A low-cost circuit board design is presented, which in one embodiment is smaller than a credit card, for biopotential (EMG, ECG, or EEG) data acquisition, with a focus on EEG for brain-computer interface applications. The device combines signal conditioning, low-noise and high-resolution analog-to-digital conversion of biopotentials, user motion detection via accelerometer and gyroscope, user-programmable digital pre-processing, and data transmission via Bluetooth communications. The full development of the device to date is presented, spanning three embodiments. The device is presented both as a functional data acquisition system and as a template for further development based on its publicly-available schematics and computer-aided design (CAD) files. The design will be made available at the GitHub repository https://github.com/kellygs/eeg.

Until approximately 50 years ago, wireless electronics was confined to military purposes. With the advancement of technology, consumer electronics found widespread applications in almost every aspect of our lives and numerous devices were developed using electromagnetic waves to transfer different types of data. In light of such advancements, the electromagnetic compatibility (EMC) evolved from a military concept to regulate the radio frequency requirements of the battlefield equipment to a mature and essential part in manufacturing and employing electronic devices. Medical devices were no exception and largely benefited from the ease of connectivity and mobility provided by usage of wireless electronics. Due to the sensitive nature of medical devices and extreme consequences of their malfunction, EMC grew to a centric issue in design and production of such devices. This work examines the electromagnetic compatibility of a wearable biomedical measurement system used for the assessment of mental stress of combatants in real time. This system was developed as a part of the ARTEC project and supported by the Spanish Ministry of Defense through the Future Combatant program [1]. We focus on the EMC of the electrocardiogram of the system and aim to identify its EMC requirements of this system while assessing it against various standards and protocols. Throughout this study, we elucidate the fundamentals of electromagnetic compatibility with specific attention to medical devices. Furthermore, we present our results after conducting several EMC tests to measure the compatibility of the electrocardiogram device using the Intertek guidelines. The emission test was performed while essential counter measures such as appropriate shielding and anti-interference filters had been applied.

Atrial fibrillation (AF) is the most common cardiac arrhythmia causing morbidity and mortality. Despite recent advances, developing effective and safe anti-AF pharmaceutical therapies remains challenging and is prone to adverse effects in the ventricles. Atrial-selective therapies are promising in managing AF. A better understanding of the role of the atrial-specific ion channels in the atrial arrhythmogenesis and contractility, as well as the anti-AF effects of blocking these channels is of interests. Also, a 3D ventricle-torso model capable of modelling ventricular electrical activities and the resulting electrocardiogram (ECG) is a valuable tool in evaluating the selectiveness and safety of an anti-AF pharmaceutical therapy. In part I, the role of an atrial-specific ion channel, IKur, in atrial electrical and mechanical activities and the potential of the current as a pharmaceutical target for anti-AF therapies were investigated in silico. The role of IKur in atrial arrhythmogenesis and mechanical contraction was revealed by elucidating the functional impacts of the KCNA5 mutations exerting either gain- or loss-in-function, on the atria. First, novel IKur models were developed and incorporated into multiscale biophysical models of human atrial electrophysiology to assess the effects of mutated IKur on atrial electrical dynamics. Then, a family of single cell human atrial electromechanical models was developed and incorporated into an updated 3D anatomical electromechanical model of human atria to clarify the effects of mutated IKur on the atrial contractile function. Finally, the antiarrhythmic effect of IKur block was assessed together with INa and other K+-current block. It was shown that the gain-of-function in IKur impaired atrial contractility and promoted atrial arrhythmogenesis by shortening the APD, whereas the down-regulated IKur exerted positive inotropic effects and increased the susceptibility of the atria to the genesis of early-afterdepolarisations. Both simulated IKur and INa block in human-AF demonstrated antiarrhythmic effects; the multi-channel block exerted synergistic anti-AF effects and enhanced the AF-selectivity of INa inhibitions. In Part II, a human ventricle-torso model was developed through proposing a new family of single cell ventricular models accounting for transmural, apicobasal and interventricular electrical heterogeneities and integrating an updated 3D biophysical and anatomical model of human ventricles with a heterogeneous anatomical model of a human torso. First, using the model, the role of heterogeneities in the genesis of T-wave was revealed. Then, ECG manifestations of bundle branch block and ventricular ischaemia were simulated. Finally, the platform was applied to investigate the impact of a long-QT-linked mutation (KCNQ1-G269S) on the ventricles and ECG. Good agreement between simulated and experimental/clinical ECG was reached under both normal and diseased conditions. It was shown that the apicobasal heterogeneity had a more pronounced effect on the T-wave than other heterogeneities. Simulations of the KCNQ1-G269S elucidated the causal link between the mutation and ECG manifestations of the patients.

The electrocardiogram (ECG) is a graphical representation of the electrical activity of the heart. The 12-lead ECG shows this activity in 12 "views" called "leads", relative to the location of sensors attached to the body surface. The ECG is a routinely applied cost effective diagnostic medical test, utilised in healthcare settings around the world. Although more than three hundred million ECGs are recorded each year, correctly interpreting them is considered a complex task. Failure to make correct interpretations can lead to injury or death and costs vast sums in litigation payments. Many automated attempts at interpreting ECGs have been implemented and continue to be developed and improved. Despite this, automated methods are still considered to be less reliable than expert human interpretation. As ECG interpretation is both a cognitive and visual task, eye-tracking holds great potential as an investigative methodology. This thesis aims to identify any cues in visual behaviour that may indicate differences in subsequent ECG interpretation accuracy. This is the first work that uses eye-tracking to analyse how practitioners interpret ECGs as a function of accuracy. In order to investigate these phenomenon, several experiments were carried out using eye-movements captured from clinical practitioners that interpret ECGs as part of their usual clinical role. The findings presented in this thesis have advanced research in the understanding of ECG interpretation. Specifically: Clinical history makes a difference to how people look at ECGs; different gaze patterns are often found in accurate and inaccurate interpretation groups. Grouping data to account for within ECG lead behaviour (eye-movement patterns within a lead) is more revealing than analysis at the level of the lead (eye-movements between leads). Findings suggest analysing visual behaviour at this level is crucial in order to detect behaviour in ECG interpretation. Further to this the thesis presents eye-tracking techniques that can be applied to wider areas of task performance. These methods work over complex stimuli, are able to deal post hoc with differently sized groups and generate appropriate areas of interest on a stimulus. These methods detect important differences in eye-movement behaviour between groups that are missed when applying standard inferential statistical techniques.

Approximately 30% of people admitted to ICU in the UK have co-existing cardiovascular disease (CVD), and this may rise as life-expectancy increases. Patients with CVD have impaired compensatory mechanisms to enable maximum oxygen delivery to the tissues in the event of critical illness, which itself increases global oxygen demand, further stressing the heart. This is exacerbated by tachycardia and hypotension, which may relatively reduce blood flow to the coronary arteries, and catecholamines which increase myocardial oxygen demand. The myocardium extracts 75% of the oxygen supplied by the coronary arteries at rest, and atheroma-related flow limitation further compromises myocardial oxygen delivery. However, the diagnosis of acute coronary syndrome in critical illness is not straightforward, due to patient inability to communicate symptoms, non-specific ECG changes, and poorly understood cardiac biomarker troponin elevation. My overall hypothesis is that patients with CVD benefit from increased oxygen delivery to the myocardium during critical illness. A focus is the importance of anaemia. The aims of the studies presented in this thesis are (i) to systematically review the literature regarding blood transfusion thresholds specifically in patients with CVD; (ii) to explore the association between Troponin I (TnI) within 24 hours of ICU admission and hospital mortality (iii) to describe and quantify the dynamics of TnI in patients with CVD during the first ten days after ICU admission; and (iv) to define myocardial infarction in the context of critical illness. I have performed a systematic review and meta-analysis of randomised controlled trials comparing a restrictive with liberal transfusion threshold and that included patients with CVD. In total, 11 trials enrolling patients with CVD (n=3033) were included for meta-analysis (restrictive n=1514, liberal=1519). The pooled risk ratio for the association between a restrictive transfusion threshold and 30 day mortality was 1.15 (95% CI 0.88 to 1.50, p=0.50, I2=14%). The risk of acute coronary syndrome in patients managed with restrictive compared with liberal transfusion was increased (nine trials, risk ratio 1.78, 95% CI 1.18 to 2.70, p=0.0, I2=0%). In contrast to broader literature supporting restrictive thresholds, our systematic review shows that a restrictive transfusion threshold of less than 80g/l may not be safe in patients with co-existing CVD, and highlights the variability in diagnostic definitions of ACS and the potential for ascertainment bias in transfusion trials. I undertook a retrospective cohort study in two independently collected cohorts of general ICU patients who had TnI measured within 24 hours of ICU admission. Importantly, the majority of TnI samples were collected routinely rather than for clinical indications. We used the Abbott ARCHITECT Stat assay (limit of detection 0.01mcg/l. We performed multivariable regression, adjusting for components of the APACHE II model. We derived the risk prediction score from the multivariable model with TnI. TnI was associated with all cause hospital mortality (OR per doubling TnI 1.16, 95% CI 1.13 to 1.20, p < 0.001) which persisted after adjustment for APACHE II model components (OR TnI 1.05, 95% CI 1.01 to 1.09, p=0.003). TnI correlated highly with the Acute Physiological Score component of APACHE II (r=0.39), suggesting that TnI release may be largely explained by acute physiological stress. Addition of TnI to the APACHE II model did not improve the performance of the risk prediction model and we would not advocate the adoption of a routine single troponin sample at admission. I designed, set up, and recruited 279 patients to a prospective cohort study TROPonin I in Cardiovascular patients in CriticAL care (TROPICCAL, UKCRN 19253) in 11 UK centres. The aims were to (i) determine the incidence of Myocardial Injury and Infarction, defined by the Third Universal Definition of Myocardial Infarction; (ii) explore factors associated with Injury and Infarction from multivariable analyses; and (iii) explore the relationship between Injury/Infarction and outcome in unadjusted and adjusted analyses. We recorded baseline characteristics, and took daily hs-TnI for ten days after ICU admission, severity of illness measures and ECGs for 5 days. There was a wide range of peak TnI (med 114ng/l (min 3, Q1 27, Q3 412, max 58820ng/l)) and a high prevalence of myocardial injury on systematic screening: 71% of patients had peak TnI greater than the sex-specific diagnostic threshold ('Injury'), and 24% had peak TnI greater than the sex-specific diagnostic threshold and dynamic changes on ECG consistent with ischaemia ('Infarction'). TnI consistently showed a rise-and-fall pattern consistent with an acute myocardial 'hit' rather than persisting injury, which peaked early during ICU stay. Importantly, only 12 (4.4%) patients were diagnosed with MI by the clinicians looking after the patients. Independent predictors of peak TnI in the preceding 24 hours were SOFA score, dynamic ECG ischaemia, lactate, haemoglobin, and age. The lack of association with CRP (representing systemic inflammation), with stronger association with lactate (representing inadequate perfusion/oxygen supply), Hb and ECG ischaemia support the conjecture that injury results in part from an acute ischaemic hit in this population. Patients with Infarction had similar baseline demographics to patients with Injury, but had higher peak TnI concentrations, and higher hospital and six month mortality (Figure 2). This supports the importance of including systematic assessment of dynamic ECG changes in the myocardial injury 'construct' in ICU. My work has shown an increased risk of ACS in patients with CVD randomised to restrictive transfusion thresholds. TnI elevation is prevalent in general ICU patients, and is independently associated with hospital mortality. A systematic approach to the detection of myocardial injury in critically ill patients with co-existing CVD who are unable to communicate symptoms, can identify a high risk population who have poorer survival than patients with no injury. Markers of ischaemia are more associated with TnI rise than markers of inflammation, supporting the hypothesis that myocardial injury in this population is at least in part due to oxygen supply-demand imbalance 'myocardial infarction'. From this work, I would recommend (i) a more liberal transfusion threshold of at least 80g/l in patients with coexisting CVD; (ii) systematic use of sequential ECGs in ICU to screen for myocardial injury in 'at risk' patients; and (iii) manipulation of physiological parameters such as anaemia, hypotension and tachycardia should be considered for patients with dynamic ECG changes plus troponin increase consistent with Infarction. Future research should include 'precision medicine' trials in the substantial cohort of ICU patients with co-existing CVD to explore whether interventions that increase myocardial oxygen supply and/or treat infarction alter outcomes.

Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2016-10-10T16:40:48Z No. of bitstreams: 1 2011 - Raquel Rodrigues Costa Mello.pdf: 1289647 bytes, checksum: f0d06ec4ba47cab82e19761e6bf670ec (MD5) / Made available in DSpace on 2016-10-10T16:40:48Z (GMT). No. of bitstreams: 1 2011 - Raquel Rodrigues Costa Mello.pdf: 1289647 bytes, checksum: f0d06ec4ba47cab82e19761e6bf670ec (MD5) Previous issue date: 2011-08-05 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / The Sindhi breed has excellent adaptability to adverse weather conditions and management, and good ability to milk production. Although many researches will be developed with Sindhi breed animals, such experiments are focused mainly on productive aspects, and researches involving the reproductive tract are still scarce in the Sindhi Zebu breed. Thus, the aim of this study was to evaluate the reproductive parameters of Sindhi cows, aiming to improve the efficiency of FTAI protocols in this breed. To this end, sixteen Sindhi cows with body condition score between 3,0 and 4,0 (scale from 1 to 5) were divided into two evaluation groups: In group I (BE protocol, n=8) animals received on day 0 an intravaginal P4 device and an application of 2mg of estradiol benzoate. On day 8 the device was removed and applied 10mg of Dinoprost (PGF2?), and on day 9, applied 1 mg of estradiol benzoate, and were fixed-time artificial inseminated 36 h later; in group II (BE + eCG protocol, n=8) animals were submitted through same treatment, and on day 8 were applied 400 IU of eCG. From day 0 for both treatments, the animals were examined daily by trans-rectal ultrasound device equipped with a 7,5MHz linear transducer (CHISON? D600 VET). This evaluation was performed up to ovulation. At each assessment, the largest follicles of each day (?4 mm) were measured. It used analysis of variance (ANOVA) to evaluate the results, and the means determined by Tukey test, with significance level of 5%. For data analysis, it was observed that there was no statistical difference (P>0.05) for groups I (Treatment I: no eCG) and II (Treatment II: 400 IU eCG) concerning to emergence of follicular wave, 4.5 ? 1.4 and 3.8 ? 0.3 days; interval between the emergence of the wave and ovulation, 5.8 ? 1.4 and 7.1 ? 0.3 days; interval between the emergence of the wave and implant removal, 3,5 ? 1,4 and 4,1 ? 0,3; interval between implant removal and ovulation, 74.0 ? 11.8 and 82.5 ? 4.2 hours; diameter of the dominant follicle (DF) at the time of implant removal, 7.5 ? 2.5 and 6.6 ? 1.5 mm; diameter maximum of DF, 10.47 ? 8.85 and 3.7 ? 1.2 mm; growth rate of the DF, 0.90 ? 0.83 and 0.7 ? 0.6 mm/day and ovulation rate, 75 % (6/8) and 100% (8/8), respectively. Regarding to pregnancy rate, it was observed that there was statistical difference (P<0.05) between protocols I and II (0% and 50%, respectively). Therefore, we conclude that the use of eCG in Sindhi breed cows was not effective in improving the reproductive parameters examined, perhaps because the cows are cycling at the beginning of treatment and had good body condition score during the experiment. On the other hand, there was an increase in pregnancy rate with the use of eCG, indicating that this gonadotropin may be a useful tool in FTAI protocols in this breed. / A ra?a Sindi apresenta excelente adaptabilidade ?s condi??es adversas de manejo e clima, e boa capacidade de produ??o de leite. Embora muitas pesquisas venham sendo desenvolvidas com animais desta ra?a, tais experimentos se concentram predominantemente em aspectos produtivos, pesquisas envolvendo a ?rea reprodutiva ainda s?o escassas na ra?a Sindi. Portanto, o objetivo deste trabalho foi avaliar os par?metros reprodutivos de vacas Sindi, buscando melhorar a efici?ncia dos protocolos de IATF nesta ra?a. Para tanto, 16 vacas da ra?a Sindi, com escore de condi??o corporal entre 3,0 e 4,0 (escala de 1,0 a 5,0) foram divididas em dois grupos de avalia??o: no grupo I (esquema BE, n=8), os animais receberam no dia 0 um implante intravaginal impregnado com 1,9g de progest?geno e uma aplica??o de 2mg de benzoato de estradiol. No dia 8 o implante vaginal foi removido, sendo aplicados 10mg de Dinoprost (PGF2?) e, no dia 9, aplicado 1mg de benzoato de estradiol, sendo realizada a IATF 36 horas ap?s; no grupo II (esquema BE + eCG, n=8), os animais passaram pelo mesmo tratamento, sendo que no dia 8 foram aplicadas 400UI de gonadotrofina cori?nica eq?ina (eCG). A partir do dia 0, para os dois tratamentos, os animais foram examinados diariamente por via trans-retal com aparelho de ultrassom (CHISON? D600 VET) equipado com um transdutor linear de 7,5 MHz. Esta avalia??o foi realizada at? o momento da ovula??o. Em cada avalia??o, os maiores fol?culos de cada dia (?4 mm) foram mensurados. Foi utilizada a an?lise de vari?ncia (ANOVA) para avalia??o dos resultados, sendo as m?dias determinadas pelo teste de Tukey, com n?vel de signific?ncia de 5%. Pela an?lise dos dados, observou-se que n?o houve diferen?a estat?stica (P>0,05) para os grupos I e II na emerg?ncia da onda folicular, 4,5 ? 1,4 e 3,8 ? 0,3 dias; no intervalo entre a emerg?ncia da onda e a ovula??o, 5,8 ? 1,4 e 7,1 ? 0,3 dias; no intervalo entre a emerg?ncia da onda e a retirada do implante, 3,5 ? 1,4 e 4,1 ? 0,3; no intervalo entre a retirada do implante e a ovula??o, 74,0 ? 11,8 e 82,5 ? 4,2 horas; no di?metro do fol?culo dominante (FD) na retirada do implante, 7,5 ? 2,5 e 6,6 ? 1,5 mm; no di?metro m?ximo do FD, 10,47 ? 3,7 e 8,85 ? 1,2 mm; na taxa de crescimento do FD, 0,90 ? 0,7 e 0,83 ? 0,6 mm/dia e na taxa de ovula??o, 75% (6/8) e 100% (8/8), respectivamente. Com rela??o ? taxa de prenhez, foi observada diferen?a estat?stica (P<0,05) entre os grupos I e II, sendo 0% (0/8) e 50% (4/8), respectivamente. Portanto, conclui-se que o uso do eCG em f?meas bovinas da ra?a Sindi n?o foi efetivo em melhorar os par?metros reprodutivos analisados, talvez pelo fato das vacas apresentarem bom escore de condi??o corporal durante a realiza??o do experimento. Por outro lado, houve um aumento na taxa de prenhez com o uso do eCG, indicando que este pode ser uma ferramenta ?til em protocolos de IATF nesta ra?a.

Tese de mestrado integrado. Engenharia Electrotécnica e de Computadores. Faculdade de Engenharia. Universidade do Porto. 2012

Sudden Cardiac Death (SCD) is the largest cause of natural deaths in the USA, accounting for over 300,000 deaths annually. The major reason for SCD is Ventricular Arrhythmia (VA). Therefore, there is need for exploration of approaches to predict increased risk for VA. Alternans of the T wave in the ECG (TWA) is widely investigated as a potential predictor of VA, however, clinical trials show that TWA has high negative predictive value but poor positive predictive value. A possible reason that TWA has a large number of false positives is that a pattern of alternans known as concordant alternans, may not be as arrhythmogenic as another pattern which is discordant alternans. Currently, it is not possible to discern the pattern of alternans using clinical ECGs. Prior studies from our group have showed that alternans of the maximum rate of depolarization of an action potential also can occur when Action Potential Duration (APD) alternans occurs and the relationship between these two has the potential to create spatial discord. These results suggest that exploration of the co-occurrence of depolarization and repolarization alternans has the potential to stratify the outcome of TWA tests. In order to investigate the link between depolarization alternans and changes in ECGs, we used a mathematical model created previously in our research group which simulated ECGs from the cellular level changes observed in our experimental studies. These results suggest that the changes in ECGs should appear as alternating pattern of the amplitude of the R wave. Because there are a variety of factors which may also cause the R wave amplitude to change, we used signal analysis and statistical modeling to determine the link between the observed changes in R wave amplitude and depolarization alternans. Results from ECGs recorded from patients show that amplitude of the R wave can change as predicted by our experimental results and mathematical model. Using TWA as the marker of repolarization alternans and R Wave Amplitude Alternans (RWAA) as the marker of depolarization alternans, we investigated the phase relation between depolarization and repolarization alternans in clinical grade ECG and observed that this relationship does change spontaneously, consistent with our prior results from animal studies. Results of the present study support further investigation of the use of RWAA as a complementary method to TWA to improve its positive predictive value.

Cette recherche a été menée dans le contexte scientifique proposé par l'équipe BIOMED (Pr. H. RIX), équipe qui regroupe des chercheurs du laboratoire I3S et des médecins (F. RAYBAUD, G. SUISSE) , Praticiens Hospitaliers, ayant une formation scientifique complémentaire (DEA ou Doctorat SPI). Cette association permet d'aborder des problèmes réels posés par la Médecine ou la Physiologie concernant l'interprétation des signaux biomédicaux. Mon activité au sein de cette équipe se situe dans le domaine du Traitement du Signal pour ce qui concerne l'élaboration de nouveaux concepts ou outils et en amont du Génie Biologique et Médical pour les applications. Dans le même type d'activité, on peut citer les équipes françaises de Jean-Louis COATRIEUX (INSERM- Rennes 1), Catherine MARQUE (CNRS-UTC), Jacques DUCHENE (UTT), Paul RUBEL (INSERM- INSA Lyon). Les principaux domaines d'application actuels sont l'électrocardiographie (ECG), les signaux électriques cérébraux (EEG et PE) et l'électromyographie (EMG) de surface. Les signaux étudiés sont donc des transitoires bruités souvent répétitifs. Ce sont soit des signaux 1D soit des signaux vectoriels constitués d'enregistrements simultanés provenant de capteurs diversement positionnés ou d'enregistrements successifs d'un même capteur. Les problèmes généraux rencontrés sont l'estimation de signaux moyens associés le plus souvent à des phénomènes permanents ou stables au cours du temps, la caractérisation de la variabilité naturelle et enfin la mesure de variations significatives de paramètres ou plus généralement de forme, liées à un agent extérieur tel qu'une pathologie, un effort ou un médicament. Les approches théoriques relèvent de la détection, de l'estimation de modèles paramétriques, semi-paramétriques ou non paramétriques et de la classification, dans le cas non stationnaire.

The influence of hyperlipidemia on the pharmacodynamic and pharmacokinetic aspects of lipophilic drugs was explored. The antiarrhythmic, amiodarone, and the antifungal, ()-ketoconazole, were used as model drugs. Experimental hyperlipidemia was induced in rat using poloxamer 407 and two sensitive novel HPLC assays were developed. In a multiple dosing study, hyperlipidemia increased amiodarone plasma concentrations, heart concentrations and electrocardiographic changes. The amiodarone heart uptake could not be totally attributed to its unbound fraction, where the cardiac very low density lipoprotein receptors seemed to play a role in the uptake of bound drug. Amiodarone liver metabolism in presence and absence of hyperlipidemia was studied using isolated primary rat liver hepatocytes. The metabolism of amiodarone was lower in hepatocytes isolated from hyperlipidemic than those from normolipidemic rats. Hyperlipidemic serum resulted in a decrease in amiodarone metabolism and when coincubated, the expected decrease in unbound fraction seemed to resulted in greater inhibition of metabolism. ()-Ketoconazole showed stereoselectivity in its pharmacokinetics in rat with (+)-ketoconazole showing higher plasma concentrations than its antipode. This was attributed to its higher protein binding. There was no difference in the total bioavailability of the two enantiomers. Ketoconazole enantiomers exhibited nonlinear pharmacokinetics. In normolipidemic rat plasma ketoconazole enantiomers were more than 95% bound to lipoprotein deficient fraction. Hyperlipidemia resulted in shifting both enantiomers 20% to very low density and low density lipoprotein fractions. In a pharmacokinetic assessment, hyperlipidemia was found to increase ketoconazole enantiomer volume of distribution. Moreover, the stereoselectivity ratios of most pharmacokinetic parameters were changed. After oral dosing, the uptake of (-)-ketoconazole was significantly decreased. Since ketoconazole is used as a potent CYP3A inhibitor, alteration in liver concentrations of (-)-ketoconazole, the more potent inhibitory enantiomer, could decrease its CYP inhibitory potential. Hyperlipidemia potentiated the CYP-mediated interaction between ketoconazole and midazolam with significantly higher midazolam AUC and lower clearance. This was attributed to the inhibitory action of ketoconazole and the effect of hyperlipidemia on the binding of midazolam. Hyperlipidemia was found to unexpectedly decrease midazolam unbound fraction in plasma. In conclusion, the findings could explain some unexpected dose versus effect outcomes in hyperlipidemic patients receiving amiodarone or ketoconazole. / Pharmaceutical Sciences