Browsing by Subject "Chemicals and Drugs"
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Item [3H] Ethynylbicycloorthobenzoate ([3H] EBOB) Binding in Native and Recombinant GABAA Receptors(2000-05-01) Yagle, Monica A.; Dillon, Glenn; Martin, Michael; de Fiebre, ChristopherYagle, Monica A., [3H] Ethynylbicycloorthobenzoate ([3H] EBOB) Binding in Native and Recombinant GABAA Receptors. Master of Science (Pharmacology), May 2000, 59 pp., 3 tables, 7 illustrations, bibliography, 75 titles. Modulation of the GABAA receptor has been studied with noncompetitive convulsant ligands such as tert-butylbicyclophosphorothionate (TBPS) and picrotoxin (PTX). EBOB is a more recently developed ligand that appears to bind in the same region of the channel at TBPS, but with a higher affinity. While only a few studies have examined the binding of EBOB to vertebrate brain tissue and insect preparations, none have examined potential subunit-dependent binding of EBOB. We have thus examined [3H] EBOB binding in rat cerebellum and HEK293 cells stably expressing human α1β2γ2, human α2β2γ2, and rat α6β2γ2 GABAA receptors. For comparison, [35S] TBPS binding was also examined in α1β2γ2 receptors. Saturation and Scatchard analyses revealed saturable [3H] EBOB binding at one site in all tissue preparations with Kd values ranging from 3 to 9nM. [3H] EBOB binding, like [35S] TBPS binding was inhibited by the CNS convulsants dieldrin, lindane, tert-butylbicyclophosphorothionate (TBOB), PTX, TBPS, and pentylenetetrazole (PTZ) at one site in a concentration dependent fashion. Affinities were in the high nM to low μM range for all compounds except PTZ (low mM range). GABA modulated [3H] EBOB binding in a biphasic manner in α1β2γ2 receptors with a 100-fold difference between stimulatory and inhibitory affinities. Inhibition of GABA-mediated current by TBOB in α1β2γ2 receptors resulted in a functional IC50 of 0.2 μM, in agreement with binding study results. Differences seen in binding between the different receptor subtypes examined suggest that some characteristics of EBOB binding are subunit dependent. In addition, we have shown that [3H] EBOB is a useful ligand in the study of recombinant GABAA receptors and that results obtained with [3H] EBOB are comparable to those obtained with [35S] TBPS.Item A Phase II Clinical Study to Evaluate the Efficacy and Safety of rhThrombin in Subjects Undergoing Arterial Bypass Surgery and AV Graft Formation for Hemodialysis(2004-12-01) Plascencia, Xochitl; Rustin E. Reeves; Della Weis; Don PeskaThe Association of American Medical Colleges Task Force on Clinical Research defines clinical research as a component of medical and health research intended to produce knowledge essential for understanding human disease, preventing and treating illness, and promoting health (Friedman, 1998). A clinical trial is defined as a research study conducted in humans which is designed to answer specific questions using scientifically controlled conditions with specified methodologies and endpoints (Gallin, 2002). Clinical research trials are essential in determining whether or not a drug is safe and effective. There are four phases that investigational drugs go through before they are allowed to be out in the market. Before beginning phase I of a study, there is usually a pre-clinical research and development phase. During this time the initial synthesis of study drug is accomplished and animal testing takes place. Phase I is the initial introduction of an investigational new study drug into humans. Phase I is usually conducted in healthy individuals and the primary goal is to determine the safety profile of the drug. Phase II trials tend to evaluate safety and initial efficacy. Subjects enrolled in this phase tend to have the disease necessary for use of study drug. Phase III studies are conducted to gather additional information about the effectiveness and safety of the drug and to determine the overall benefit-risk relationship of the drug. Finally, phase IV studies are usually referred to as post-marketing studies. During this phase, additional safety information is identified and the drug’s safety during routine use is evaluated. Each phase can range from two to ten years depending on the complexity of the clinical trial (Gallin, 2002). A phase II, randomized, double blind study of the safety and efficacy of topical recombinant human thrombin in patients undergoing peripheral arterial bypass surgery and arterio-venous graft formation for hemodialysis is the focus of the prospective drug study to be carried out in the surgery department at The University of North Texas Health Science Center. The primary objective of this study is to evaluate the safety and efficacy of recombinant human thrombin when used in different types of surgeries. Prior to signing an informed consent, subjects will have to meet inclusion and exclusion criteria set by study protocol. Study specific assessments and procedures will be performed after the informed consent is signed and dated. If bleeding at the anastomosis is found to necessitate intervention, a single application of either rhThrombin or placebo in combination with an absorbable hemostatic sponge to each anastomosis requiring hemostasis will be applied by the surgeon. The safety and efficacy of rhThrombin will be determined by measuring the incidence and severity of adverse events and of laboratory abnormalities. Occurrence of hemostasis within 600 seconds of application of the study drug at the anastomotic surgical site, incidence of anti-rhThrombin product antibodies, and time to hemostasis will also be measured.Item A Study of the Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for Three Months Versus Daily Isoniazid for Nine Months for the Treatment of Latent Tuberculosis Infection(2004-11-01) Lemp, Jessie; Patricia Gwirtz; Walter McConathy; Richard EasomLemp, Jessie M. A Study of the Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for Three Months Versus Daily Isoniazid for Nine Months for the Treatment of Latent Tuberculosis Infection. Master of Science, November, 2004, 107 pp., 4 tables, 4 figures, references, 29 titles. The standard treatment for latent tuberculosis infection, nine months of daily isoniazid, is effective at preventing active tuberculosis; however, its full benefits are limited by non-adherence. A shorter intermittent regimen of rifapentine plus isoniazid once weekly for three months is equally effective as the standard regimen in animal models. This regimen facilitates the use of directly observed therapy, a method that significantly improves adherence. The Center for Disease Control is sponsoring Study 26 to test the effectiveness and tolerability the three-month rifapentine based regimen in latently infected persons with risk factors for progression to active tuberculosis. This thesis will describe the background rationale and methods for the clinical trial, and the internship experience.Item An Epidemiological Profile of Poisoning Episodes Among Texans Utilizing Hospital Discharge Survery Data(2003-05-01) Ramisetty-Mikler, Suhasini; Rene, Antonio; Blakely, Sally; Mains, DouglasRamisetty-Mikler, Suhasini, An Epidemiological Profile of Poisoning Episodes Among Texans Utilizing Hospital Discharge Survey Data. Master of Public Health (Epidemiology), May, 2003, 68pp., 15 tables, references, 43 titles. This retrospective study of hospital discharge data provides an epidemiological profile of admissions, type of poisoning causing the hospitalization, and the intent of injury among Texans (N=12,541) during 1999. Overall, females are more frequently admitted, the rates increased with age through age 50 and declined thereafter among non-HIV patients. Psychotropic drugs and analgesics are the top two substances causing more than half of all admissions and one-third among children under age 14. Approximately 61% of all poisoning admissions are self-inflicted. The self-infliction risk is two times greater among non-HIV females and is highest (8 fold) among teenagers (age 15 to 17) compared to children 14 years or younger. The risk decreased with age (7 fold) through middle ages and dropped significantly after age 40 (4.5 times). Self-infliction is less likely after age 60. Whites are 1.5 times more likely than Blacks to self inflict among both HIV and non-HIV patients.Item An Open-Label Pilot Study Evaluating the Effects of Travoprost on Eyebrow Regrowth Among Patients Undergoing Chemotherapy for Cancer(2005-12-01) Habib, Nausheen; Jamboor Vishwanatha; Harold J. Sheedlo; Michael W. MartinHabib, Nausheen. Master of Science, Biomedical Sciences, December 2005, An Open-Label Pilot Study Evaluating the Effects of Travoprost on Eyebrow Regrowth Among Patients Undergoing Chemotherapy for Cancer. The primary objective of this study is to determine the effect of eyebrow hair growth of a twice daily application of travoprost among patients undergoing chemotherapy or those who have already completed chemotherapy. Travoprost, used clinically in the treatment of glaucoma, is topically and unilaterally applied to a total of 15 patients to induce eyebrow hair growth. This is an ongoing pilot study in which the screening, treatment and follow-up visits are scheduled on day 0, week 4, week 8, week 12, and week 14. After an eight week treatment period, 69% of the patients demonstrated increased eyebrow density. This increase in eyebrow hair is consistent with travoprost’s ability to prolong the anagen or growing phase of the hair cycle.Item Analysis of the Clinical Research Methodologies Employed During a Phrase Three Efficacy Study for Ultracet as a Post-Herniorrhaphy Analgesic(2001-08-01) Aguilar-Zanatta, Jorge; Rustin Reeves; Don Peska; Della WeisThe history of pain management stems back many thousands of years. However, not until recent times have significant advancements in biochemistry and pharmacology allowed analgesics to be incorporated in clinical interventions and everyday life. Due to these advancement, attempts to refine pharmacological action on receptors in terms of specificity would render medications with fewer side effects. The technology is present, but the application and development of modern analgesics in post-surgical settings is substandard. According to C.L. Ireson and R.W. Schwartz, (2001), the outcomes of ailment interventions in the United States are “…no better and in numerous situations worse that those achieved in other countries,” even though the United States has the most expensive healthcare in the world. Furthermore, a study performed by Carr et al. (1998), has identified the United States as demonstrating consistent inadequacies in postoperative pain management. Several factors have been identified as being contributors of poor post-surgical pain control in America. Lack of awareness of the available strategies in acute pain control and its implementation in post surgical care are labeled as being problematic observations (Puid et al., 2001). In response to these conditions as well as the managed health care time and cost limitations, new and efficacious pharmaceuticals must be made available to a broad spectrum of socio-economic strata. Currently, there is a great debate over the use of laparoscopic herniorrhaphy versus open tension free approaches. In terms of cost, the laparoscopic herniorrhaphy versus open tension free approaches. In terms of cost, the laparoscopic herniorrhaphy versus open tension free approaches. In terms of cost, the laparoscopic procedure is more expensive and yields less postoperative pain, however the open tension free approaches are less expensive and yield more postoperative pain (Sarli et al., 2001, Medical Research Council Laparoscopic Groin Hernia Trial Group, 2001, Parviz et al., 1995). There are advantages and disadvantages to both procedures. Assuming that efficacious postoperative analgesics were available, the open tension free repair would be more feasible in terms of cost and hernia recurrence rates (Sarli et al., 2001). In terms of pharmaceutical development, the laws and guidelines by the regulatory agencies such as the Food and Drug Administration, institutional review boards, and pharmaceutical sponsor protocols must be followed. Along with good clinical practice standards, interdisciplinary collaboration in pain studies produce results that are statistically and clinically salient. The patient’s well-being and comfort is the ultimate goal in clinical pain studies and in medicine in general, therefore postoperative pain should be aggressively managed.Item Analyzing the Scientific Debate of Coxibs and The Ethics Impact of Vioxx's Withdrawal on Drug Regulation and an Ongoing Phase III Clinical Trial with a New Cox-2 Inhibitor(2005-11-01) Fu, Jingwei; Gwirtz, Patricia A.; Rubin, Bernard R.; Jiminez-Williams, CynthiaOn September 30, 2004, Merck & Co. Inc announced voluntary withdrawal of its $25 billion blockbuster drug Vioxx from the market, five and a half years after Voixx received FDA approval. This is the largest prescription drug withdrawal in history. Merck made the decision based on the results of APPROVe (Adenomaous Polyp Prevention on Vioxx) clinical trial, which showed that Voixx had an increased risk of myocardial infarction and cerebral vascular stoke compared with placebo. The repercussions of Merck’s action were tremendous from both a financial aspect and an ethical aspect. The recalling of Vioxx has become an important public health issue and has placed drug regulation agencies in controversy. In April, 2005, Pfizer agreed to voluntarily suspend sales and marketing of its COX-2 inhibitor, Bextra in the United States as requested by the FDA. Vioxx and Bextra withdrawal has left a huge impact on the pharmaceutical industry. Debates are ongoing in the scientific community regarding the use of Cox-2 inhibitors and have caused much confusion in the medical community and in those who use these drugs for pain control for osteo- and rheumatoid arthritis disease. The goal of this report is to analyze the impact of Vioxx withdrawal and comment on how to apply this incident in guiding the industry with regards to drug development, drug regulation, and clinical practice in order to ensure the effectiveness in the drug development and safe usage of new pharmaceutical agents.Item Anionic Ligand-Gated Ion Channels: The Convulsive Site and Mechanism of Action(2001-08-01) Dibas, Mohammed I.; Hriday Das; Thomas Yorio; Neeraj AgarwalDibas, Mohammed, Anionic Ligand-Gated Ion channels: The Convulsive Site And Mechanism of Action. Doctor of Philosophy (Biomedical Sciences), August 2001, pp153, 1 table, 24 illustrations, 76 titles. Picrotoxin, a CNS convulsant inhibits all anionic ligand gated ion channels. The mechanism and the binding site for picrotoxin and its related ligands are still undefined. The second transmembrane (TMII) domain of these ligand gated ion channels is found to play a key role in the mechanism of block by picrotoxin. It has been shown that the incorporation of a phenylalanine residue in place of threonine at position 6’ within the TMII domain of B2 subunit conferred high resistance toward picrotoxin in GABAA a3B2(T6’F)y2 receptors. Mediating their blocking effect through the PTX-site, PTZ, TBPS, and U-93631 lost their inhibitory effects due to the same mutation B2(T6’F). Interestingly, this mutation uncovered a low affinity, highly efficacious stimulatory site for PTZ. PTZ seems to mediate its stimulatory effect through a novel distinct site different from that for benzodiazepine. The effect of varying subunit configuration of GABAA receptors dramatically affected the ability of the mutation B2(T6’F) to abolish the inhibitory effect of picrotoxin. While picrotoxin failed to block the current induced by GABA in a3B2(T6’F)y2 receptors, picrotoxin partially blocked the current in a3B2(T6’F)y2 receptors. In B2(T6’F)y2 receptors, picrotoxin restores its full efficacy. When phenylalanine was incorporated at position 6’ in the a1 subunit, picrotoxin completely blocked the current induced by GABA in a1(T6’F)B2y2 receptors. The combined results showed that the ability of (T6’F) mutation to regulate the inhibitory mechanism of picrotoxin as dependent on the subunit configurations and at which subunit is mutated. In addition, picrotoxin is known to inhibit GABAA receptors in use-facilitated mechanism, while it inhibits the glycine receptor in a non-use facilitated fashion. The molecular determinant behind the use-facilitated mechanism was modulated by the nature of the amino acid at position 15’ within the second transmembrane domain. The mutation of serine 15’ to either glutamine or asparagine in the glycine a1 receptors converted picrotoxin from a non-use facilitated blocker to a use-facilitated one. The latter finding suggested that this residue might residue within the PTX binding site or play a key role in the transduction pathway for picrotoxin mechanism. The overall results further support the fact that TMII domain plays a key role in the picrotoxin mechanism.Item Cardiac Parasympathetic Dysfunction in Morphine Addiction(1997-12-01) Napier, Leslie D.; Caffrey, James L.; Raven, Peter B.; Gwirtz, Patricia A.Napier, Leslie D., Cardiac Parasympathetic Dysfunction in Morphine Addiction. Doctor of Philosophy (Biomedical Sciences), December, 1997, 137 pp., 9 tables, 22 figures, references, 163 titles. The effects of chronic morphine treatment on parasympathetic control of the heart and associated cellular mechanisms were examined using a canine model. Vagal bradycardia was significantly blunted in dogs treated for one week with subcutaneous morphine pellets. In a separate group of dogs, heart rate and high frequency fluctuations in heart rate declined during the first three hours of subcutaneous morphine infusion consistent with the vagatonic action of acute morphine. Heart rate remained below baseline on Day 2 of the morphine infusion but had returned to normal by Day 10. Ambient sympathetic tone was increased on Days 2 and 10, and plasma catecholamines were elevated on Day 2. The intrinsic heart rates on Days 2 (160 bpm) and 10 (162 bpm) of morphine treatment were lower than the pre-treatment rate (182 bpm). Suggested mechanisms include a fundamental change in sinoatrial nodal cell function or attenuated tachycardia induced by vasoactive intestinal peptide co-released with acetylcholine from post-ganglionic parasympathetic neurons. The time to 50% maximal bradycardia during vagal nerve stimulation was increased with chronic and acute morphine suggesting an effect on the rate of acetylcholine synthesis, release or degradation. Muscarinic receptor density in left ventricular and right atrial sarcolemmal membranes from dogs treated chronically with morphine were 34% and 17% higher, respectively, than in control animals. Chronic morphine had no effect on basal or MnCl2-stimulated cyclase activity in either region. Similarly, maximal β-adrenergic and muscarinic receptor/G-protein coupling to adenylate cyclase were not altered by chronic morphine. Atrial norepinephrine content was higher than that in the ventricles and was unaltered by morphine. Ventricular norepinephrine was decreased with chronic but not acute morphine treatment. Epinephrine was evenly distributed throughout the myocardium and was reduced in both the atria and the ventricles by either acute or chronic morphine. This pattern suggests that morphine may reduce extraneuronal uptake of catecholamines. Collectively these studies show that chronic morphine treatment and the accompanying persistent vagal activity may reduce parasympathetic function. This attenuated function, however, is short-lived since sympathetic systems adapt with compensatory responses masking, or perhaps reversing, initial parasympathetic deficits.Item Cellular and Molecular Mechanisms that Distinguish the Effects of Progestorone and Medroxyprogesterone Acetate on Neuroprotection(2006-07-28) Kaur, Paramjit; Goldfarb, Ronald; Singh, Meharvan; Agarwal, NeerajKaur, Paramjit. Cellular and Molecular Mechanisms That Distinguish the Effects of Progesterone and Medroxyprogesterone Acetate on Neuroprotection., Doctor of Philosophy, (Pharmacology and Neuroscience), July, 2006, 203 pp., 5 illustrations, 20 figures and bibliography. Women have a higher prevalence for Alzheimer’s disease (AD) than men, suggesting that the precipitous decline in gonadal hormone levels following the menopause may contribute to the risk of developing AD. However, principal results from the Women’s Health Initiative concluded that women taking conjugated equine estrogens combined with medroxyprogesterone acetate (MPA, tradename: Prempro) incurred more harmful than beneficial outcomes versus the placebo group (Rossouw et al., 2002). This dissertation was aimed at determining if the discrepancy between basic science reports and these clinical studies could have been due to the synthetic progestin, MPA. I hypothesized that P4 and MPA differed in their ability to protect against the excitotoxic/oxidative insult, glutamate. Further, I proposed that this difference in neuroprotective potential would be reflected in the difference in the ability of these hormones to elicit key effectors of two neuroprotection-associated signaling pathways, the ERK/MAPK and P13-Kinase pathways. Finally, studies were initiated to evaluate the potential importance of BDNF (brain-derived neurotrophic factor) in mediating the protective effects of P4. I used organotypic explants of the cerebral cortex, and found that both P4 and MPA elicit the phosphorylation of ERK and Akt, two signaling pathways implicated in neuroprotection, with maximal phosphorylation occurring at a concentration of 100 nM. Interestingly, P4 protected against glutamate- induced toxicity however, while an equimolar concentration of MPA (100nM) did not. Further, P4 resulted in an increase in BDNF, while MPA did not. Our data bring into question the relevance of using MPA as a component of hormone therapies in postmenopausal women, and instead, argue that the relevant progestin for use in treating brain-related disorders is progesterone. Collectively, the data presented here suggest that P4 is protective via multiple, and potentially related mechanism, and importantly, its neurobiology is different from the clinically used progestin, MPA.Item Characterization of Recombinant Lecithin: Cholesterol Acyltransferase, Secreted by a Human Lung Cell Line (1069-111) and by Pichia Pastoris Yeast Cells(2004-05-01) Tchedre, Kissaou T.; Caffrey, James L.; Harris, Ben G.; Wu, Ming-ChiTchedre, Kissaou T., Characterization of Recombinant Lecithin: Cholesterol Acyltransferase, Secreted by a Human Lung Cell Line (1069-111) and by Pichia pastoris Yeast Cells (Biomedical Sciences), May, 2004, Lecithin: cholesterol acyltransferase (LCAT) is a key enzyme in mammalian lipoprotein metabolism. Associated with the surface of high-density lipoproteins (HDL), LCAT contributes to the homeostasis of circulating free and esterified cholesterol via the reverse cholesterol transport pathway. The purpose of these studies was to characterize a recombinant form of LCAT, secreted by a human lung cell line (Beta gene 1069/111) and to evaluate a new expression system for LCAT using transformed Pichia pastoris cells. A human lung cell line (Beta gene 1069/111), transfected with pBIISK (Stratagene)+ vector was used as the source of recombinant (rLCAT) for the first stage of characterization studies. Human lung cells were expanded in Dulbecco’s minimal essential medium (DMEM) supplemented with 10% fetal bovine serum for the expression of the recombinant LCAT. At 80 – 90% confluency, the medium was changed to a serum free preparation and the flasks were incubated for 48 hrs at 37°C to facilitate the secretion of the enzyme. Beta gene (1069/111) LCAT was purified from the conditioned medium using phenyl sepharose chromatography. The purified enzyme was characterized according to: carbohydrate composition, and enzyme kinetic parameters. The enzymatic characteristics, of the human lung cell line LCAT had similar Km and Vmax values to other LCAT preparations, isolated from other expression systems and human plasma. Deglycosylation reduced the molecular weight of the enzyme from about 67,000 to about 43,000 suggesting a carbohydrate component of 25-32% of the enzyme’s total mass. Detailed analysis of the carbohydrate structures revealed N-glycan structures in a complex pattern of sialylated and fucosylated tri and tetra-antennary glycosides (8). In addition to the Beta gene expression, a Pichia pastoris yeast expression system was also developed consisting of human LCAT cDNA cloned into pPICZαA vector along with a removable amino-terminal polyhistidine tag. The Pichia pastoris cells were transformed with a vector containing the LCAT gene cDNA and transformants were selected on agar plates containing zeocine (100μg/ml). Polymerase chain reaction (PCR) and reverse transcription polymerase chain reaction (RT-PCR) were used to confirm the correct integration of the LCAT gene cDNA into the pPICZαA vector. The recombinant LCAT produced by the yeast cultures was purified by Talon affinity chromatography, taking advantage of the removable histidine tag. The enzymatic activity was determined using proteoliposome vesicles. The Yeast expression system yielded ~18 mg of enzyme protein/500 ml and thus may provide an appropriate enzyme source for characterization studies via NMR analysis and x-ray crystallography.Item Clinical Diagnosis: A Manual of Laboratory Methods(W.B. Saunders Company, 1913-01-01) Todd, JamesWhile the original purpose of this book- to present Clearly and concisely the various laboratory methods which are of use in clinical medicine- has not been lost Sight of, its scope has been somewhat enlarged in the present edition. Each section has been carefully revised and much new Material has been added to every chapter. Among the many additions may be mentioned: the use of artificial light and the importance of numerical aperture in microscopic work; photomicrography with simple apparatus; The antiformin method for tubercle bacilli; detection and significance of albumin in the sputum; Tsuchiya's modification, of Esbach's test; the formalin test for ammonia And benedict's methods for sugar in urine; volume index Of red blood-corpuscles; wright and Kinnicutt's method of counting blood-platelets; Harlow’s blood-stain; a simple Technic for the diagnosis of typhoid fever by blood cultures; The Wassermann reaction, and Frothingham's Impression method in the diagnosis of rabies. Because of the growing importance of animal parasites, this chapter has been entirely rewritten and more than Doubled in extent. Two new chapters have been added: One upon bacteriologic methods, which supplements the Methods given in other portions of the book, and one upon preparation and use of vaccines, including therapeutic and diagnostic use of tuberculin.Item Clinical Internship with the Division of Gynecologic Oncology at UT Southwestern Medical Center: Carboplatin and Doxil for Gynecologic Cancers(2003-12-01) Epps, Camitria N.; Victoria Rudick; David S. Miller; Barbara RichardsonEpps, Camitria N., Master of Science, Clinical Research Management, December 2003, Carboplatin and Doxil for Gynecologic Cancers, 107 Pages, 9 Tables, 42 titles in Bibliography. Objective: To examine the safety and efficacy of administering the drugs carboplatin and doxil in combination chemotherapy for the treatment of gynecologic cancers, mainly endometrial and ovarian cancer. Materials and Methods: Carboplatin and doxil were previously administered intravenously to 6 patients. Each patient received 3 to 8 cycles of chemotherapy. Doses of carboplatin ranged from 310 mg to 665 mg. The doses of doxil ranged from 54 mg to 80 mg. This is a retrospective study. The 6 patient’s medical charts were reviewed. Data was extracted and a spreadsheet formatted database was created. Results: Data were extracted and a spreadsheet formatted database was created. Results: Due to the small number of patients the results are not statistically significant. 2 patients showed tumor progression while receiving treatment. All patients tolerated doses very well and experienced minimal toxicities. Conclusion: Carboplatin plus doxil combination chemotherapy given intravenously has a potent effect on endometrial and ovarian cancers. Studies using this chemotherapy for the treatment of gynecologic cancers should be conducted on a wider scale to access the statistical significance of the treatment.Item Clinical Research: Drug Studies and Device Trials, Theory and Approach(2002-07-01) McCormick, Timothy Chad; Rustin Reeves; Don Pesca; Dellas WeisA clinical trial is composed of four different phases. Each of these phases serve a purpose such as testing safety, efficacy, and dosage. These phases are essential to provide the best possible model for mass use of a drug or a new device. Drug studies differ from device studies in their design and their delivery. In this case, a post-operative pain medication was tested, as well as a differential study between two types of cutting devices used in laparoscopic cholecystectomy. The post-operative pain study is a phase III study that is testing the efficacy, safety, and the pharmacokinetics of a proposed drug. The device study is considered a phase IV study because it is evaluating two commonly used techniques for laparoscopic cholecystectomy. Both of these techniques have previously been approved by the FDA and are mass marketed. These two studies were followed for six weeks and evaluated for protocol design, differences and similarities, and for hands on experience in the clinical research arena. Upon completion of the six week opportunity, it is evident that clinical research is a viable piece of medicine today. Following these two studies allowed for an understanding of the differences and similarities encountered when executing a drug study, as well as a device study. The complexities of the two studies were evaluated, and without doubt, the drug study included much more paper work, patient testing, inclusion/exclusion criteria, study evaluation, and most of all, man hours. All in all, this was a very rewarding experience that allowed for a greater understanding of the implementation and value of today’s clinical research.Item Combined Chemo/Anti-Angiogenic Cancer Therapy in Lewis Lung Metastases(2002-05-01) Sinha-Datta, Anjuli; Goldfarb, Ronald H.; Agarwal, Neeraj; Mathew, Porunelloor A.Datta, Anjuli. Combined Chemo/Anti-Angiogenic Cancer Therapy in Lewis Lung Metastases. Master of Science (Microbiology and Immunology), May 2002. 41 pp., 17 illustrations, bibliography. The focus of my dissertation studies is an eight amino acid peptide (Å6) derived from the non-receptor binding region of urokinase plasminogen activator (uPA), which partially inhibits the binding of uPA to its receptor (uPAR). Å6 has been synthesized as a potential novel anti-cancer agent and kindly provided by Ångstrom Pharmaceuticals, Inc. (San Diego, CA). We further examined potential therapeutic properties of Å6 in vivo and in vitro. Å6 appeared to directly inhibit the invasion of Lewis lung carcinoma cells through Matrigel by approximately 40-45% compared to control. In addition, Å6 had a morphological effect resulting in thicker tubes on small vessel endothelial tube formation compared to no treatment. Interestingly, doxorubicin had similar effects when added to growing endothelial cells. Moreover, Å6 was administered alone and in combination with a standard clinically used chemotherapeutic agent, doxorubicin, in a Lewis lung carcinoma mouse model to test possible synergy between an anti-angiogenic compound (Å6) and a chemotherapeutic agent. This is the first observation that Å6 has the potential to display a direct anti-metastatic therapeutic effect for established pulmonary metastases in this model. Therefore, we believe that Å6 in combination with doxorubicin has the potential to provide better therapy to cancer patients with tumor metastases than potent chemotherapeutics agents alone, by increasing the dose of non-toxic Å6 and reducing the recommended dose of doxorubicin.Item Conformational Properties of Circulating and Recombinant Forms of Human Plasma Lecithin Cholesterol ACYL Transferase(1995-06-01) Sundarrajan, Geetha; Walter McConathySundarrajan, Geetha, Conformational properties of circulating and recombinant forms of human plasma LCAT Master of Science (Biomedical Sciences), June, 1995, 69pp., 3 tables, 18 figures, 47 references. The relationship between enzymatic activity and conformational properties of the circulating and recombinant forms of human plasma LCAT were examined in the native and denatured states. The two denaturing agents used in this study were guanidine hydrochloride and heat. These studies led to the following conclusions: (1) Although the alpha helical content of desialylated recombinant LCAT (d-LCAT) is comparable to that of the other two forms of the enzyme (p-LCAT and r-LCAT), the desialylation of LCAT is associated with an increase in the beta sheet and a decrease in beta turn content. (2) The presence of sialic acids, in addition, seems to influence the local environments of aromatic amino acid residues. (3) From the denaturation and renaturation studies with guanidine hydrochloride and heat, it appears that the N-glycan structures of p-PCAT and r-LCAT may contribute differentially to the conformational stability of the enzyme. (4) The alpha helical structure of LCAT may not be involved in maintaining the active conformation of the enzyme.Item Corticotropin-Releasing Factor and Corticosterone Modulate the Anxiogenic-Like Effects of mCPP(1998-06-01) Jenkins, Jennifer A.; Michael Forster; Robert Luedtke; Patricia GwirtzJenkins, Jennifer A., Corticotropin-Releasing Factor and Corticosterone Modulate the Anxiogenic-Like Effects of mCPP. Doctor of Philosophy (Pharmacology), June 1998, 119 pp., 2 tables, 29 figures, bibliography, 100 titles. The administration of PTZ or mCPP produces anxiety-like behavior as measured by an increase in the percentage of entries into the open arms and the time spent on the open arms of the elevated plus maze (Prunell et al., 1994). Reportedly, PTZ and mCPP substitute for each other in the drug discrimination paradigm (Wallis and Laz, 1998). It is therefore suggested that commonality exists among anxiogenic drugs as perceived by trained animals. Andrews and Stephen (1990) suggested that this overall parallelism is an indication that anxiogenic agents may possess similar properties. Therefore, the question posed is as follows: Is there a common denominator anxiety? The global hypothesis is that the core component of anxiety produced by anxiogenic agents or processes involves stimulation of the HPA axis to release CRF, ACTH and/or CORT. Long Evans rats were trained to discriminate either mCPP (1.4 mg/kg) or PTZ (16mg/kg) from saline in a two-lever choice procedure (FR10) which is food reinforced. Animals were pretreated with CRF, α-helical CRF (a CRF antagonist), two steroid synthesis inhibitors (ketoconazole, KETZ and aminoglutethimide, AMG), CORT or underwent an adrenalectomy prior to behavioral testing in order to test the hypothesis that the release of CRF and/or CORT are components of the discriminate stimulus of the mCPP and/or PTZ. Pretreatment with CRF, KETZ, AMG and an adrenalectomy facilitated mCPP level selection. However in the absence of mCPP neither drug nor adrenalectomy produced drug lever selection. In addition CORT did not alter the mCPP dose response curve. However, CORT replacement therapy returned the does response curve to baseline in adrenalectomized animals. Alpha-helical CRF did not block mCPP discrimination. Unlike mCPP-trained animals, KETZ and AMG decreased PTZ-lever selection in PTZ-trained animals. In addition, CORT enhanced and partially substituted for the discriminative stimulus of PTZ. However, adrenalectomy completely abolished drug lever selection in PTZ animals. To compare the discriminative stimulus effects of mCPP and PTZ, PTZ-trained animals were injected with cumulative doses of mCPP. mCPP-trained animals were injected with cumulative doses of PTZ. mCPP and PTZ minimally substituted for each other. The results suggested that neither CRF nor CORT are components of the discriminative stimulus of mCCP and that the role of the HPA axis in mCPP discrimination maybe be a modulator of the stress response. However, CORT is a component of the discriminative stimulus of PTZ such that CORT is necessary for drug lever selection in PTZ trained animals.Item Cross-Tolerance Between the Discriminative Stimulus Properties of Ethanol, Diazepam and Pentobarbital(1995-12-01) Lytle, Douglas A.; Michael Forster; Glenn Dillon; Thomas YorioLytle, Douglas A., Cross-Tolerance Between the Discriminative Stimulus Properties of Ethanol, Diazepam and Pentobarbital. Doctor of Philosophy (Biomedical Sciences), December, 1995, 132 pp., 8 tables, 19 figures, bibliography, 176 titles. Ethanol, benzodiazepine agonists and barbiturates all facilitate GABA-mediated CT flux. The present experiments tested the hypothesis that, because these agents share this common action, tolerance to discriminative stimulus properties of one of these drugs would result in cross-tolerance to the others. Rats were trained to detect either ethanol (EtOH; 1.0 g/kg), the benzodiazepine diazepam, (DZP; 5.6 mg/kg), or the barbiturate pentobarbital (PB; 10.0 mg/kg) from vehicle using a two-lever choice procedure where food was available under a fixed-ration ten schedule of reinforcement. Subsequently, dose-effect curves for EtOH (0.1-1.78 g/kg), DZP (0.56-17.8 mg/kg), or PB (1.0-17.8 mg/kg) were tested before and after chronic administration of EtOH 96.0 g/kg/12hrs for seven days), DZP (20.0 mg/kg/8hrs for seven days), or PB (32.0 mg/kg/8hrs for seven days). The chronic administration of EtOH conferred tolerance to itself in all cases and cross-tolerance to DZP and PB in subjects trained to detect EtOH, but did not confer cross-tolerance to these agents in their respective discriminations. The chronic administration of DZP conferred tolerance to itself substituting for DZP. Although tolerance developed to DZP substituting for PB after treating animals with chronic DZP, this regimen on DZP did not confer tolerance to itself substituting for EtOH. This regimen of DZP failed to confer significant cross-tolerance to either EtOH or PB under any conditions. The chronic administration of PB conferred tolerance to itself substituting for PB. Although tolerance developed to PB substituting for DZP after treating animals with chronic PB, this regimen of PB did not confer tolerance to itself substituting for EtOH. This regimen of PB failed to confer significant cross-tolerance to either EtOH or DZP under any conditions. In summary, EtOH was found to confer cross-tolerance to DZP and PB only in animals trained to detect EtOH. The chronic administrations of DZP and PB failed to confer tolerance to themselves substituting for EtOH. These results are parsimonious with the heterogeneous nature of the GABA receptor. Finally, tolerance to either DZP or PB does not result in cross-tolerance to the discriminative stimulus properties of the other drug. These results suggest that the mechanisms mediating tolerance to BZs and barbiturates are not linked.Item Discriminative and Negative Reinforcing Properties of the Periaqueductal Gray and the Medial Hypothalamus(1994-12-01) Jung, Marianna E.; Emmett-Oglesby, Michael W.; Yorio, ThomasMarianna Eunsun, Jung, Discriminative and Negative Reinforcing Properties of Electrical brain stimulation of the Periaqueductal Gray and the Medial Hypothalamus. Master of Science [Biomedical Sciences, (Pharmacology)], December, 1994, 123 pp., 24 figures, references, 137 titles. Electrical brain stimulation (EBS) of the periaqueductal gray (PAG) and the medial hypothalamus (MH) is known to serve as a discriminative and a negative reinforcing stimulus (NRS). Using a two-lever food reinforced discrimination paradigm and a switch-off paradigm, the present study investigated the effects of anxiolytic drugs and an anxiogenic drug on these stimulus effects. A prototypic anxiogenic, pentylenetetrazole (PTZ) potentiated both discriminative stimulus and NRS effects, whereas the full benzodiazepine (BZD) agonist diazepam (DZP), the partial BZD agonist abecarnil (ABC) and 5-HT1A agonist buspirone (BUS, chronic regimen) attenuated a NRS effect. A BZD antagonist, flumazenil (FLU) blocked the effects of DZP and ABC on the NRS effects. DZP failed to attenuate the discriminative stimulus effect. Thus, present study extended the use of a switch-off paradigm to detect novel anxiolytic ABC (putative) and BUX as well as an anxiogenic PTZ. In addition, under the condition used in this study, the use of NRS in a switch-off paradigm more reliably detected both anxiolytic drugs and an anxiogenic drug than the use of discriminative stimulus in a two-lever food reinforced paradigm.Item Dobutamine Increases Mechanical Function and Cytosolic Phosphorylation Potential During Moderate Right Ventricular Hypoperfusion(2000-08-01) Yi, Kun Don; H. Fred Downey; Robert Mallet; Eugene E. QuistYi, Kun Don. Dobutamine increases mechanical function and cytosolic phosphorylation potential during moderate right ventricular hypoperfusion Master of Science (Biomedical Sciences), August, 2000, 101 pp, 4 tables, 18 figures, references, 108 titles. This study was conducted to investigate the functional and metabolic effects of regional inotropic stimulation with dobutamine during right ventricular (RV) hypoperfusion. Right coronary perfusion pressure was incrementally lowered to 40 mmHg from 100 mmHg, and two-doses of dobutamine (0.01 and 0.06 μg/kg/min) were continuously infused for 15 min into the right coronary artery in pentobarbital sodium-anesthetized mongrel dogs of either sex. Myocardial energy metabolites, glycolytic intermediates, glycogen, and phosphorylation potential were measured in freeze-clamped RV biopsies. RV hypoperfusion caused a 54% decrease in right coronary blood flow, a decrease in lactate uptake, and an increase in glucose uptake. Systolic segment shortening, isometric force, MVO2, and oxygen utilization efficiency (O2UE: power/MVO2) decreased significantly. Energy reserves were unaffected by the hypoperfusion. Low-dose dobutamine during hypoperfusion improved regional mechanical function without increasing MVO2, and thus, improved O2UE. Remarkably, low-dose dobutamine markedly increased phosphocreatine content and phosphorylation potential. In contrast, high-dose dobutamine produced only transient improvements in function and efficiency and sharp decreases in energy reserves. Analysis of glycolytic intermediates showed a sustained augmentation of glycolysis during low-dose dobutamine, but glycolysis was limited by high-dose dobutamine at the level of glyceraldehyde-3-phosphate dehydrogenase. Dobutamine is capable of improving both contractile function and cellular energetics in underperfused RV myocardium at low but not high dose dobutamine. Therefore, dosage should be carefully selected.