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InfluÃncia da AlimentaÃÃo na Biodisponibilidade da Venlafaxina Administrada em CÃpsulas de LiberaÃÃo Prolongada / INFLUENCE OF FOOD ON BIOAVAILABILITY OF VENLAFAXINE ADMINISTERED IN EXTENDED RELEASE CAPSULESMarina Becker Sales Rocha 18 July 2012 (has links)
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / O sucesso do tratamento terapÃutico depende da biodisponibilidade do fÃrmaco, que pode ser afetada pela presenÃa de alimentos. Este estudo teve como objetivo avaliar a influÃncia da alimentaÃÃo na biodisponibilidade de duas formulaÃÃes de venlafaxina, administrada em cÃpsulas de liberaÃÃo prolongada em voluntÃrios sadios. Tratou-se de um estudo clÃnico, aberto, randomizado, cruzado, quatro perÃodos, duas sequÃncias, nos quais voluntÃrios sadios de ambos os sexos receberam 01 cÃpsula de venlafaxina 75mg de liberaÃÃo prolongada da formulaÃÃo teste e outra da formulaÃÃo referÃncia em cada perÃodo distinto em jejum ou alimentado, com um intervalo de sete dias. Foram coletadas 24 amostras de sangue em horÃrios previamente determinados. A concentraÃÃo da venlafaxina foi determinada utilizando o mÃtodo HPLC-MS/MS. A ausÃncia de efeito dos alimentos sobre a biodisponibilidade da venlafaxina foi indicada quando o intervalo de confianÃa de 90% para a razÃo geomÃtrica entre os estado em jejum e alimentado, esteve contido nos limites de equivalÃncia de 80-125% para o ASC0-inf, ASC0-t e Cmax quando comparado com a administraÃÃo do fÃrmaco no estado em jejum. Os eventos adversos foram monitorados durante todo o estudo. Trinta e trÃs voluntÃrios foram incluÃdos, 51,5% eram do sexo masculino (17 homens) e 48,5% do sexo feminino (16 mulheres). A idade mÃdia encontrada foi de 28,2 anos  8,6 anos, peso mÃdio de 66 kg  11,1 kg, altura mÃdia de 1,60 metros  0,1 m e Ãndice de massa corporal mÃdio (IMC) de 24,4 kg/m2  3,0 kg/m2. Os eventos adversos mais encontrados foram: cefaleia, representando 32,4%, sonolÃncia com 16,2% dos casos e nÃuseas, que representou 14,7%, dos episÃdios, nÃo havendo ocorrÃncia mais frequente em algum grupo (referÃncia ou teste) ou em estado alimentado ou jejum. Em relaÃÃo à farmacocinÃtica, nÃo foi encontrada diferenÃa estatisticamente significante na ASC0-tÃltimo e na ASC0-inf nos estados jejum versus alimentado nos grupos do medicamento referÃncia e teste; o Tmax foi menor e Cmax maior em ambos os grupos alimentados, o T1/2 foi menor no estado alimentado no medicamento teste. Em todos os parÃmetros exigidos para avaliaÃÃo do efeito dos alimentos na biodisponibilidade da medicaÃÃo referÃncia e teste estava contido no intervalo de confianÃa de 80-125%. Em relaÃÃo à bioequivalÃncia dos medicamentos, as formulaÃÃes referÃncia e teste no estado alimentado e em jejum tambÃm estavam dentro deste intervalo. Apesar de modificar alguns parÃmetros farmacocinÃticos, a alimentaÃÃo nÃo influenciou a biodisponibilidade da venlafaxina referÃncia e teste. As formulaÃÃes estudadas, cÃpsulas de liberaÃÃo prolongada de venlafaxina (produto teste e produto referÃncia) apresentaram biodisponibilidades semelhantes, quando administradas em dose Ãnica de 75 mg, por via oral a voluntÃrios sadios de ambos os sexos, em jejum e alimentados, sendo entÃo consideradas bioequivalentes para a velocidade e extensÃo de absorÃÃo. / The success of a therapeutic treatment depends upon the bioavailability of the drug, which can be influenced by food intake. This study aimed to evaluate the influence of food in the bioavailability of two formulations of venlafaxine administered at extended-release capsules in healthy volunteers. This open, randomized, crossover clinical trial was consisted of four periods, two sequences, in which healthy adult volunteers received 01 extended-release capsule of venlafaxina 75mg of test formulation and another of reference formulation in each distinct period under fasting or fed conditions, with an interval of seven days. 24 Blood samples were collected at predetermined times. Venlafaxine concentrations were determined through a HPLC-MS/MS method. The food did not influence the venlafaxine bioavailability when the 90 percent of confidence interval for the geometric ratio between fed and fasted treatment was contained in the equivalence limits of 80-125% for AUC0-inf, AUC0-t and Cmax when compared to administration of the drug in fasting condition. Adverse events were monitored during the study. Thirty-three subjects were included, 51.5% were male (17 men) and were 48.5% female (16 women). The mean age was 28.2 years  8.6 years, mean weight was 66 kg  11.1 kg, mean height was 160 cm  0.1 cm and the mean body mass index (BMI) was 24.4 kg/m2  3.0 kg/m2.. The most frequent adverse events were: headache representing 32.4%, drowsiness with 16.2% and nausea with 14.7% of all events. There was no significant difference in the frequency of occurrence in the groups (reference and test) related to the fasting or fed state. Regarding the pharmacokinetic parameters, in the statistical comparison, no difference was found in the AUC0-t and the AUC0-inf in the fasted versus fed conditions in the reference and test formulation groups. The Tmax was lower and the Cmax higher in both fed groups and the T1/2 was lower in the fed state in the test formulation. The confidence interval for all parameters required to evaluate the effect of food on the bioavailability of the reference and test formulations were within the range of 80-125%. Regarding the bioequivalence of drugs, both formulations in fed and fasted state were within the established range (80-125%). Although the food did change some pharmacokinetic parameters, feeding did not influence the bioavailability of venlafaxine in both reference and test formulations. The studied capsules of venlafaxine extended-release (test and reference products) showed similar bioavailability when administered a single oral dose of 75mg to healthy adult volunteers, fasting and fed and, thus, were considered bioequivalent to the rate and extent of absorption.
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The Effect of Indomethacin Administration on the Splenic Changes Induced by Estradiol Supplementation in Ovariectomized New Zealand White RabbitsThurmond, Thane S., Ferslew, Kenneth E., Mccracken, Malcolm D., Coogan, Philip S. 01 January 1996 (has links)
In an effort to elucidate the mechanism by which indomethacin (IN) lessens the stimulatory effect of estradiol (E2) on rabbit splenic red pulp macrophages (RPMs), 39 female New Zealand White rabbits were divided into 10 groups: ovariectomized (OVX) and OVX/ IN at 0.1 and 5.0 mg/kg body weight (bw)/day; sham OVX (SOVX) and SOVX/IN at 0.1 and 5.0 mg/kg bw/day; OVX/25 mg E2 and OVX/25 mg E2/IN at 0.1 and 5.0 mg/kg bw/day; and intact control. Changes in RPM population in response to treatment were measured using a 0-4 histologic grade. Estradiol treatment resulted in increased RPM grade when compared to the OVX groups. Indomethacin addition lowered mean RPM grade in the SOVX/IN 5.0 group when compared to its E2 control group. Indomethacin administration had no significant effect on levels of prostaglandin E 2 in spleen, urine, or blood. Hematocrits were reduced in both OVX and OVX/E2 groups; this decrease was exacerbated by the high IN dose. In summary, the results from this study suggest that the effect of IN on E2-induced RPM activation may be mediated through a nonprostaglandin pathway. The observed hematocrit changes are possibly the result of direct action of IN and E2 on erythrocytes, resulting in their accelerated clearance from the circulation by splenic RPM.
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Study designs and statistical methods for pharmacogenomics and drug interaction studiesZhang, Pengyue 01 April 2016 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Adverse drug events (ADEs) are injuries resulting from drug-related medical
interventions. ADEs can be either induced by a single drug or a drug-drug interaction (DDI).
In order to prevent unnecessary ADEs, many regulatory agencies in public health maintain
pharmacovigilance databases for detecting novel drug-ADE associations. However,
pharmacovigilance databases usually contain a significant portion of false associations due
to their nature structure (i.e. false drug-ADE associations caused by co-medications).
Besides pharmacovigilance studies, the risks of ADEs can be minimized by understating
their mechanisms, which include abnormal pharmacokinetics/pharmacodynamics due to
genetic factors and synergistic effects between drugs. During the past decade,
pharmacogenomics studies have successfully identified several predictive markers to
reduce ADE risks. While, pharmacogenomics studies are usually limited by the sample
size and budget.
In this dissertation, we develop statistical methods for pharmacovigilance and
pharmacogenomics studies. Firstly, we propose an empirical Bayes mixture model to
identify significant drug-ADE associations. The proposed approach can be used for both
signal generation and ranking. Following this approach, the portion of false associations
from the detected signals can be well controlled. Secondly, we propose a mixture dose
response model to investigate the functional relationship between increased dimensionality
of drug combinations and the ADE risks. Moreover, this approach can be used to identify high-dimensional drug combinations that are associated with escalated ADE risks at a
significantly low local false discovery rates. Finally, we proposed a cost-efficient design
for pharmacogenomics studies. In order to pursue a further cost-efficiency, the proposed
design involves both DNA pooling and two-stage design approach. Compared to traditional
design, the cost under the proposed design will be reduced dramatically with an acceptable
compromise on statistical power. The proposed methods are examined by extensive
simulation studies. Furthermore, the proposed methods to analyze pharmacovigilance
databases are applied to the FDA’s Adverse Reporting System database and a local
electronic medical record (EMR) database. For different scenarios of pharmacogenomics
study, optimized designs to detect a functioning rare allele are given as well.
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Specificity and Sensitivity of Drug Interaction Databases to Detect Meaningful QTc Interactions with Oral AntineoplasticsEskens, D., Gardner, A. 01 September 2019 (has links)
Abstract available in the Clinical Pharmacology in Drug Development.
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Prevalence, Predictors, and Economic Impact of Drug-Drug Interaction Associated with Antipsychotic Medications among Adults in United StatesAlmalki, Ziyad S. 16 June 2017 (has links)
No description available.
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Increased hospitalization for hemorrhages in patients taking amiodarone with warfarin: a population-based cohort studyLam, Jason 10 1900 (has links)
<p><strong>BACKGROUND</strong></p> <p>Amiodarone is believed to inhibit the hepatic metabolism of warfarin, potentiating its hypoprothrombinemic effect and increasing the risk of hemorrhage. The consequences of this drug interaction on important clinical outcomes are unknown.</p> <p><strong>METHODOLOGY</strong></p> <p>Using linked health administrative databases, we conducted a population-based retrospective cohort study among Ontario residents aged 66 years or older who had been treated with warfarin therapy for at least 6 months. Within this group, we identified subjects who initiated amiodarone while on warfarin. Each of these subjects was matched to a subject not treated with amiodarone on age, sex, year of cohort entry, and a high dimensional propensity score. The primary outcome was a hospitalization due to a hemorrhagic event within 30 days of follow-up. In a secondary analysis, we examined in-hospital mortality following hospitalization for major hemorrhage.</p> <p><strong>RESULTS</strong></p> <p>We identified 60,497 eligible patients between July 1, 1994 and March 31, 2009. Of these, 11,665 (19.3%) received a new prescription for amiodarone while receiving ongoing warfarin therapy and 7,124 (61.1%) of these were matched to a subject who was not exposed to amiodarone while receiving warfarin therapy. The median age at cohort entry of the matched cohort was 76 years, 51.6% in the cohort were male, 14.5% lived in a rural location, 2.8% had a bleed in the past year, and 21.6% had a diagnosis of congestive heart failure in the past year. Fifty-six amiodarone recipients experienced a hemorrhagic event (0.8%) as compared to 23 individuals (0.3%) in the non-exposed group at 30 day follow-up (adjusted hazard ratio (HR) = 2.45; 95% CI, 1.49 to 4.02). Seven patients in the amiodarone group died after hospitalization for a hemorrhage versus four in the non-exposed group (adjusted HR = 1.74; 95% CI, 0.25 to 12.24).</p> <p><strong>CONCLUSION</strong></p> <p>Initiation of amiodarone in patients on chronic warfarin therapy was associated with a two-fold increase in the risk of hospitalization due to a hemorrhagic event. Physicians should closely monitor the response to warfarin following initiation of amiodarone.</p> / Master of Science (MSc)
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Improvement of Gastroparesis Management By Addressing Challenges in Drug Metabolism: Studies with Metabolite Identification, Reaction Phenotyping and In Vitro Drug-Drug InteractionsYoussef, Amir Samaan Bishara January 2013 (has links)
Gastroparesis is a disorder characterized by delayed gastric emptying due to chronic abnormal gastric motility. Prokinetic agents such as domperidone and metoclopramide are the cornerstone in treatment of gastroparesis. Although these medications have been used for decades, essential information about their metabolism is not available. Lack of knowledge about the metabolites formed in the body upon administration of the aforementioned medications as well as the enzymes involved in their metabolism limits key information needed to make sound medical decisions. Accurate and comprehensive identification of the metabolites along with reaction phenotyping of prokinetic agents will ensure safe and effective use of these drugs and hence enhance the clinical outcome. The thesis starts with an introductory chapter which comprises a comprehensive literature review on gastroparesis and the available pharmacological treatment options. The chapter also emphasizes the importance of metabolic profiling of prokinetic agents (domperidone and metoclopramide) and its impact on enhancing the safety and efficacy of these medications. Chapter 2 of this project was aimed to determine phase oxidative and conjugative metabolites of domperidone in the plasma and urine of gastroparesis patients using tandem mass spectrometry. First, the metabolites were identified in in-vitro human subcellular fractions. The knowledge gained in this experiment helped identifying the metabolites in the biological fluids of patients. In total, 12 metabolites including 7 new metabolites were identified, 5 of which were not reported previously. Chapter 3 aimed to identify the cytochrome P450 (CYP) enzymes responsible for the metabolism of metoclopramide. The parent depletion approach was used and a novel LC-MS/MS method was developed and validated to enable metoclopramide quantification. CYP2D6 was showed to the predominant isoform in metoclopramide metabolism; other isoforms also contribute to a minor extent. Chapter 4 discusses the possibility of potential drug-drug interaction (DDI) in the current management practice of gastroparesis. We identified and investigated some frequently used drug combinations that are known to share common metabolic pathways. Domperidone in combination with pioglitazone and ondansetron was evaluated. Results showed that pioglitazone inhibited domperidone metabolism in-vitro. Our experiments did not predict a DDI for the domperidone - ondansetron combination. In summary, the ultimate goal of this thesis was to improve the management of gastroparesis by increasing information about the metabolic disposition of prokinetic agents and to investigate the magnitude of putative drug combinations. The knowledge provided by this work will help in making more effective and less hazardous clinical decisions which will ultimately lead to more successful gastroparesis management. / Pharmaceutical Sciences
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糖尿病之藥物交互作用與用藥分析廖彗嵐 Unknown Date (has links)
隨著國人之生活習慣改變與社會進步,糖尿病逐年上升,並成為國人十大死因之一,此外,糖尿病易引發其他疾病而產生併發症,當患者同時患有多種疾病,進而接受多重藥物治療,在使用多種藥物情況下易導致藥物產生交互作用,而中央健保局之「全民健康保險資料庫」囊括全體國人珍貴的醫療資料,其中包含詳細的糖尿病病患相關資料,本研究藉由分析中央健保局之糖尿病資料,目的在於分析糖尿病用藥中產生藥物交互作用之情形,希望能發掘有用資訊。
糖尿病資料中具有藥物交互作用處方佔有29%,藉由不同變數來探討糖尿病之藥物交互作用情形,譬如從年齡、性別、用藥藥品數、就醫科別等,進而得知資訊,諸如病患年齡與處方用藥數會影響是否有無藥物交互作用之產生;此外,藥物交互作用組合中,最多為口服低血糖用藥,這是糖尿病用藥,但產生最嚴重之藥物交互作用為心血管疾病用藥,並利用資料採礦技術挖掘有意義之規則。 / Incidence of diabetes mellitus is on the rise year over year in today’s modern living life style. It has been ranked as the tenth leading cause of death in Taiwan. When a patient suffers from more than a single cause of illness, he is treated by multiple medications which in turn could trigger drug interactions side effect. National health insurance research database has kept information containing data of patients with diabetes mellitus from which this research has based its data on. The purpose of this research is to analyze the side effects of drug interactions from diabetes mellitus medications.
Of all prescriptions given for diabetes mellitus, 29% were resulted in having drug side effects. This research attempts to isolate the factor causing side effects of drug interaction of diabetes mellitus medications by difference variables, such as patient’s age, sex (male or female) and numbers of medicines. The techniques we employed in reaching our attempts is data mining.
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USING SEMIPHYSIOLOGICALLY-BASED PHARMACOKINETIC (SEMI-PBPK) MODELING TO EXPLORE THE IMPACT OF DIFFERENCES BETWEEN THE INTRAVENOUS (IV) AND ORAL (PO) ROUTE OF ADMINISTRATION ON THE MAGNITUDE AND TIME COURSE OF CYP3A-MEDIATED METABOLIC DRUG-DRUG INTERACTIONS (DDI) USING MIDAZOLAM (MDZ) AS PROTOTYPICAL SUBSTRATE AND FLUCONAZOLE (FLZ) AND ERYTHROMYCIN (ERY) AS PROTOTYPICAL INHIBITORSLi, Mengyao 01 January 2016 (has links)
The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI.
Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ PK profiles were compared with observed data from available clinical PK and DDI studies, by visual predictive check and exposure metrics comparison. DDI magnitude and time course for CYP3AI (IV vs. PO) followed by MDZ (IV vs. PO) at various time points were predicted by the validated semi-PBPK-DDI models. Two hypothetical CYP3A substrates and four CYP3AI (derived from MDZ, FLZ and ERY, with GW metabolism removed, hepatic metabolism reduced, or oral bioavailability (Foral) and/or elimination half-life (t1/2) modified) were also simulated to generalize conclusions.
The final semi-PBPK-DDI models predict well the PK profiles for IV/PO MDZ in absence/presence of IV/PO CYP3AI, with deviations between model-predicted and observed exposure metrics within 30%. Prospective simulations demonstrate that:
1) CYP3A substrates, e.g., MDZ, are consistently more sensitive to metabolic inhibition after PO than after IV administration, due to pre-systemic hepatic and/or GW metabolism. For substrates without GW metabolism and limited hepatic metabolism, only a marginal route difference for substrate administration is observed.
2) For high-Foral CYP3AIs, e.g., FLZ, no inhibitor IV-PO route DDI differences are expected, unless they are given simultaneously with PO MDZ.
3) For low-Foral CYP3AIs, e.g., ERY, greater inhibition is expected after IV than after PO administration for IV MDZ, but is difficult to predict for PO MDZ.
4) In addition to Foral and plasma t1/2 of CYP3AIs, the DDI onset, peak and duration are determined by their oral absorption rate and by the resulting hepatic and/or GW concentration profiles relative to Ki for noncompetitive CYP3AIs, but by CYP3A kinetics (synthesis, degradation rate) for MBI CYP3AIs.
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Síntese e ensaio de análogos estruturais de prolina no estudo da interação com trombina. / Synthesis and assay of structural analogues of proline in the study of interaction with thrombin.Silva, Roberta Noguci da 11 December 2013 (has links)
Rotas sintéticas foram empregadas no grupo funcional ligado ao carbono 4 da trans-hidroxi-L-prolina para a obtenção de quatro análogos de prolina com amino e guanido grupos nesta posição e isomeria espacial cis e trans. Adicionalmente, o aminoácido guanidino fenilalanina foi comparado com os análogos de prolina em todos os ensaios realizados. Entre os análogos de prolina sintetizados, o peptídeo contendo o aminoácido não natural com o grupo funcional guanido e isomeria trans apresentou a melhor atividade inibitória contra trombina. Entretanto, o peptídeo sintetizado com o aminoácido guanidino fenilalanina ainda demonstra ter uma melhor atividade inibitória em comparação com os análogos de prolina. / Synthetic routes were employed in the functional group attached to the carbon 4 of trans-4-hydroxy-L-proline to obtain four proline analogues with amino and guanido groups in this position and cis and trans spatial isomerism. Additionally, the amino acid guanidino phenylalanine was compared with the analogues of proline in all tests. Among the proline analogues synthesized, the peptide containing the unnatural amino acid functional group with guanido and trans isomerism showed the best inhibitory activity against thrombin. However, the peptide synthesized with the amino acid guanidino phenylalanine exhibits an even better inhibitory activity in comparison to proline analogues.
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