Introduction: The main pharmacovigilance system in the United Kingdom is the ‘Yellow Card’ spontaneous reporting system which suffers from low reporting rate, and long lag time between drug launch and ADR recognition. Aim: The aim of this study is to develop a pharmacovigilance system to permit the early detection of adverse drug reactions using routinely acquired NHS health data with minimal cost and resources. Methods: There are 2 methods for this study; Phase 1: The extraction of drug persistence data from routinely acquired NHS health data, and Phase 2: Identifying the exact reason(s) for patient discontinuation of drug therapy within 6 months of the index prescription. Results: Phase1: During the study period 4243 patients were initiated on ramipril, 8849 patients on simvastatin, 3242 patients on ARBs, 3646 patients on amlodipine and 269 patients on lercanidipine. The 1, 2-3 and 4-6 month discontinuation rates were 9.9%, 4.9% and 4.2% respectively for ramipril, 9.5%, 3.4% and 3.2% for simvastatin, 8.7%, 2.9% and 2.5% for ARBs, 16.2%, 6.3% and 4.8% for amlodipine, and 17.8%, 3.7% and 3.7% for lercanidipine. Drug discontinuation rates determined agree closely with published data from trials and post marketing surveys in terms of the peak time at which ADRs and discontinuations occur (1 month), the populations most frequently affected (females and the young or elderly depending on drug), and the relationship between the frequency of ADRs and discontinuations relative to the drug of interest, especially for antihypertensive (CCBs>ACEIs>ARBs). Phase 2: Six (20%) of 30 participating primary care practices, contributing to the PTI database, agreed to be approached directly. Completed data was returned for 98% of patients whom discontinued amlodipine due to a specific ADR. Conclusions: Drug discontinuation rates obtained from health care databases is a good surrogate for ADR/E rates. Specific reasons for discontinuation, such as adverse drug reactions, can be identified directly from such electronic databases or more effectively from the primary care medical records held in primary care practices.

Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / There is a dearth of high level evidence for the benefit of digoxin therapeutic drug monitoring on clinical endpoints. A pilot randomised controlled trial of digoxin TDM was conducted in hospital inpatients. The benefit of the knowledge of the serum digoxin concentration (SDC) in determining the likelihood of digoxin toxicity was assessed by presenting blinded clinicians clinical and SDC data using a computerised interface. The main benefit of the knowledge of the SDC was to reduce the percentage of patients classified as "possibly toxic", and to increase the agreement between clinicians. The study found that an increase in the prevalence of cardiac and non-cardiac manifestations of digoxin toxicity became clear at approximately 1.0 ng/ml which is at the lower end of the currently quoted therapeutic range. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1274191 / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2007

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

No description available.

MMed, Psychiatry, University of the Witwatersrand, Faculty of Health Sciences / Introduction Antipsychotics are used for the treatment of psychotic disorders, most commonly schizophrenia, as well as mood disorders e.g. bipolar mood d isorder. The efficacy of the newer second generation (atypical) antipsychotics is equivalent to first generation antipsychotics. The apparent advantage of the second generation antipsychotics is related to their purported reduced side effect profile, thus making them more desirable due to improved compliance and relapse prevention. The limiting factor with this class of drugs, especially in the state sector in South Africa, has been the cost. However, reports of treatment-emergent adverse events such as diabetes mellitus, diabetic ketoacidosis, hyperglycaemia and dyslipidaemia in patients receiving second generation antipsychotics have increased in recent times. This has lead to growing concern about the link between metabolic complications and their use, with consequent reconsideration of the implications of prescribing. Aims The study aimed to establish the extent to which metabolic and cardiovascular screening and monitoring has been undertaken on patients who have been prescribed olanzapine, a second generation antipsychotic. Specifically the extent to which the American Diabetes Association Consensus Conference monitoring protocols were being implemented in a specialist psychiatric South African setting i.e.: at Tara: The H. Moross Centre’s outpatient department. Objectives The study objectives were to describe the demographic profile, clinical diagnosis and risk factors for metabolic complications in a sample of patients receiving olanzapine. Further, to establish the extent to which metabolic and cardiovascular screening and monitoring has been undertaken on patients prescribed olanzapine as well as to what extent the patients’s demographics, diagnosis and metabolic risk factors influenced the treating doctor’s adherence to screening guidelines. Method This study was undertaken at Tara: The H. Moross Centre (outpatient department). A convenience sample of patients prescribed olanzapine were selected as the study group. The study involved a review of case records. It was a retrospective descriptive study. Relevant data was entered on a data sheet, designed for the study in accordance with the objectives and adapted from the American Diabetes Association Consensus Development Conference on Antipsychotic Drugs, Obesity and Diabetes. The data sheet is based on an existing protocol for monitoring metabolic status. v Frequencies for the presence or absence of evidence of screening or monitoring for metabolic complications were established, as per American Diabetes Association monitoring protocol requirements. Although the study involved outpatients, not all patients were intiated on olanzapine as outpatients i.e. some of the prescribing was inpatient initiated. Results The sample comprised of 19 females and 20 males. 48.72% female and 51.28% male. The mean age of females in the sample was 52.38 years (SD=16.20) and the mean age of males was 41.28 (SD=17.05) years. The sample were predominantly single ( 61.54% n=24 ) with the majority being white (79.49% n=31 ); most had either tertiarty (43% n=17 ) or secondary (53.85% n =21 ) level of education. Only 2.56% (n=1) had only primary level education. With regards to the diagnoses of patients in the sample, 17,95% (n=7) were diagnosed with bipolar 1 disorder, 7.69% (n=3) with major depressive disorder with psychosis, 20,51% (n=8) schizoaffective disorder and 53,84% (n=21) with schizophrenia. The percentage of screening for all the parameters was generally less than 20% and it continued to decline to less than 20% until 4 months. The exception was weight, where frequency increased slightly over time. Comparing inpatient vesus outpatient initiated treatment there were apparent differences in the extent of screening i.e. greater for inpatient initiated treatment, specifically with respect to weight and blood pressure. Conclusion The current study was conducted in a very specific setting, but the findings demonstrated an area requiring attention i.e. adherence to acceptable clinical guidelines. Whilst one can only speculate on the basis for non-adherence, having established the status quo, there is a requirement for an appropriate strategy to address the deficit, given the implications of inadequate monitoring.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: mass balance approach; bioavailability; drug delivery; dynamic modeling; partial differential equations; sensitivity analysis; dynamic simulations. Includes bibliographical references (p. 62-67).

In der antiretroviralen Therapie bei Kindern bleibt die Rolle von Therapeutischem Drug Monitoring bisher unklar. Es war Ziel vorliegender Arbeit, bei Kindern unter antiretroviraler Therapie (ART) in Südafrika die Lopinavir (LPV) und Efavirenz (EFV) Serumkonzentrationen in der klinischen Routine zu messen und Risikofaktoren für unzureichende Medikamentenexposition zu identifizieren. Zu diesem Zweck wurde eine prospektive Erhebung im Tygerberg Hospital, Stellenbosch durchgeführt. Siebenundfünfzig Serumkonzentrationen von 53 Patienten wurden mit einer etablierten High-performance liquid Chromatography (HPLC) Methode im Universitätsklinikum Würzburg gemessen. Für Efavirenz wird in der Literatur ein therapeutischer Bereich von 1.000-4.000 ng/ml empfohlen. Bei Lopinavir wurden die Serumkonzentrationen vorliegender Arbeit ins Verhältnis zu der pharmakokinetischen Größe Cmin von 5.500 ng/ml gesetzt. Es wurde das Serum von 53 HIV-infizierten Kindern im Alter von 0,2-15,8 Jahren untersucht. Insgesamt zeigten 12 Kinder Serumkonzentrationen außerhalb des therapeutischen Bereichs bei EFV oder kleiner Cmin bei LPV. Eine LPV-haltige ART nahmen 29 der Kinder ein (Medianalter 1,83 Jahre). Eine Messung der Konzentration von Lopinavir zeigte eine mittlere Serumkonzentration von 8.618±6018 (nicht nachweisbar-24.629) ng/ml. 17% der LPV-Serumkonzentrationen waren kleiner Cmin. Bei der Untersuchung folgender Faktoren zeigten sich keine signifikanten Unterschiede der mittleren Serumkonzentrationen und keine Assoziation mit Serumkonzentrationen <Cmin: Geschlecht, Dauer der ART <12 Monate, Anzahl der CD4-Lymphozyten, Viruslast, Komorbiditäten und angegebene Therapieadhärenz. Kinder im fortgeschrittenen HIV-Stadium nach World Health Organization (WHO) Stadium IV zeigten mit 6.817±4.273 ng/ml niedrigere LPV-Serumkonzentrationen als Kinder in WHO Stadien I, II, III mit 11.331±6.819 ng/ml. Der Unterschied war allerdings nicht signifikant. (p=0,074) Tendenziell waren die LPV-Serumkonzentrationen bei Kindern mit Untergewicht (n=9) mit 6.859±4.322 ng/ml niedriger als bei normalgewichtigen Kindern (n=9) mit einer mittleren LPV-Serumkonzentration von 10.542±6.275 ng/ml (p=0,133). Es fiel weiterhin auf, dass 3 von 10 Kinder mit gastroenteritischen Symptomen in den letzten sieben Tagen Serumkonzentrationen <Cmin zeigten. (p=0,358) Ein ART-Regime mit dem Nicht-Nukleosidischen Reverse-Transkriptase-Inhibitor Efavirenz nahmen 24 der untersuchten Kinder ein (Medianalter 9,3 Jahre). Die Zeit von EFV-Einnahme bis zur Blutentnahme variierte zwischen 12 und 19 Stunden. Es konnte eine große Varianz mit 156-36.340 ng/ml gemessen werden. Im Mittel war die Serumkonzentration 4.049±6862 ng/ml. 27% der Serumkonzentrationen lagen außerhalb des therapeutischen Bereichs. Für folgende Faktoren zeigte sich keine signifikante Assoziation mit nicht-therapeutischen EFV-Serumkonzentrationen: Geschlecht, WHO Stadium, Dauer der ART >12 Monate, HI-Viruslast, Komorbiditäten, Untergewicht und angegebene Therapieadhärenz. Kinder mit CD4-Lymphozyten <350 Zellen/µl Blut zeigten signifikant häufiger Serumkonzentrationen außerhalb des therapeutischen Bereichs als Kinder mit >350 CD4-Lymphozyten/µl Blut. (p=0,016) Bei dem Vergleich des Anteils der EFV-Serumkonzentrationen im therapeutischen Bereich zeigte sich ein signifikanter Unterschied zwischen ambulant vorgestellten versus hospitalisierten Patienten (p=0.009). Es ließ sich eine Assoziation zwischen hospitalisierten Patienten und nicht-therapeutischen Serumkonzentrationen finden. Es zeigte sich außerdem bei Kindern, die eine Rifampicin-haltige tuberkulostatische Therapie gleichzeitig zur ART einnahmen, ein Trend zu nicht therapeutischen EFV-Serumkonzentrationen (p=0,076) bei sehr kleiner Fallzahl. Die Ergebnisse dieser Arbeit zeigen, zusammen mit den Ergebnissen anderer Studien, dass mithilfe von Therapeutischem Drug Monitoring von Efavirenz und Lopinavir Risikosituationen für Therapieversagen oder Medikamententoxizität frühzeitig erkannt werden können. / In antiretroviral treatment the role of therapeutic drug monitoring via measurement of serum levels remains unclear, especially in children. Of 53 HIV-infected children in South Africa treated with lopinavir or efavirenz, 12 showed serum levels for either antiretroviral drug outside the expected therapeutic range. Low body weight, advanced WHO-stage, low CD4 count, significant comorbidites and rifampicin-co-treatment were associated with inadequate serum levels. Our findings, together with previous studies, indicate that therapeutic drug monitoring can improve antiretroviral therapy in children at risk.

The purpose of this study was to determine the predictive utility of the theory of planned behavior (TPB) in predicting and explaining pharmacists’ intention to utilize a prescription drug monitoring program (PDMP) database, when the validity of the prescription/patient need is in question. The study tested the significance of each TPB model construct variable (attitude [A], subjective norm [SN], and perceived behavioral control [PBC]) in predicting pharmacists’ high intention, compared to non-high intention (dichotomous variable). In addition, the study examined the additional contribution of pharmacists’ perception of prescription (PPDA) drug abuse and perceived obligation (PO) to the TPB model. Demographic and practice characteristics were also explored in relation to the TPB model predictors, A, SN and PBC. A mail questionnaire was sent to a random sample of 998 Texas community pharmacists with active licenses. Three focus groups were conducted to collect information regarding pharmacists’ beliefs toward PDMP database utilization. The usable survey response rate was 26.2%. Due to data that were not normally distributed, intention was dichotomized into high intention and non-high intention. The TPB constructs were significant predictors of pharmacists’ high intention. Pharmacists with positive attitudes were almost twice as likely to have high intention (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.2 – 2.8). However, SN was the strongest predictor of pharmacists’ high intention (OR = 2.2, 95% CI = 1.4 – 3.3). Pharmacists who reported substantial PBC were also twice as likely to have high intention (OR = 1.9, 95% CI = 1.2 – 3.0). PPDA was not significantly related to pharmacists’ high intention. However, pharmacists’ PO was shown to predict high intention above that explained by the TPB model (OR = 1.8, 95% CI = 1.0 – 3.1). The results of this study support the utility of the TPB model with PO in predicting pharmacists’ high intention to utilize a PDMP database. Interventions that address pharmacists’ A, SN, PBC, and PO may be necessary to increase pharmacists’ high intention to utilize a PDMP database when it becomes available. Future studies using intention as a predictor of pharmacists’ behavior are needed to assess the influence of intention on PDMP utilization. / text

The role of therapeutic drug monitoring in pediatric antiretroviral therapy is unclear. A little pharmacokinetic datum from clinical practice exists beyond controlled approval studies including clinically stable children. The aim of this study is to quantify LPV exposure of critically ill infants in an ICU and-by identifying risk factors for inadequate exposure-to define sensible indications for TDM in pediatric HIV care; in addition, assume total drug adherence in ICU to compare LPV exposure with a setting of unknown adherence. In this prospective investigation, 15 blood samples from critically ill infants in the pediatric ICU at Tygerberg Hospital were analyzed for LPV-serum concentrations. They were then compared to those of 22 blood samples from out-patient children. Serum-level measurements were performed with an established high-performance liquid chromatography method. All LPV-serum levels of ICU patients were higher than a recommended Ctrough (= 1.000 ng/ml), 60% of levels were higher than Cmax (8.200 ng/ml). Partly, serum levels reached were extremely high (Maximum: 28.778 ng/ml). Low bodyweight and age correlated significantly with high LPV concentrations and were risk factors for serum levels higher than Cmax. Significantly fewer serum levels from infants in ICU care (mean: 11.552 ng/ml ± SD 7760 ng/ml) than from out-patient children (mean: 6.756 ng/ml ± SD 6.003 ng/ml) were subtherapeutic (0 vs. 28%, p = 0.008). Under total adherence in the ICU group, there were no subtherapeutic serum levels, while, in out-patient, children with unknown adherence 28% of serum levels were found subtherapeutic. Low bodyweight and age are risk factors for reaching potentially toxic LPV levels in this extremely fragile population. TDM can be a reasonable tool to secure sufficient and safe drug exposure in pediatric cART. / Die Rolle des Therapeutischen Drug Monitorings (TDM) in der antiretroviralen Therapie bei Kindern ist unklar. Es existieren nur wenige pharmakokinetische Daten - insbesondere von kleinen Kindern – abseits der kontrollierter Zulassungsstudien an klinisch stabilen Patienten. Es ist das Ziel dieser Untersuchung, die Lopinavir-Exposition kritisch kranker Säuglinge auf einer pädiatrischen Intensivstation zu quantifizieren und durch die Identifikation von Risikofaktoren für inadäquate Exposition sinnvolle Indikation für einen Einsatz von TDM in der pädiatrischen HIV-Versorgung zu definieren. Des Weiteren verglichen wir unter Annahme totaler Adhärenz auf die Lopinavir-Exposition auf einer Intensivstation mit der einer ambulanten Versorgungsstruktur. In dieser prospektiven Studie untersuchten wir 15 Serum Proben kritisch kranker Säuglinge auf der pädiatrischen Intensivstation des Tygerberg Hospitals im Hinblick auf LPV-Serumkonzentrationen. Sie wurden verglichen mit 22 Konzentrationen von ambulant betreuten Kindern. Die Messungen wurden mit einer etablierten HPLC-Methode durchgeführt. Alle LPV-Konzentrationen der Intensiv-Patienten waren höher als die empfohlene Talspiegel (Ctrough = 1.000 ng/ml), 60% waren höher als Cmax (8.200 ng/ml). Es wurden zum Teil extrem hohe Konzentrationen erreicht (Max. 28.778 ng/ml). Ein geringes Körpergewicht und Alter korrelierten signifikant mit hohen LPV-Konzentrationen und waren Risikofaktoren für Spiegel, die über Cmax lagen. Signifikant weniger Konzentrationen von Intensivpatienten (MW: 11.552 ng/ml ± SD 7760 ng/ml) waren subtherapeutisch als von ambulant betreuten Kindern (mean: 6.756 ng/ml ± SD 6.003 ng/ml) (0 vs. 28%, p = 0.008). Unter totaler Adhärenz in der Intensiv-Gruppe waren keine subtherapeutischen Konzentrationen festzustellen, während 28% der ambulant betreuten Kinder subtherapeutischen Spiegel aufwiesen. Ein geringes Körpergewicht und Alter sind Risikofaktoren für das Erreichen potenziell toxischer Konzentrationen von Lopinavir in dieser extrem fragilen Population. TDM kann helfen LPV-Toxizität von anderen klinischen Erscheinungen zu differenzieren. TDM kann ein sinnvolles Hilfsmittel sein, um eine sichere und effektive antiretrovirale Therapie bei Kindern zu garantieren.