Browsing by Subject "Other Chemicals and Drugs"
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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 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 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 Sensitization to Cocaine: Behavioral and Genetic Characterization(1998-04-01) Odom, Linda Ann; Michael Forster; Glenn Dillon; Harbans LalOdom, Linda Ann, Sensitization to Cocaine: Behavioral and Genetic Characterization. Doctor of Philosophy (Pharmacology). April 1998, 141 pages, 2 tables, 23 figures, 89 references. Conditioned associations between environmental context and cocaine effects may play a significant role in acquisition and maintenance of cocaine dependence. Conditioning may also contribute significantly to cocaine sensitization, a leftward shift in the cocaine dose-response curve that is attributable to cocaine pre-exposure. Both studies examined the sensitization of cocaine’s behavioral effects after one or four prior exposures to cocaine in two distinct environments, allowing evaluation of the acquisition and magnitude of sensitization to cocaine and the contribution of conditioning to sensitization. An extinction component was added to the second study to allow determination of persistence of context-dependent sensitization in C57BL/6 and DBA/2 mice. The purpose of the first study was to fully characterize the quantity and quality of the sensitized behavioral response to cocaine in Swiss Webster mice and to determine parameters for sensitization in the second study. Results of this study indicated that pairing cocaine to the testing environment resulted in a leftward shift of the dose-response curves for both horizontal and stereotypy measures and a concurrent decrease in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on stereotypy. The multivariate behavior profile indicated that the sensitized response to cocaine was best observed in response to 1 to 5 mg/kg cocaine, and that the conditioned response elicited by saline following cocaine pre-exposure closely resembled the 10 mg/kg acute cocaine response. The overall purpose of the second study was to determine if genetic differences in various aspects of such conditioned associations could contribute to individual differences in cocaine dependence. It was determined that, although DBA/2 mice had a faster rate of acquisition of context-dependent sensitization to cocaine than C57/BL6 mice, the multivariate behavior profile of the conditioned response of C57BL/6 mice resembled the behavior observed with a higher dose of acute cocaine and had greater magnitude and greater persistence than that of DBA/2 mice, which may explain in part the susceptibility of the C57BL/6 mice to cocaine dependence.Item The Effectiveness of Outpatient Antiemetic for Patients on Platinum, Camptosar, and Anthracycline-Based Chemotherapy(2002-07-25) Wiggins, Jenny Marie; Victoria Rudick; Julie PrejeanAbstract. Chemotherapy-induced nausea and vomiting (CINV) is a serious problem affecting at least 50% of patients. Some nausea and vomit pathways involve serotonin and serotonin type-3 (5-HT3) receptors for propagation of the reflex. 5-HT3 antagonists were developed to block the 5-HT3 receptors and inhibit emesis. Anzemet, Kytril, and Zofran are 5-HT3 antagonists used as antiemetics in patients receiving emetogenic chemotherapy. This study was designed to determine if current antiemetic therapy involving these 5-HT3 antagonists is effective for patents on platinum, camptosar, and anthracycline-based chemotherapy. The data from this study could be used to assert or adjust antiemetic therapy in patients on these chemotherapy regimens, thus providing better quality of life for patients as they undergo chemotherapy. Patients on platinum, camptosar, or anthracycline-based chemotherapies from three Fort Worth area clinics of Texas Cancer Care were chosen to gauge the effectiveness of their antiemetic regimen based on chemotherapy regimen, patient compliance, and specific 5-HT3 antagonist. Data was gathered based on questionnaires filled out by the patient for seven days and their chemotherapy nurse on the day of their treatment. It was found that Zofran was the 5-HT3 antagonist most often prescribed by the nurses. Patient compliance was not a factor in patient perception of CINV, because of the high levels of patient cooperation. Each of the chemotherapy regimens differed by day in overall average level of CINV. Patients on Kytril were found to experience more “severe” CINV than those taking Anzemet or those not taking a 5-HT3 antagonist as an outpatient. A recommendation from this study would be a larger sample size and a larger span of time. Each of the study sites should also be compared for nurse prescribing habits and patient compliance, as well as a higher level of decadron usage for patients experiencing moderate and severe CINV.Item The Relationship Between Atrazine Exposure and Breast and Ovarian Cancer Incidence Rates in Texas Agricultural Statistical Districts(2006-05-01) Hull, Kimberly M.; Terrance Gratton; Eric Johnson; Sejong BaeHull, Kimberly M., The Relationship Between Atrazine Exposure and Breast and Ovarian Cancer Incidence Rates in Texas Agricultural Statistical Districts. Masters of Public Health (Environmental Health), May 2006, 95pp., 16 tables, 7 illustrations, reference, 74 titles. The herbicide, atrazine, is suspected to cause cancer primarily through drinking water. This ecological study analyzed relationships between potential atrazine exposures and female breast and ovarian cancer incidence rates in Texas Agricultural Statistical Districts. Atrazine exposures are: atrazine usage, rural population, and public water systems. Study results indicate an inverse relationship between four atrazine exposures and breast and ovarian cancer incidence rates (county level). There is a positive relationship between surface water systems and ovarian cancer incidences rates (county level). There also is an inverse relationship between one atrazine usage index and ovarian cancer incidence rates (district level). Study results are similar to other atrazine and cancer studies; correlations prevent statements of causal inference.Item The Role of Dopamine, Nicotine Acetylcholine, Opioid and Sigma Receptors in Ketamine Self-Administration and Reward(2000-05-01) Stoffel, Stephen A.; Michael Forster; Glenn Dillon; Robert LuedtkeStoffel, Stephen A., The Role of Dopamine, Nicotinic Acetylcholine, Opioid and Sigma Receptors in Ketamine Self-Administration and Reward. Doctor of Philosophy in Pharmacology, May 2000, 114 pp 15 figures, bibliography. The rewarding effects of ketamine were postulated to involve dopaminergic neural tracts modulated by nicotinic, sigma, or opioid receptor mechanisms. In support of the hypothesized involvement of dopamine, an increase in extracellular dopamine was detected in the nucleus accumbens using electrochemical chronoamperometry following intravenous ketamine self-administration. When rats were permitted unlimited access to ketamine via self-administration, a greater concentration of dopamine was detected in the nucleus accumbens than was detected in the nucleus accumbens than was detected when self-administration was limited. In a subsequent set of experiments, the effects of agonists or antagonists of dopaminergic, nicotinic, sigma, or opioid receptors were examined for their effect on ketamine self-administration. Decreases in the rate of self-administration following treatment were interpreted to represent an increase in rewarding effect, whereas increases in self-administered were interpreted as a decrease in rewarding effect. The rate of self-administered intraperitoneally prior to ketamine self-administration sessions, but intravenous BMS181-100 would not substitute for ketamine in the self-administration occurred following intraperitoneal (i.p.) administration of: ketamine, SCH23390 (a D1 receptor antagonist), naloxonazine (a mu opioid receptor antagonist), and mecamylamine, a central nicotinic acetylcholine receptor antagonist. An increase in the rate of ketamine self-administration followed nicotine and dihydrexidine (a D1 receptor agonist) intraperitoneal injection. In previous studies, published in the literature, SCH23390 increased the rate of self-administration of amphetamines and cocaine, indicating a competitive effect on drug reward. However, the current studies indicate that the rewarding effects of ketamine were facilitated by SCH23390. The results are consistent with the hypothesis that the rewarding effects of ketamine are mediated through dopaminergic neural pathways. The rewarding effects of ketamine were facilitated by SCH23390. The results are consistent with the hypothesis that the rewarding effects of ketamine are mediated through dopaminergic neural pathways. The rewarding effects of ketamine may be modulated, in an inhibitory fashion, via sigma receptors, presynaptic D1 receptors, nicotinic acetylcholine receptors, and/or μ opioid receptors. Ligands at nicotinic acetylcholine and dopamine receptors yielded effects opposite to that hypothesized based on their ability to modulate the rewarding effects of other abused chemicals.