinger Suite™ 2010. The 2009 pandemic H1N1 neuraminidase (PDB: 3NSS) was used throughout the docking studies as the wild type structure. Five mutants (H274Y, N294S, H274N, A346N and I222V) and three ligands (sialic acid, oseltamivir and zanamivir) were built using the maestro module. The grid-based ligand docking with energetics (GLIDE) module and induced fit docking (IFD) module were used for docking studies. The binding affinities, Gibbs free energy change (∆G) and molecular mechanics-generalized born energy/ solvent accessible area (MM-GB/SA) values for wild-type NA interactions show that both the antiviral drugs studied interact strongly with the wild-type protein. The ∆G values for all antiviral interactions with mutant NA forms were reduced in magnitude, thereby indicating that they are less favourable than interactions with the wild-type protein. A similar trend was observed with MM-GB/SA results. Amongst all of the computed values, MM-GB/SA was the closest to the experimental data. In several cases, the interactions between the anti-viral drugs and NA mutants were markedly less favourable than those between sialic acid and the same mutants, indicating that these mutations could confer anti-viral resistance.
Influenza NA wild-type and H274Y mutant were expressed in baculovirus expression system (BVES) in insect cells. The expressed proteins were partially purified using the standard purification techniques of anion exchange and size exclusion chromatography (SEC). A fluorometric activity assay was performed on the recombinant proteins. Both the wild type and the mutant showed similar level of activities. In addition, the recombinant NAs were used in an inhibition assay. Oseltamivir was found to be sensitive to wild type protein (IC50 = 0.59 nM) and resistant to the H274Y mutant protein (IC50 = 349.43 nM). On the other hand, zanamivir was sensitive to both wild type (IC50 = 0.26 nM) and the H274Y mutant (IC50 = 0.44 nM). This indicated that zanamivir was a more potent inhibitor than oseltamivir. These findings were in good agreement with the literature.
An SPR assay for accurate monitoring of influenza antiviral drug resistance was developed. A spacer molecule (1, 6- hexanediamine) was site-specifically tethered to the inert 7-hydroxyl group of zanamivir. The tethered zanamivir was immobilized onto an SPR GLC chip to obtain a final immobilization response of 431 response units (RU). The reference subtracted binding responses obtained for NA wild-type and H274Y mutant were analysed using the ProteOn Manager™ Software tools. The SPR curves were fitted to a simple Langmuir 1:1 model with drift to obtain association rate constant (ka) and dissociation rate constants (kd). The relative binding values obtained from literature and the current SPR assay (1.9 and 1.7 respectively) suggested that the current SPR assay yielded similar results to the existing labelled enzymatic assay. In addition, an SPR inhibition assay was developed. The calculated IC50-spr values were compared and it was observed that oseltamivir was sensitive to wild type protein (IC50-spr = 7.7 nM) and resistant to the H274Y mutant protein (IC50-spr = 256 nM). On the other hand, zanamivir was sensitive to both wild type (IC50-spr = 2.16 nM) and the H274Y mutant (IC50-spr = 2.4 nM). Sialic acid was also found to be sensitive to both wild type (IC50-spr = 5.5 nM) and H274Y mutant (IC50-spr = 3.25 nM). In the cases studied, the viral proteins remained sensitive to sialic acid, consistent with retention of virulence of these mutant strains. It was concluded that zanamivir is a more potent inhibitor than oseltamivir for treating the H274Y mutant. Comparison of the SPR inhibition results with the docking results revealed a similar trend. The wild-type NA and H27Y mutant retained binding affinity for sialic acid and zanamivir. Oseltamivir showed a significant decrease in binding affinity for the H274Y mutant compared with the wild-type. This was because of the disruption of the salt bridge formation within NA that was vital for oseltamivir activity.
To my knowledge, this is the first SPR biosensor assay developed to monitor influenza antiviral drug resistance. There is a tremendous scope to extend this study to more mutants and new antiviral drugs. This could pave the way for a reliable SPR biosensor assay to replace low consistency labelled enzymatic assays.
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Van, der Weyde Marlene P. "The effects of the beta-adrenergic agonist, ritodrine, in the fetal lamb." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/30417.
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Ritodrine is a beta-adrenergic agonist commonly used to inhibit premature labor contractions in women. The primary goal of ritodrine tocolysis is to prolong gestation, however, other indications may include fetal distress. The purpose of the current study was to examine the metabolic and behavioral effects of ritodrine in the fetus, using the chronically instrumented pregnant sheep as an experimental model.
Ritodrine was infused continuously into 11 fetal lambs at a rate of 2.6 ug/minute for a period of 8, 12 or 24 hours. Samples were taken simultaneously at predetermined time periods from a fetal femoral artery, umbilical vein, maternal femoral artery and uterine vein for the analysis of fetal and maternal arterial and umbilical and uterine venous blood gases, acid-base status, hematocrit, ritodrine concentration, uterine and umbilical blood flow, and glucose, lactate and oxygen concentrations and fluxes. Cardiovascular and behavioral variables were monitored continuously.
The average concentration of ritodrine in fetal arterial plasma was 20.0 ± 2.7 ng/ml (range 9.5 to 3 4.7 ng/ml) at the end of the infusion. This concentration is within the range of cord levels obtained in ritodrine exposed human fetuses at birth (7 to 79 ng/mL) . Fetal arterial plasma ritodrine levels at 8 hours post-infusion were still sufficiently elevated to exert considerable fetal effects. The apparent tolerance of the fetus to given plasma levels of drug varied considerably among animals.
The infusion of ritodrine resulted in many typical beta-adrenergic receptor mediated responses in the fetus. Fetal arterial glucose levels rose to 79% above the control by the end of the infusion. This was associated with an increase in fetal glucose delivery (70% above the control), a decrease in the umbilical veno-arterial glucose concentration difference and a tendency for fetal glucose uptake to decline. Fetal arterial plasma lactate concentrations rose more than fivefold during the infusion of ritodrine. This was associated with a rise in fetal lactate delivery (540% above the control), a slight increase in the umbilical veno-arterial plasma lactate concentration difference and a tendency for fetal lactate uptake to rise.
Fetal oxygen consumption rose progressively and significantly throughout the infusion of ritodrine and during the first 8 hours of post-infusion, reaching a maximum of 22% above the control by 8 hours post-infusion. Umbilical blood flow remained unchanged, therefore umbilical oxygen delivery was not increased to meet the additional oxygen demands of the fetus. The rise in fetal oxygen consumption was hence accomplished through an increase in fetal fractional oxygen extraction (from a control value of 32.0±1.1% to a maximum of 51.6±1.8% by 1.5 hours of infusion). The rise in fetal oxygen extraction resulted in concurrent declines in fetal arterial Po₂ (78% of the control) and O₂ content (55% of the control) and a widening of the veno-arterial oxygen content difference. By the end of the infusion, umbilical venous Po₂ and O₂ content values had also fallen significantly to 78% and 75% of the control respectively. These latter changes resulted in a concurrent 25% decline in fetal oxygen delivery which in turn contributed to the rise in fetal oxygen extraction.
Fetal arterial and umbilical venous pH declined rapidly and significantly from control values of 7.370±0.004 and 7.401±0.005 to 7.274±0.025 and 7.306±0.023 respectively by the end of the infusion. The acidemia was reflected by significant declines in base excess values and appeared to be entirely metabolic in nature, resulting from elevated blood lactate levels. The acidemia likely contributed to the progressive fall in fetal blood O₂ content through a rightward shift of the oxyhemoglobin dissociation curve (Bohr effect).
The rise in fetal oxygen consumption was reflected by a similar (although nonsignificant) increase in uterine oxygen consumption. Uteroplacental oxygen consumption appeared to remain unaltered. The rise in uterine oxygen consumption was not accompanied by a corresponding increase in uterine oxygen delivery, hence uterine oxygen extraction rose to 23.8±1.9% (from a control value of 19.5±1.6%) by 1.5 hours post-infusion. The rise in uterine oxygen extraction resulted in significant declines in uterine venous Po₂ and CO₂ values which likely contributed to the fall in fetal oxygen delivery.
Fetal heart rate increased significantly to 21% (34 beats per minute, bpm) above the control (162±7 bpm) during the first 1.5 hours of ritodrine infusion. It remained elevated by an average of 16% (26 bpm) throughout the remainder of the infusion and the first 8 hours of post-infusion, returning to the control by the end of the post-infusion period. Fetal arterial pressure remained unchanged from the control (46.2±1.5 mm Hg).
The incidence of fetal breathing activity fell significantly from an overall average control value of 43.2±2.6% to an average of 28.1±6.8% during the ritodrine infusion period. In most animals, breathing was most depressed near the end of the infusion. The incidence of low voltage electrocortical (ECoG) activity also fell significantly by an average of 7.5% while that of high voltage ECoG rose by 7.3%. Alterations in intermediate voltage activity were not observed. The incidence of fetal rapid eye movement also tended to fall by an average of 8.2% during the infusion of ritodrine. These behavioral changes may have resulted from the development of fetal hypoxemia, rather than as a direct effect of ritodrine.
In conclusion, these data have demonstrated that ritodrine infusion to fetal lambs results in significant physiological and behavioral changes in the fetus. These effects may put the fetus at risk, particularly in situations where fetal oxygen delivery is already reduced, as in various states of compromised pregnancy.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate