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In this study, four different chromatographic column chemistries (octadecylsilane/ C18, pentafluorophenyl/ PFP, octadecylated polystyrene-divinylbenzene/ PRP and underivatized silica/ HILIC) were compared under optimal conditions to evaluate the relative strengths and weaknesses of the phases for use in the determination of pain management drugs by LC-MS. Furthermore, different column scaffoldings, traditional silica, porous shell, and porous polymer, were also compared. The drugs included in this study included buprenorphine, fentanyl, methadone, naloxone, oxycodone, and tramadol. Factors such as peak area, peak resolution, theoretical plates, and reproducibility were compared among the columns and analytes using a 2-way analysis of variance (ANOVA). Because of the lipophilic nature of these drugs, the C18 columns tended to offer the best performance; however, PFP and PRP columns were viable alternatives. Finally, HILIC separation was also suitable for most of the compounds under study; often providing higher peak areas (sensitivity) likely associated with higher organic (% B) conditions, thus favoring mass spectrometric detection. To our knowledge, this is the first study to explore viability of other non-C18 stationary phases such as PRP and HILIC for this drug class.

Le protocole TICE (Taxol, Ifosfamide, Carboplatine et Etoposide) représente le traitement standard du cancer germinal réfractaire en première ligne ou en rechute de mauvais pronostic. Une étude de phase II a été réalisée consistant en une adaptation de posologie du carboplatine (utilisé à haute dose) basée sur un suivi thérapeutique pharmacologique (TDM) de ses concentrations ultrafiltrables (UF) alors que les pratiques habituelles se limitent à des doses calculées à partir d'une valeur cible de l'aire sous la courbe (AUC) des concentrations UF et la clairance UF prédite du patient. Les analyses pharmacocinétiques effectuées dans le cadre de cette thèse ont permis de démontrer la faisabilité du TDM ainsi que sa performance dans la maîtrise de l'AUC du carboplatine utilisé dans le protocole TICE. Cependant, la réalisation de cette pratique est limitée, dans certains hôpitaux, par les contraintes matérielles et humaines liées à l'obtention des concentrations UF par l'ultrafiltration des prélèvements plasmatiques. Une méthodologie a donc été développée et validée pour permettre la réalisation du TDM à partir des concentrations plasmatiques totales. Par ailleurs, l'étude pharmacocinétique réalisée pour l'étoposide, médicament associé au carboplatine dans la phase d'intensification de ce protocole, indique que le calcul actuel de la dose en fonction de la surface corporelle s'accompagne d'une variabilité interindividuelle limitée de l'exposition et qu'il n'y a pas lieu de pratiquer un TDM pour ce médicament. Enfin, l'implication de différents facteurs génétiques correspondant, d'une part, à la toxicité auditive du carboplatine et, d'autre part, à la pharmacologie de l'étoposide a été aussi évaluée. En conclusion, ces travaux permettront d'améliorer la prise en charge des patients traités par ce protocole à haute dose de carboplatine et étoposide et, au-delà de cette indication thérapeutique, notre connaissance de ces deux médicaments cytotoxiques importants. / The TI-CE protocol ((Taxol, Ifosfamide, Carboplatin and Etoposide) is the standard treatment of germ cell tumor refractory to first-line chemotherapy or relapsed germ cell tumor having unfavorable prognostic features. A phase II study was conducted and consisted in adapting the dose of (high dose) carboplatin using therapeutic drug monitoring (TDM) of unbound concentrations instead of the usual method of dose individualization based on a target area under the curve (AUC) of unbound concentrations and predicted unbound clearance. Pharmacokinetic analyses carried out in the context of this thesis have demonstrated the feasibility of conducting the TDM as well as its performance in terms of controlling the variability of AUC of carboplatin in the TI-CE protocol. However, the use of this practice is limited, in some hospitals, by material and human constraints related to the ultrafiltration of plasma samples to obtain unbound concentrations. A method was developed and validated to enable the use of total plasma concentrations for the TDM instead of unbound concentrations. Furthermore, the pharmacokinetic study of etoposide, used in combination with carboplatin during the dose intensification phase of the protocol, showed that the usual dose calculation method based on body surface area is associated with a low interindividual variability of exposure and that TDM is, therefore, not necessary for this drug. Finally, the role of different genetic factors in the ototoxicity of carboplatin and in the pharmacology of etoposide was also assessed. In conclusion, these analyses help to improve the level of care of patients treated with this protocol of high dose carboplatin and etoposide as well as our current knowledge of these two important cytotoxic drugs.

Prescription opioid pain reliever utilization has been increasing since the 1990s, due in part to changes in recommendations for the treatment of chronic pain, but also to abuse and diversion. One innovative policy solution to the abuse and diversion of prescription opioids is state prescription drug monitoring programs (PDMPs), which provide prescribers and other selected parties with patient controlled substance dispensation history; thereby, correcting an information asymmetry problem between prescribers and patients. The widespread implementation of state PDMPs, which vary in program design and requirements, has resulted in a variety of intended and unintended consequences. Previous PDMP evaluations have suggested such outcomes as the reduction of consumer access to opioids, the influencing of healthcare provider prescribing behaviors for opioids, and the re-shaping of the United States market for prescription opioids. PDMPs may also be associated with unintended outcomes: namely, the restriction of pharmaceutical opioids could be associated with an increase in heroin use, as evidenced by increases in heroin substance abuse treatment facility discharges. The analyses in this project examine the influence of PDMPs on healthcare providers and the market for prescription drugs by comparing trends in opioid utilization in states with varying PDMP features using Medicaid prescription utilization data and commercial insurance claims. The effect of PDMPs on consumers is explored with an analysis comparing substance abuse treatment facility discharge data for heroin abuse with pharmaceutical opioid prescriptions before and after PDMP regulatory change. Finally, the impact of other related opioid policy interventions, opioid overdose medication access laws, are analyzed by comparing opioid overdose mortality across states with differing overdose medication access policies over time. Contributions to the understanding about the impacts of these state-level opioid abuse and diversion policies can be used to improve or amplify intended outcomes and ameliorate unintended consequences.

OBJECTIVE: To review existing PDMP statutes, and to provide recommendations for good legislative drafting that will create effective statutory components that will enhance the function and increase the use of PDMPs. METHODS: This policy review was conducted from July 2014 to December 2014, using articles dated January 01, 2004 to July 01, 2014. All PubMed searches were artificially limited to peer reviewed articles that were available as “free full text.” To ensure a comprehensive review of the policies, statutes from all fifty states were surveyed using the legal database, Westlaw Next. The search used terms associated with PDMPs. Each statute was reviewed by title and content to determine applicability to the study. The list of statutes compiled from Westlaw Next was compared with existing publications that survey PDMP statutes. The recommendations are based on the investigator’s experience and training in law and public health in consultation with a legislative expert, and supported by peer reviewed articles and legislative drafting guides. RESULTS: There are twelve main topical components that are addressed in existing state PDMP statutes. The policy brief’s primary three recommendations are to implement an advisory committee with an outlined membership, impose a duty for the committee to routinely review database information and to report on the findings, mandate practitioners to consult the database prior to administering controlled substances, and enact a PDMP educational component for practitioners. Appendix A of this policy review (attached) provides a full list of the recommendations for effective legislation on all twelve topical components.

Pharmacogenetics is the study of variability in drug response attributed to genetic variation. Olanzapine (OLA) is a widely used antipsychotic drug for schizophrenia treatment. The pharmacokinetics of OLA display large inter-individual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need of individualized dosing in order to avoid concentration-dependent adverse effects and therapeutic failure. The observed variability has been partially explained by environmental and physiological factors. Genetically determined differences in drug metabolism represent a less studied source of variability. Precluded contribution by cytochrome P450 (CYP) 2D6 calls for evaluation of the other major OLA metabolizing enzymes. The objective of this thesis was to study pharmacogenetic influence of flavin-containing monooxygenase (FMO) 1 and 3, CYP1A2 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4 on therapeutic OLA exposure. We conducted genetic association studies applying gene re-sequencing and genotyping of candidate and tagging SNPs. Patients carrying the FMO1*6 allele displayed increased dose-adjusted concentrations (C/Ds) of OLA, in serum as well as cerebrospinal fluid. Patients who were homozygous for the FMO3 K158-G308 compound variant showed reduced C/Ds of OLA N-oxide metabolite, but no alteration in OLA exposure. This compound variant is expected to have clinical relevance primarily for non-African populations, since low frequencies were detected among native Africans. Deviation in OLA exposure was observed in carrier of a rare FMO3 mutation, predicted in silico to affect gene splicing. Reduced OLA exposure was observed in UGT1A4*3 carriers. The CYP1A2 -163(A) (CYP1A2*1F) variant was not associated with increase in CYP1A2-catalyzed OLA metabolism or reduction in OLA exposure. Correlations were detected for two cis-acting variants within the inter-genetic region of the CYP1A cluster and a trans-acting variant located upstream the locus encoding aryl hydrocarbon receptor. The inconsistent data reported for CYP1A2*1F could be explained by presence of ethnic specific haplotype structures incorporating the -163(A) variant. A continuously improved understanding of the wide range of factors that can influence pharmacokinetics and pharmacodynamics will increase the likelihood of achieving optimal treatment response for individual patients.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Antibiotic resistance is one of the most serious medical problems in the world. To counteract the increase in antibiotic resistance, new rapid and effective analytical methods are needed. To effectively treat infections in critically ill patients, optimal antibiotic dosages are required. DrugLog® is an instrument that uses a spectrophotometric method to analyze antibiotics in plasma in the wavelength range 200-800 nm. The aim of this study was to do a method validation of the instrument DrugLog®.     The study material that was used was whole blood from healthy donor and routine citrate plasma samples from the laboratory. The precision of the method and stability of plasma, the best way to filtrate lipids from plasma and four antibiotics (meropenem, cefotaxime, vancomycin, piperacillin/tazobactam) were investigated.     The precision of the method, measured as CV% was less than 0.62 and stability plasma showed a CV% of 135.74 after 24 h in room temperature. The stability for the different antibiotics after 24 h in room temperature showed a CV% of 8.11 for meropenem, 40.80 for vancomycin, 16.55 for cefotaxime and 2.92 for the combination antibiotic piperacillin/tazobactam. It was also determined that bacterial filter was the best way to remove lipids from plasma.     In conclusion DrugLog® is a suitable instrument to analyze concentration of antibiotics in patients during antibiotic treatment, however further validations are needed.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2016-09-29T13:44:49Z No. of bitstreams: 1 PDF - Palas Atenéia Dantas de Medeiros.pdf: 2158304 bytes, checksum: bf27754a7517b804bb7e707c432b84ad (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2016-10-05T16:59:28Z (GMT) No. of bitstreams: 1 PDF - Palas Atenéia Dantas de Medeiros.pdf: 2158304 bytes, checksum: bf27754a7517b804bb7e707c432b84ad (MD5) / Made available in DSpace on 2016-10-05T16:59:28Z (GMT). No. of bitstreams: 1 PDF - Palas Atenéia Dantas de Medeiros.pdf: 2158304 bytes, checksum: bf27754a7517b804bb7e707c432b84ad (MD5) Previous issue date: 2014-08-27 / Proeac/Proapex - UEPB / Introduction: This study characterized the profile of patients treated at the “Alcides Carneiro” University Hospital (HUAC), users of phenobarbital in order to support actions of therapeutic drug monitoring. Methods: Fifty patients were interviewed using a standardized questionnaire. Results: It was observed that 50% of patients have been using the drug for a long time (7.68 years on average). About 74% of respondents are under monotherapy and 59.5% of these have their seizures controlled. The patients under monotherapy have more chance of success in controlling seizures. The main anticonvulsant drug combination observed was phenobarbital with carbamazepine (66% of patients). Sedation and dizziness are among the main adverse effects, reported by 34% of patients. Monotherapy seems to be a protective factor only for adverse effect dizziness (OR=3.1). Conclusions: The analysis of these and other results presented in this paper may be useful in promoting rational use of anticonvulsants at the HUAC. / Este trabalho caracteriza o perfil clínico e epidemiológico dos pacientes atendidos no Hospital Universitário Alcides Carneiro (HUAC), que usam fenobarbital como anticonvulsivante, a fim de subsidiar ações de monitorização terapêutica. Entrevistou-se 50 pacientes, de 2011 a 2012, mediante um questionário padronizado. Observou-se que, 74% dos entrevistados estão sob monoterapia e 59,5% destes possuem suas crises controladas. Nos pacientes sob politerapia (26%) o índice de controle das crises é de 23,07%. É possível afirmar que pacientes sob monoterapia têm mais chance de sucesso no controle das crises convulsivas (Odds Ratio = 4,400). A principal associação anticonvulsivante observada foi do fenobarbital com a carbamazepina (66%). Entre os efeitos adversos relatados destacam-se a sedação e a tontura (34% dos pacientes). A monoterapia parece se constituir como fator de proteção apenas para o efeito adverso tontura (OR de 3,1). Esses resultados poderão ser úteis na promoção do uso racional de anticonvulsivantes no HUAC.

As recentes técnicas miniaturizadas de preparo de amostra, microextração em fase sólida (SPME) e in tube SPME, apresentam uma série de vantagens em relação aos métodos clássicos de extração (extração líquido-líquido e extração em fase sólida), tais como: não requer instrumentação analítica sofisticada, utilização de pequenas quantidades de solventes orgânicos, rápido processo operacional, permite automação das análises, a reutilização das fases extratoras, e integra em um único sistema a extração, concentração e introdução da amostra no cromatográfico. Esta dissertação tem como objetivo a padronização, validação e comparação dos métodos SPME/LC-UV com dessorção off line e in tube SPME/LC-UV, para a análise dos antidepressivos da nova geração (mirtazapina, citalopram, paroxetina, duloxetina, fluoxetina e sertralina) em amostras de plasma para fins de monitorização terapêutica. As variáveis: fase extratora, pH da matriz, tempo e temperatura de extração e de dessorção e força iônica apresentaram grande influência na eficiência do processo SPME. O método SPME/LC-UV padronizado, apresentou limite de quantificação (LQ) de 25 a 50 ng mL-1, ampla faixa de linearidade (LQ ? 500 ng mL-1, r2 > 0,9970) e precisão inter ensaios com coeficientes de variação menor que 15% para todos os analitos. Apesar das baixas taxas de recuperação obtidas, de 8,1% (citalopram) a 17,1% (mirtazapina), o método SPME/LC-UV apresentou seletividade e sensibilidade analítica adequada. As variáveis: pH da matriz, fluxo e número de ciclos aspirar/dispensar e volume de amostra apresentaram grande influência na eficiência do processo in tube SPME. A etapa de precipitação de proteínas do plasma, anterior ao processo de extração, foi necessária para a eliminação dos compostos endógenos. O método in tube SPME/LC-UV padronizado apresentou seletividade adequada, precisão inter ensaios com coeficiente de variação menor que 10%, LQ de 20 a 50 ng mL-1, linearidade na faixa de concentração do LQ a 500 ng mL-1, com r2 > 0,9983 para todos os analitos e recuperação absoluta de 5,32% (mirtazapina) a 43,5% (sertralina). A técnica in tube SPME, quando comparada à SPME, permitiu a automação das análises, menor exposição do analista às amostras biológicas e solventes orgânicos, menor tempo de análise e menor volume de amostra de plasma. A eficácia dos métodos, SPME/LC-UV e in tube SPME/LC-UV, foi comprovada através das análises de amostras de plasma de pacientes em terapia com os antidepressivos, para fins de monitorização terapêutica. / The recent miniaturized sample techniques preparation, solid phase microextraction (SPME) and in tube SPME, present several advantages when compared with classic extraction methods (liquid-liquid extraction and solid phase extraction), such as: it does not require sophisticated analytical instrumentation, use small organic solvent amounts, fast operational process, automation of the analyses, reuse extraction phases, and incorporates, into a single procedure, sample extraction, concentration and sample introduction. The aim of this work is development, validation and comparison of methods SPME/LC-UV with off line desorption and in tube SPME/LC-UV, for analyses of antidepressants of the new generation (mirtazapine, citalopram, paroxetine, duloxetine, fluoxetine and sertraline) in plasma samples for therapeutic drug monitoring. Variables: extraction phase, matrix pH, time and temperature of extraction and desorption and ionic strength showed great influence in SPME process efficiency. The method SPME/LC-UV presented limit of quantification (LOQ) variety from 25 to 50 ng mL-1, wide range the of linearity (LOQ 500 ng mL-1, r2 > 0.9970) and interassays precision with coefficient of variation lower than 15% for all analytes. Although the low recovery, from 8.1% (citalopram) to 17.1% (mirtazapine), the method SPME/LC-UV presented adequate selectivity and analytical sensitivity. Variables: matrix pH, flow and number of aspirate/dispense cycles and sample volume showed great influence in the in tube SPME process efficiency. The protein precipitation of the plasma steps, previous to the extraction process, was necessary for the endogenous compounds elimination. The method in tube SPME/LC showed adequate selectivity, interassays precision with coefficient of variation lower than 10%, LOQ variety from 20 to 50 ng mL-1, linearity in range concentration from LOQ to 500 ng mL-1, with r2 > 0.9983 for all analytes and recovery from 5.32% (mirtazapine) to 43.5% (sertraline). The technique in tube SPME, compared with the SPME, permitted the automation of the analyses, minor exposition of the analyst to the biological samples and organic solvent, shorter analyses time and minor plasma sample volume. The effectiveness methods, SPME/LC-UV and in tube SPME/LC-UV, was proven through the analyses of plasma samples of patients in therapy with antidepressants, for therapeutic drug monitoring.